Hematology

Acute mesenteric ischemia (AMI) results when oxygen delivery to the mesenteric artery is compromised, and is a serious diagnosis that should be considered in patients of all ages to avoid significant morbidity and mortality. The majority of cases are due to arterial embolism, arterial thrombus, or intestinal hypoperfusion (non-occlusive). Acute mesenteric venous thrombosis (MVT) accounts for only 2% to 10% of AMI cases, and only 0.01% of emergency surgery admissions.¹ A large systematic review showed a 44% mortality rate for MVT, in contrast to 66% to 89% for all other forms of AMI.² The typical age range for MVT is reported between 45 and 60 years, with a slight male predominance.³ Dull, central abdominal pain is the most frequently reported symptom of MVT, although it is generally less impressive than the pain described in other forms of AMI.³Along with the hallmark of abdominal pain out of proportion to the examination, other gastrointestinal symptoms include weight loss and non-specific altered bowel function (constipation, diarrhea, abdominal distention, and bloating), which are present in half of all patients with MVT.¹ Peritoneal signs and bloody stools portend poor outcomes, as they often occur with disease progression.⁴

Case

A 26-year-old man presented to the ED with periumbilical and lower abdominal pain for 1 week. The pain was described as constant and dull, worsened by movement and oral intake, and improved with lying flat. He described bloating and decreased volume of bowel movements. He denied nausea, vomiting, fever, colicky pain, blood in stool, testicular pain, urinary complaints, trauma, or any similar episodes in the past. The patient had no known medical conditions or surgical history, except for a remote history of alcohol dependence (in remission) and tobacco use. There was no personal or family history of coagulopathy. Of note, he was seen by his primary care physician a few days prior to his ED presentation and had been instructed to take acetaminophen, which did not provide relief.

The patient’s vital signs at presentation were: blood pressure, 122/70 mm Hg; heart rate, 93 beats/min; respiratory rate, 18 breaths/min; and temperature, 37.5°C (99.5°F). Oxygen saturation was 99% on room air. The physical examination was remarkable only for mild abdominal tenderness diffusely, greater in the lower and central abdomen than in the upper abdomen. The remainder of the physical examination was unremarkable.

Laboratory studies ordered included a complete blood count, comprehensive metabolic profile, lipase, and urinalysis. The patient did have a mild transaminitis (aspartate aminotransferase, 48 U/L; alanine aminotransferase, 84 U/L); the remainder of the studies were normal. A serum lactate, drawn after the 1 L of normal saline was administered intravenously (IV), was within normal limits (0.7 mmol/L). No prior laboratory studies were available for comparison.

The patient’s continued abdominal pain and transaminitis prompted an ED bedside right upper quadrant ultrasound, which showed a small gallbladder polyp; no signs of gallbladder disease were present. The patient required three doses of morphine 4 mg IV without complete pain relief. Given the concern for pain out of proportion to physical examination, a computed tomography (CT) scan of the abdomen/pelvis with IV and oral contrast was ordered. The radiologist interpreted the scan as showing a superior mesenteric vein (SMV) thrombus extending into the splenic/portal vein confluence and the intrahepatic portal veins (Figures 1 and 2).

Discussion

Mesenteric venous thrombosis is seen predominantly in middle-aged patients presenting with vague symptoms, which makes this a challenging diagnosis to make in the acute care setting. Risk factors for MVT include recent injury (causing trauma to the vasculature), recent surgery (causing stagnant blood flow), inflammatory conditions, and hypercoagulable states.¹ In this patient’s case, no risk factors were identified; although the majority of cases of MVT will have an identifiable risk factor.² Still, 21% to 49% of cases of MVT are considered idiopathic.^1,3It is possible that our patient had a prior undiagnosed pancreatitis associated with his history of alcoholism that contributed to his thrombosis. Pancreatitis and other inflammatory conditions, including diverticulitis or inflammatory bowel disease, are more commonly associated with thrombus formation in the large veins, as opposed to an undiagnosed hypercoagulable state, which would more likely affect distal venuoles, vasa recta, or venous arcades.^1,5 The patient’s mild transaminitis was likely secondary to hepatic congestion from the venous thrombus extending to the splenic-portal vein confluence and intrahepatic portal vein. One study looked at patients with pancreatitis and found that 16.7% of their study population had an SMV thrombus, while 4.1% had a SMV thrombus with a concomitant portal vein thrombus.⁶

Although there are no pathognomonic laboratory findings of MVT, elevated lactate, leukocytosis, and elevated D-dimer levels may be helpful in supporting the diagnosis.^7,8 A recent study found that elevated D-dimer levels may be a specific marker in the early recognition of acute SMV thrombosis, as well as predicting risk, outcomes, and treatment options.⁸ However, emergency physicians should maintain a high index of suspicion in patients with concerning features of the disease, since normal laboratory values, including lactate, do not reliably exclude the diagnosis.

Computed tomography scanning and CT angiography (CTA) are quite helpful in diagnosing MVT. Ultrasound of the upper abdomen may also play a role, noting dilated or thickened bowel wall with intraluminal air or echogenic material in the superior mesenteric vein or portal vein.⁹ Although magnetic resonance venography most reliably demonstrates thrombi, its lack of widespread availability makes CT with IV contrast the preferred initial study.³Computed tomography not only has high sensitivity, but also offers alternative diagnoses in the undifferentiated presentation.¹One study found CT to be 100% sensitive in detecting any abnormality associated with MVT or bowel ischemia.¹⁰ Common CT findings of MVT include dilated and thickened bowel loops, mesenteric fat standing, ascites, a halo or target appearance of bowel, vessel filling defects from a thrombus, and pneumatosis intestinalis.¹¹ The latter usually indicates transmural infarction, and can extend as portomesenteric vein gas.¹¹ Of note, if the initial CT scan is non-diagnostic and a high clinical suspicion for mesenteric ischemia remains with no alternative diagnosis, CTA is the gold standard.^3,7Expeditious diagnosis of MVT is imperative, given the potential complications of intestinal infarction, submucosal hemorrhage secondary to edema, and third spacing of the venous outflow into the bowel wall due to collateral vessels being unable to redirect blood flow in conjunction with complete venous occlusion.¹²Not all MVTs progress to infarction, given the extensive collateral circulation. Early diagnosis, however, is crucial for conservative management to be effective.⁹Acute MVT without signs of infarction necessitates anticoagulation therapy to decrease clot propagation and recurrence.¹ In addition, prophylactic antibiotics to limit bacterial translocation, and bowel rest are advised.^13,14 If the patient is unresponsive to anticoagulation, thrombolytic and endovascular therapies may be of benefit in select patients.¹⁵ Once intestinal ischemia or infarction develops, the prognosis is poor: mortality approaches 75% with infarction.¹ If signs of bowel infarction are present, a laparotomy must be performed promptly, although in most cases, delayed patient presentation makes small bowel resection unavoidable.⁹ Further testing for hypercoagulability is recommended, particularly in isolated thrombosis, since long-term anticoagulation therapy may be necessary if a coagulopathy is discovered.¹

Conclusion

Mesenteric venous thrombosis is atypical in a young, healthy patient. However, due to high mortality rates with disease progression, it is important to consider in any patient with unrelenting abdominal pain and vague gastrointestinal symptoms of uncertain cause, even in those without risk factors. Early detection and management of MVT before progression to mesenteric ischemia and infarction considerably lowers the mortality rate. Emergency physicians must be vigilant when treating a patient with abdominal pain out of proportion to physical examination, unrelenting pain despite analgesic medications, or repeat ED visits for the same abdominal complaints.

Acute mesenteric ischemia (AMI) results when oxygen delivery to the mesenteric artery is compromised, and is a serious diagnosis that should be considered in patients of all ages to avoid significant morbidity and mortality. The majority of cases are due to arterial embolism, arterial thrombus, or intestinal hypoperfusion (non-occlusive). Acute mesenteric venous thrombosis (MVT) accounts for only 2% to 10% of AMI cases, and only 0.01% of emergency surgery admissions.¹ A large systematic review showed a 44% mortality rate for MVT, in contrast to 66% to 89% for all other forms of AMI.² The typical age range for MVT is reported between 45 and 60 years, with a slight male predominance.³ Dull, central abdominal pain is the most frequently reported symptom of MVT, although it is generally less impressive than the pain described in other forms of AMI.³Along with the hallmark of abdominal pain out of proportion to the examination, other gastrointestinal symptoms include weight loss and non-specific altered bowel function (constipation, diarrhea, abdominal distention, and bloating), which are present in half of all patients with MVT.¹ Peritoneal signs and bloody stools portend poor outcomes, as they often occur with disease progression.⁴

Case

A 26-year-old man presented to the ED with periumbilical and lower abdominal pain for 1 week. The pain was described as constant and dull, worsened by movement and oral intake, and improved with lying flat. He described bloating and decreased volume of bowel movements. He denied nausea, vomiting, fever, colicky pain, blood in stool, testicular pain, urinary complaints, trauma, or any similar episodes in the past. The patient had no known medical conditions or surgical history, except for a remote history of alcohol dependence (in remission) and tobacco use. There was no personal or family history of coagulopathy. Of note, he was seen by his primary care physician a few days prior to his ED presentation and had been instructed to take acetaminophen, which did not provide relief.

The patient’s vital signs at presentation were: blood pressure, 122/70 mm Hg; heart rate, 93 beats/min; respiratory rate, 18 breaths/min; and temperature, 37.5°C (99.5°F). Oxygen saturation was 99% on room air. The physical examination was remarkable only for mild abdominal tenderness diffusely, greater in the lower and central abdomen than in the upper abdomen. The remainder of the physical examination was unremarkable.

Laboratory studies ordered included a complete blood count, comprehensive metabolic profile, lipase, and urinalysis. The patient did have a mild transaminitis (aspartate aminotransferase, 48 U/L; alanine aminotransferase, 84 U/L); the remainder of the studies were normal. A serum lactate, drawn after the 1 L of normal saline was administered intravenously (IV), was within normal limits (0.7 mmol/L). No prior laboratory studies were available for comparison.

The patient’s continued abdominal pain and transaminitis prompted an ED bedside right upper quadrant ultrasound, which showed a small gallbladder polyp; no signs of gallbladder disease were present. The patient required three doses of morphine 4 mg IV without complete pain relief. Given the concern for pain out of proportion to physical examination, a computed tomography (CT) scan of the abdomen/pelvis with IV and oral contrast was ordered. The radiologist interpreted the scan as showing a superior mesenteric vein (SMV) thrombus extending into the splenic/portal vein confluence and the intrahepatic portal veins (Figures 1 and 2).

Discussion

Mesenteric venous thrombosis is seen predominantly in middle-aged patients presenting with vague symptoms, which makes this a challenging diagnosis to make in the acute care setting. Risk factors for MVT include recent injury (causing trauma to the vasculature), recent surgery (causing stagnant blood flow), inflammatory conditions, and hypercoagulable states.¹ In this patient’s case, no risk factors were identified; although the majority of cases of MVT will have an identifiable risk factor.² Still, 21% to 49% of cases of MVT are considered idiopathic.^1,3It is possible that our patient had a prior undiagnosed pancreatitis associated with his history of alcoholism that contributed to his thrombosis. Pancreatitis and other inflammatory conditions, including diverticulitis or inflammatory bowel disease, are more commonly associated with thrombus formation in the large veins, as opposed to an undiagnosed hypercoagulable state, which would more likely affect distal venuoles, vasa recta, or venous arcades.^1,5 The patient’s mild transaminitis was likely secondary to hepatic congestion from the venous thrombus extending to the splenic-portal vein confluence and intrahepatic portal vein. One study looked at patients with pancreatitis and found that 16.7% of their study population had an SMV thrombus, while 4.1% had a SMV thrombus with a concomitant portal vein thrombus.⁶

Although there are no pathognomonic laboratory findings of MVT, elevated lactate, leukocytosis, and elevated D-dimer levels may be helpful in supporting the diagnosis.^7,8 A recent study found that elevated D-dimer levels may be a specific marker in the early recognition of acute SMV thrombosis, as well as predicting risk, outcomes, and treatment options.⁸ However, emergency physicians should maintain a high index of suspicion in patients with concerning features of the disease, since normal laboratory values, including lactate, do not reliably exclude the diagnosis.

Computed tomography scanning and CT angiography (CTA) are quite helpful in diagnosing MVT. Ultrasound of the upper abdomen may also play a role, noting dilated or thickened bowel wall with intraluminal air or echogenic material in the superior mesenteric vein or portal vein.⁹ Although magnetic resonance venography most reliably demonstrates thrombi, its lack of widespread availability makes CT with IV contrast the preferred initial study.³Computed tomography not only has high sensitivity, but also offers alternative diagnoses in the undifferentiated presentation.¹One study found CT to be 100% sensitive in detecting any abnormality associated with MVT or bowel ischemia.¹⁰ Common CT findings of MVT include dilated and thickened bowel loops, mesenteric fat standing, ascites, a halo or target appearance of bowel, vessel filling defects from a thrombus, and pneumatosis intestinalis.¹¹ The latter usually indicates transmural infarction, and can extend as portomesenteric vein gas.¹¹ Of note, if the initial CT scan is non-diagnostic and a high clinical suspicion for mesenteric ischemia remains with no alternative diagnosis, CTA is the gold standard.^3,7Expeditious diagnosis of MVT is imperative, given the potential complications of intestinal infarction, submucosal hemorrhage secondary to edema, and third spacing of the venous outflow into the bowel wall due to collateral vessels being unable to redirect blood flow in conjunction with complete venous occlusion.¹²Not all MVTs progress to infarction, given the extensive collateral circulation. Early diagnosis, however, is crucial for conservative management to be effective.⁹Acute MVT without signs of infarction necessitates anticoagulation therapy to decrease clot propagation and recurrence.¹ In addition, prophylactic antibiotics to limit bacterial translocation, and bowel rest are advised.^13,14 If the patient is unresponsive to anticoagulation, thrombolytic and endovascular therapies may be of benefit in select patients.¹⁵ Once intestinal ischemia or infarction develops, the prognosis is poor: mortality approaches 75% with infarction.¹ If signs of bowel infarction are present, a laparotomy must be performed promptly, although in most cases, delayed patient presentation makes small bowel resection unavoidable.⁹ Further testing for hypercoagulability is recommended, particularly in isolated thrombosis, since long-term anticoagulation therapy may be necessary if a coagulopathy is discovered.¹

Conclusion

Mesenteric venous thrombosis is atypical in a young, healthy patient. However, due to high mortality rates with disease progression, it is important to consider in any patient with unrelenting abdominal pain and vague gastrointestinal symptoms of uncertain cause, even in those without risk factors. Early detection and management of MVT before progression to mesenteric ischemia and infarction considerably lowers the mortality rate. Emergency physicians must be vigilant when treating a patient with abdominal pain out of proportion to physical examination, unrelenting pain despite analgesic medications, or repeat ED visits for the same abdominal complaints.

Acute mesenteric ischemia (AMI) results when oxygen delivery to the mesenteric artery is compromised, and is a serious diagnosis that should be considered in patients of all ages to avoid significant morbidity and mortality. The majority of cases are due to arterial embolism, arterial thrombus, or intestinal hypoperfusion (non-occlusive). Acute mesenteric venous thrombosis (MVT) accounts for only 2% to 10% of AMI cases, and only 0.01% of emergency surgery admissions.¹ A large systematic review showed a 44% mortality rate for MVT, in contrast to 66% to 89% for all other forms of AMI.² The typical age range for MVT is reported between 45 and 60 years, with a slight male predominance.³ Dull, central abdominal pain is the most frequently reported symptom of MVT, although it is generally less impressive than the pain described in other forms of AMI.³Along with the hallmark of abdominal pain out of proportion to the examination, other gastrointestinal symptoms include weight loss and non-specific altered bowel function (constipation, diarrhea, abdominal distention, and bloating), which are present in half of all patients with MVT.¹ Peritoneal signs and bloody stools portend poor outcomes, as they often occur with disease progression.⁴

Case

A 26-year-old man presented to the ED with periumbilical and lower abdominal pain for 1 week. The pain was described as constant and dull, worsened by movement and oral intake, and improved with lying flat. He described bloating and decreased volume of bowel movements. He denied nausea, vomiting, fever, colicky pain, blood in stool, testicular pain, urinary complaints, trauma, or any similar episodes in the past. The patient had no known medical conditions or surgical history, except for a remote history of alcohol dependence (in remission) and tobacco use. There was no personal or family history of coagulopathy. Of note, he was seen by his primary care physician a few days prior to his ED presentation and had been instructed to take acetaminophen, which did not provide relief.

The patient’s vital signs at presentation were: blood pressure, 122/70 mm Hg; heart rate, 93 beats/min; respiratory rate, 18 breaths/min; and temperature, 37.5°C (99.5°F). Oxygen saturation was 99% on room air. The physical examination was remarkable only for mild abdominal tenderness diffusely, greater in the lower and central abdomen than in the upper abdomen. The remainder of the physical examination was unremarkable.

Laboratory studies ordered included a complete blood count, comprehensive metabolic profile, lipase, and urinalysis. The patient did have a mild transaminitis (aspartate aminotransferase, 48 U/L; alanine aminotransferase, 84 U/L); the remainder of the studies were normal. A serum lactate, drawn after the 1 L of normal saline was administered intravenously (IV), was within normal limits (0.7 mmol/L). No prior laboratory studies were available for comparison.

The patient’s continued abdominal pain and transaminitis prompted an ED bedside right upper quadrant ultrasound, which showed a small gallbladder polyp; no signs of gallbladder disease were present. The patient required three doses of morphine 4 mg IV without complete pain relief. Given the concern for pain out of proportion to physical examination, a computed tomography (CT) scan of the abdomen/pelvis with IV and oral contrast was ordered. The radiologist interpreted the scan as showing a superior mesenteric vein (SMV) thrombus extending into the splenic/portal vein confluence and the intrahepatic portal veins (Figures 1 and 2).

Discussion

Mesenteric venous thrombosis is seen predominantly in middle-aged patients presenting with vague symptoms, which makes this a challenging diagnosis to make in the acute care setting. Risk factors for MVT include recent injury (causing trauma to the vasculature), recent surgery (causing stagnant blood flow), inflammatory conditions, and hypercoagulable states.¹ In this patient’s case, no risk factors were identified; although the majority of cases of MVT will have an identifiable risk factor.² Still, 21% to 49% of cases of MVT are considered idiopathic.^1,3It is possible that our patient had a prior undiagnosed pancreatitis associated with his history of alcoholism that contributed to his thrombosis. Pancreatitis and other inflammatory conditions, including diverticulitis or inflammatory bowel disease, are more commonly associated with thrombus formation in the large veins, as opposed to an undiagnosed hypercoagulable state, which would more likely affect distal venuoles, vasa recta, or venous arcades.^1,5 The patient’s mild transaminitis was likely secondary to hepatic congestion from the venous thrombus extending to the splenic-portal vein confluence and intrahepatic portal vein. One study looked at patients with pancreatitis and found that 16.7% of their study population had an SMV thrombus, while 4.1% had a SMV thrombus with a concomitant portal vein thrombus.⁶

Although there are no pathognomonic laboratory findings of MVT, elevated lactate, leukocytosis, and elevated D-dimer levels may be helpful in supporting the diagnosis.^7,8 A recent study found that elevated D-dimer levels may be a specific marker in the early recognition of acute SMV thrombosis, as well as predicting risk, outcomes, and treatment options.⁸ However, emergency physicians should maintain a high index of suspicion in patients with concerning features of the disease, since normal laboratory values, including lactate, do not reliably exclude the diagnosis.

Computed tomography scanning and CT angiography (CTA) are quite helpful in diagnosing MVT. Ultrasound of the upper abdomen may also play a role, noting dilated or thickened bowel wall with intraluminal air or echogenic material in the superior mesenteric vein or portal vein.⁹ Although magnetic resonance venography most reliably demonstrates thrombi, its lack of widespread availability makes CT with IV contrast the preferred initial study.³Computed tomography not only has high sensitivity, but also offers alternative diagnoses in the undifferentiated presentation.¹One study found CT to be 100% sensitive in detecting any abnormality associated with MVT or bowel ischemia.¹⁰ Common CT findings of MVT include dilated and thickened bowel loops, mesenteric fat standing, ascites, a halo or target appearance of bowel, vessel filling defects from a thrombus, and pneumatosis intestinalis.¹¹ The latter usually indicates transmural infarction, and can extend as portomesenteric vein gas.¹¹ Of note, if the initial CT scan is non-diagnostic and a high clinical suspicion for mesenteric ischemia remains with no alternative diagnosis, CTA is the gold standard.^3,7Expeditious diagnosis of MVT is imperative, given the potential complications of intestinal infarction, submucosal hemorrhage secondary to edema, and third spacing of the venous outflow into the bowel wall due to collateral vessels being unable to redirect blood flow in conjunction with complete venous occlusion.¹²Not all MVTs progress to infarction, given the extensive collateral circulation. Early diagnosis, however, is crucial for conservative management to be effective.⁹Acute MVT without signs of infarction necessitates anticoagulation therapy to decrease clot propagation and recurrence.¹ In addition, prophylactic antibiotics to limit bacterial translocation, and bowel rest are advised.^13,14 If the patient is unresponsive to anticoagulation, thrombolytic and endovascular therapies may be of benefit in select patients.¹⁵ Once intestinal ischemia or infarction develops, the prognosis is poor: mortality approaches 75% with infarction.¹ If signs of bowel infarction are present, a laparotomy must be performed promptly, although in most cases, delayed patient presentation makes small bowel resection unavoidable.⁹ Further testing for hypercoagulability is recommended, particularly in isolated thrombosis, since long-term anticoagulation therapy may be necessary if a coagulopathy is discovered.¹

Conclusion

Mesenteric venous thrombosis is atypical in a young, healthy patient. However, due to high mortality rates with disease progression, it is important to consider in any patient with unrelenting abdominal pain and vague gastrointestinal symptoms of uncertain cause, even in those without risk factors. Early detection and management of MVT before progression to mesenteric ischemia and infarction considerably lowers the mortality rate. Emergency physicians must be vigilant when treating a patient with abdominal pain out of proportion to physical examination, unrelenting pain despite analgesic medications, or repeat ED visits for the same abdominal complaints.

Crizanlizumab effectively reduced vaso-occlusive crises among patients with sickle cell disease (SCD) who have numerous crises, exhibit the HbSS genotype, and take concomitant hydroxyurea, according to investigators.

CDC/Janice Haney Carr

Across subgroups, crizanlizumab was safe and more effective than placebo at delaying time to first vaso-occlusive crisis (VOC) and eliminating crises, reported lead author Abdullah Kutlar, MD, of the Sickle Cell Center at the Medical College of Georgia, Augusta, and his colleagues.

The phase 2 SUSTAIN trial recently showed that crizanlizumab – a humanized, anti–P-selectin monoclonal antibody – reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months (N Engl J Med. 2017;376:429-39).

Additionally, a subgroup analysis showed that there was a lower frequency of pain crises with crizanlizumab 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post hoc analysis took a deeper look at these observations across the same subgroups; specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events. They reported the findings in the American Journal of Hematology.

Crizanlizumab eliminated pain crises about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (28.0% vs. 4.2%), and about twice as often in patients with the HbSS genotype (31.9% vs. 17.0%), and patients who were using concomitant hydroxyurea (33.3% vs. 17.5%).

Further analysis showed that crizanlizumab delayed time to first pain crisis across all subgroups, most dramatically in patients with the HbSS genotype (4.07 months for crizanlizumab vs. 1.12 months for placebo). Safety was comparable across subgroups.

“These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with hydroxyurea for the prevention of VOCs,” the investigators wrote.

An ongoing phase 2 pharmacokinetic/pharmacodynamic study is evaluating a higher dose of crizanlizumab (7.5 mg/kg), and another trial seeks to evaluate pediatric doses of the drug.

The study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

SOURCE: Kutlar A et al. Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308.

Crizanlizumab effectively reduced vaso-occlusive crises among patients with sickle cell disease (SCD) who have numerous crises, exhibit the HbSS genotype, and take concomitant hydroxyurea, according to investigators.

CDC/Janice Haney Carr

Across subgroups, crizanlizumab was safe and more effective than placebo at delaying time to first vaso-occlusive crisis (VOC) and eliminating crises, reported lead author Abdullah Kutlar, MD, of the Sickle Cell Center at the Medical College of Georgia, Augusta, and his colleagues.

The phase 2 SUSTAIN trial recently showed that crizanlizumab – a humanized, anti–P-selectin monoclonal antibody – reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months (N Engl J Med. 2017;376:429-39).

Additionally, a subgroup analysis showed that there was a lower frequency of pain crises with crizanlizumab 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post hoc analysis took a deeper look at these observations across the same subgroups; specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events. They reported the findings in the American Journal of Hematology.

Crizanlizumab eliminated pain crises about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (28.0% vs. 4.2%), and about twice as often in patients with the HbSS genotype (31.9% vs. 17.0%), and patients who were using concomitant hydroxyurea (33.3% vs. 17.5%).

Further analysis showed that crizanlizumab delayed time to first pain crisis across all subgroups, most dramatically in patients with the HbSS genotype (4.07 months for crizanlizumab vs. 1.12 months for placebo). Safety was comparable across subgroups.

“These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with hydroxyurea for the prevention of VOCs,” the investigators wrote.

An ongoing phase 2 pharmacokinetic/pharmacodynamic study is evaluating a higher dose of crizanlizumab (7.5 mg/kg), and another trial seeks to evaluate pediatric doses of the drug.

The study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

SOURCE: Kutlar A et al. Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308.

Crizanlizumab effectively reduced vaso-occlusive crises among patients with sickle cell disease (SCD) who have numerous crises, exhibit the HbSS genotype, and take concomitant hydroxyurea, according to investigators.

CDC/Janice Haney Carr

Across subgroups, crizanlizumab was safe and more effective than placebo at delaying time to first vaso-occlusive crisis (VOC) and eliminating crises, reported lead author Abdullah Kutlar, MD, of the Sickle Cell Center at the Medical College of Georgia, Augusta, and his colleagues.

The phase 2 SUSTAIN trial recently showed that crizanlizumab – a humanized, anti–P-selectin monoclonal antibody – reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months (N Engl J Med. 2017;376:429-39).

Additionally, a subgroup analysis showed that there was a lower frequency of pain crises with crizanlizumab 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post hoc analysis took a deeper look at these observations across the same subgroups; specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events. They reported the findings in the American Journal of Hematology.

Crizanlizumab eliminated pain crises about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (28.0% vs. 4.2%), and about twice as often in patients with the HbSS genotype (31.9% vs. 17.0%), and patients who were using concomitant hydroxyurea (33.3% vs. 17.5%).

Further analysis showed that crizanlizumab delayed time to first pain crisis across all subgroups, most dramatically in patients with the HbSS genotype (4.07 months for crizanlizumab vs. 1.12 months for placebo). Safety was comparable across subgroups.

“These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with hydroxyurea for the prevention of VOCs,” the investigators wrote.

An ongoing phase 2 pharmacokinetic/pharmacodynamic study is evaluating a higher dose of crizanlizumab (7.5 mg/kg), and another trial seeks to evaluate pediatric doses of the drug.

The study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

SOURCE: Kutlar A et al. Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308.

SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.

In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.

“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”

Dr. Osborn reported having no financial disclosures related to her presentation.

[email protected]

SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.

In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.

“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”

Dr. Osborn reported having no financial disclosures related to her presentation.

[email protected]

SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.

In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.

“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”

Dr. Osborn reported having no financial disclosures related to her presentation.

[email protected]

EVIDENCE SUMMARY

No head-to-head studies or umbrella meta-analyses assess all the main treatments for VTE against each other.

Long-term LMWH decreases VTE recurrence compared with VKA

Two meta-analyses of RCTs evaluating LMWH and VKA for long-term treatment (3-12 months) of confirmed VTE in patients with cancer found that LMWH didn’t change mortality, but reduced the rate of VTE recurrence compared with VKA (40% relative reduction).^1,2 The comparison showed no differences in major or minor bleeding or thrombocytopenia between LMWH and VKA (TABLE^1-5).

The studies included patients with any solid or hematologic cancer at any stage and from any age group, including children. Overall, the mean age of patients was in the mid 60s; approximately 50% were male when specified. Investigators rated the evidence quality as moderate for VTE, but low for the other outcomes.¹

The most recent meta-analysis of the same RCTs comparing LMWH with VKA evaluated intracranial hemorrhage rates and found no difference.³

Initial therapy with LMWH: A look at mortality

A meta-analysis of RCTs that compared LMWH with UFH/VKA for initial treatment of confirmed VTE in adult cancer patients (any type or stage of cancer, mean ages not specified) found that LMWH reduced mortality by 30%, but didn’t affect VTE recurrence or major bleeding.⁴

The control groups received UFH for 5 to 10 days and then continued with VKA, whereas the experimental groups received different types of LMWH (reviparin, nadroparin, tinzaparin, enoxaparin) initially and for 3 months thereafter. Investigators rated all studies low quality because of imprecision and publication bias favoring LMWH.

Fondaparinux shows no advantage for initial therapy

The same meta-analysis compared initial treatment with fondaparinux and initial therapy with enoxaparin or UFH transitioning to warfarin.⁴ It found no differences in any outcomes at 3 months. Investigators rated both studies as low quality for recurrent VTE and moderate for mortality and bleeding.

Continue to: Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA

A meta-analysis of RCTs comparing NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) with VKA for 6 months found no differences in recurrent VTE or major bleeding.²

A second meta-analysis of RCTs that compared NOACs (rivaroxaban, dabigatran, apixaban) with control (LMWH followed by VKA) in adult cancer patients (mean ages, 54-66 years; 50%-60% men) reported no difference in the composite outcome of recurrent VTE or VTE-related death nor clinically significant bleeding over 1 to 36 months (most RCTs ran 3-12 months).⁵ Separate comparisons for rivaroxaban and dabigatran found no difference in the composite outcome, and rivaroxaban also produced no difference in clinically-significant bleeding.

RECOMMENDATIONS

The 2016 CHEST guidelines recommend LMWH as first-line treatment for VTE in patients with cancer and indicate no preference between NOACs and VKA for second-line treatment.⁶

EVIDENCE SUMMARY

No head-to-head studies or umbrella meta-analyses assess all the main treatments for VTE against each other.

Long-term LMWH decreases VTE recurrence compared with VKA

Two meta-analyses of RCTs evaluating LMWH and VKA for long-term treatment (3-12 months) of confirmed VTE in patients with cancer found that LMWH didn’t change mortality, but reduced the rate of VTE recurrence compared with VKA (40% relative reduction).^1,2 The comparison showed no differences in major or minor bleeding or thrombocytopenia between LMWH and VKA (TABLE^1-5).

The studies included patients with any solid or hematologic cancer at any stage and from any age group, including children. Overall, the mean age of patients was in the mid 60s; approximately 50% were male when specified. Investigators rated the evidence quality as moderate for VTE, but low for the other outcomes.¹

The most recent meta-analysis of the same RCTs comparing LMWH with VKA evaluated intracranial hemorrhage rates and found no difference.³

Initial therapy with LMWH: A look at mortality

A meta-analysis of RCTs that compared LMWH with UFH/VKA for initial treatment of confirmed VTE in adult cancer patients (any type or stage of cancer, mean ages not specified) found that LMWH reduced mortality by 30%, but didn’t affect VTE recurrence or major bleeding.⁴

The control groups received UFH for 5 to 10 days and then continued with VKA, whereas the experimental groups received different types of LMWH (reviparin, nadroparin, tinzaparin, enoxaparin) initially and for 3 months thereafter. Investigators rated all studies low quality because of imprecision and publication bias favoring LMWH.

Fondaparinux shows no advantage for initial therapy

The same meta-analysis compared initial treatment with fondaparinux and initial therapy with enoxaparin or UFH transitioning to warfarin.⁴ It found no differences in any outcomes at 3 months. Investigators rated both studies as low quality for recurrent VTE and moderate for mortality and bleeding.

Continue to: Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA

A meta-analysis of RCTs comparing NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) with VKA for 6 months found no differences in recurrent VTE or major bleeding.²

A second meta-analysis of RCTs that compared NOACs (rivaroxaban, dabigatran, apixaban) with control (LMWH followed by VKA) in adult cancer patients (mean ages, 54-66 years; 50%-60% men) reported no difference in the composite outcome of recurrent VTE or VTE-related death nor clinically significant bleeding over 1 to 36 months (most RCTs ran 3-12 months).⁵ Separate comparisons for rivaroxaban and dabigatran found no difference in the composite outcome, and rivaroxaban also produced no difference in clinically-significant bleeding.

RECOMMENDATIONS

The 2016 CHEST guidelines recommend LMWH as first-line treatment for VTE in patients with cancer and indicate no preference between NOACs and VKA for second-line treatment.⁶

EVIDENCE SUMMARY

No head-to-head studies or umbrella meta-analyses assess all the main treatments for VTE against each other.

Long-term LMWH decreases VTE recurrence compared with VKA

Two meta-analyses of RCTs evaluating LMWH and VKA for long-term treatment (3-12 months) of confirmed VTE in patients with cancer found that LMWH didn’t change mortality, but reduced the rate of VTE recurrence compared with VKA (40% relative reduction).^1,2 The comparison showed no differences in major or minor bleeding or thrombocytopenia between LMWH and VKA (TABLE^1-5).

The studies included patients with any solid or hematologic cancer at any stage and from any age group, including children. Overall, the mean age of patients was in the mid 60s; approximately 50% were male when specified. Investigators rated the evidence quality as moderate for VTE, but low for the other outcomes.¹

The most recent meta-analysis of the same RCTs comparing LMWH with VKA evaluated intracranial hemorrhage rates and found no difference.³

Initial therapy with LMWH: A look at mortality

A meta-analysis of RCTs that compared LMWH with UFH/VKA for initial treatment of confirmed VTE in adult cancer patients (any type or stage of cancer, mean ages not specified) found that LMWH reduced mortality by 30%, but didn’t affect VTE recurrence or major bleeding.⁴

The control groups received UFH for 5 to 10 days and then continued with VKA, whereas the experimental groups received different types of LMWH (reviparin, nadroparin, tinzaparin, enoxaparin) initially and for 3 months thereafter. Investigators rated all studies low quality because of imprecision and publication bias favoring LMWH.

Fondaparinux shows no advantage for initial therapy

The same meta-analysis compared initial treatment with fondaparinux and initial therapy with enoxaparin or UFH transitioning to warfarin.⁴ It found no differences in any outcomes at 3 months. Investigators rated both studies as low quality for recurrent VTE and moderate for mortality and bleeding.

Continue to: Non-vitamin K oral anticoagulants vs LMWH/VKA or VKA

A meta-analysis of RCTs comparing NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) with VKA for 6 months found no differences in recurrent VTE or major bleeding.²

A second meta-analysis of RCTs that compared NOACs (rivaroxaban, dabigatran, apixaban) with control (LMWH followed by VKA) in adult cancer patients (mean ages, 54-66 years; 50%-60% men) reported no difference in the composite outcome of recurrent VTE or VTE-related death nor clinically significant bleeding over 1 to 36 months (most RCTs ran 3-12 months).⁵ Separate comparisons for rivaroxaban and dabigatran found no difference in the composite outcome, and rivaroxaban also produced no difference in clinically-significant bleeding.

RECOMMENDATIONS

The 2016 CHEST guidelines recommend LMWH as first-line treatment for VTE in patients with cancer and indicate no preference between NOACs and VKA for second-line treatment.⁶

Cancer survivors represent a rapidly increasing population. In 1971, there were 3 million cancer survivors; this number increased to 15.5 million in 2016 and will reach 20 million by 2026.¹TABLE 1¹ shows the percentage of survivors by type of cancer. Cancer survivors tend to be older,* comprising nearly 1 of every 5 people older than 65 years.²

The Institute of Medicine (IOM) identified 3 key characteristics of cancer survivors³:

• Trajectories of survivorship are variable; many cancer patients have periods of relative health between episodes of their disease.
• Survivors require careful cancer monitoring; in addition to the risk that their primary cancer will recur, they have an elevated risk for another, second cancer.
• Both cancer and its treatments increase the risk of other medical and psychiatric problems.

Family physicians (FPs) have optimal skills for navigating the chronic risks and health concerns of the well cancer survivor. This article reviews the primary care management of the functional cancer survivor, focusing on the management of chronic conditions and preventive care.

Survivorship follows any of 6 paths

Cancer survivorship is increasing in importance as treatment has steadily reduced mortality. Six trajectories of cancer survivors have been identified¹:

• living cancer-free after treatment with minimal effects
• living cancer-free but suffering serious treatment complications
• Suffering late recurrence
• Developing a second cancer
• Living with intermittent cancer recurrences
• Living with cancer continuously.

Only patients in the last 2 groups are likely to be managed primarily by oncologists.

Survivors look to their FPs for ongoing care

Cancer survivors routinely see their primary care physician after initial treatment. A study of 30,000 Canadian breast cancer survivors demonstrated that follow-up care was limited to an oncologist in only 2%; 84% saw a primary care provider and an oncologist; and 14% saw a primary care provider only.⁴ A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily⁵; in that study, primary care physicians delivered more preventive care than oncologists did.⁵ Similar to what is done in other chronic conditions, the various effects of cancer are best managed as a whole.

The IOM recommends that cancer survivor care comprise 4 elements²:

1. coordination between oncologist and primary care physician
2. surveillance for recurrence or spread of existing cancer
3. screening for new cancer
4. intervention for the effects of cancer and treatment.

Continue to: The following discussion summarizes...

The following discussion summarizes evidence and recommendations for each element of the IOM recommendations for survivor care.

Implementing the 4 elements of cancer survivor care

1. Coordinate care through a unified survivorship care plan

The IOM has noted that the needs of cancer survivors are rarely met²; communication between oncology and primary care is often deficient during transition of care. The IOM has recommended that oncologists provide a survivorship care plan that details the cancer (ie, tumor characteristics), the type of treatment (ie, enrollment in a clinical trial; medical, surgical, or radiation), support services, and follow-up recommendations for the primary care provider. (Examples of elements of a survivorship care plan can be found at www.mskcc.org/hcp-education-training/survivorship/survivorship-care-plan⁶ and http://sma.org/southern-medical-journal/article/cancer-survivors-history-physical/⁷).

Regrettably, survivorship care plans have been rarely and poorly employed. Studies show that fewer than one-half of oncologists provide a plan, and that when they do, the plan often lacks recommended information.^8,9 Survivorship care plans may soon become common practice, however; the Commission on Cancer of the American College of Surgeons has required their use in all certified cancer centers since 2015.¹⁰

2. Provide surveillance of existing cancer

Cancer follow-up is challenging after the initial treatment phase. Although there are many conflicting guidelines for surveillance after cancer, guidelines of the National Comprehensive Cancer Network (NCCN) (summarized in TABLE 2¹¹ for the 10 most common cancers in survivors) are the ones generally accepted.^12,13

Although individual surveillance recommendations are based on limited evidence, studies confirm the importance of surveillance. A systematic review showed that surveillance mammography after breast cancer reduces breast cancer mortality by 36%.¹⁴ A study showed that bladder cancer recurrence diagnosed by surveillance instead of by symptoms led to a 35% increase in 5-year survival.¹⁵

Continue to: Yet adherence to cancer surveillance...

Yet adherence to cancer surveillance recommendations is poor. A study of patients with colon cancer demonstrated that only 12% met all recommended surveillance guidelines.¹⁶ A study of patients with bladder cancer after radical cystectomy showed that only 9% met recommended surveillance more than 2 years after diagnosis.¹⁷ Those dismal statistics may be the result of provider oversight—not patient reluctance.

In the colon cancer study, for example, compliance with follow-up colonoscopy was 80% but compliance with carcinoembryonic antigen testing was only 22%.¹⁶ In the bladder cancer study, follow-up urine cytology was obtained in only 23% of patients, although 75% completed recommended imaging.¹⁷

Although surveillance remains the oncologist’s responsibility, visits to the FP provide an opportunity to review surveillance and order needed laboratory testing and other studies, including imaging.

3. Screen for new cancers

The risk of a second cancer is elevated for cancer survivors compared with the risk of a primary cancer in the healthy general population; some survivors have a lifetime risk of a second cancer as high as 36%.¹⁸ Risk varies by cancer type (TABLE 3¹⁹). Some of this variation is due to the impact of smoking: Smoking-related cancers have the highest risk of second malignancy.¹⁹ Genetic predisposition to malignant transformation is also theorized to contribute to increased risk. Second malignancies are dangerous; 55% of patients die of the second cancer compared with only 13% of their initial cancer.¹⁹

A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily.

Studies show that cancer survivors display varying adherence with recommended screening for second cancers. In a study of Latina cancer survivors, depressive symptoms were associated with lower screening compliance.²⁰ A study of survivors of hematologic cancer showed a low rate of cancer screening and high fear of cancer recurrence—suggesting avoidance due to fear.²¹ Other studies, however, show similar or increased compliance with screening in cancer survivors.^22,23 A meta-analysis of 19 studies determined that, overall, cancer survivors receive 25% to 38% more recommended screening than the general population.²⁴

Continue to: Few guidelines exist to guide FPs...

Few guidelines exist to guide FPs in adjusting screening for the cancer survivor. For women who received radiation therapy for a tumor in the chest, for example, the recommendation offered by several groups is to start breast cancer screening 8 to 10 years after treatment or by 30 years of age, and to consider combining magnetic resonance imaging and mammography.²⁵ Recommendations for breast cancer screening do not account for a history of other gynecologic cancers unless genetic markers are present.²⁵ On the other hand, the impact of a history of cancer on the risk of prostate cancer and on screening decisions has not been studied,²⁶ and cervical cancer screening guidelines, which recommend that screening continue after 65 years of age for patients who are immunocompromised, do not address a history of other cancer.²⁷

4. Manage the effects of both the cancer and the treatment

Medical issues faced by cancer survivors are familiar to FPs, but there are some specific recommendations regarding evaluation and treatment that stand in contrast to what would be considered for a healthy, or non-cancer, patient. For example, each chemotherapeutic agent has characteristic adverse effects; TABLE 4⁷ lists the principal adverse effects of common agents and recommendations for testing when these problems develop. Common long-term problems in cancer survivors include fatigue, chronic pain, cognitive dysfunction, psychiatric illness, and cardiovascular disease. Although these symptoms and manifestations are common, the physician must be careful: New or changing symptoms could signal the spread or recurrence of disease. Fear of recurrence can lead patients to exaggerate or minimize symptoms.

Fatigue is the most common symptom seen in cancer survivors during treatment and following remission.²⁸ More than 40% of cancer survivors report significant fatigue.²⁹ Although fatigue is concerning for cancer recurrence, other causes are common in cancer survivors. Both depression and anxiety commonly present with worsened fatigue.³⁰ Sleep disturbances are common, even without a psychiatric diagnosis.³¹ Effects of treatment, including nausea, anemia, heart failure, and medication adverse effects can cause or worsen fatigue. Pain is associated with fatigue, but to a lesser extent than are depression, anxiety, and nausea.³²

Pharmacotherapy of cancer-related fatigue is challenging. Psychostimulants have been most studied. A recent systematic review shows that methylphenidate produces mild or moderate improvement in fatigue, whereas modafanil has minimal effectiveness.³³ Antidepressants have not been shown to relieve fatigue.³³

A recent meta-analysis showed that nonpharmaceutical treatments for cancer-related fatigue are more effective than pharmacotherapy. In this review, both exercise and pharmacotherapy had a mild-to-moderate effect on fatigue.³⁵ Exercise is best studied in this regard, and has shown the most consistent results.³¹

Continue to: Chronic pain

Chronic pain. Pain is common in cancer survivors: As many as 40% experience pain for years after initial therapy.³⁶ Treatment of some cancers—eg, thoracotomy (80%), amputation (50%-80%), neck dissection (52%), and surgical management of breast cancer (63%)—increase the likelihood of chronic pain.³⁷ Reports of pain in cancer survivors that should be considered red flags that might signal recurrence of cancer include new or worsening pain; pain worse at night or when recumbent; new neurologic symptoms; and general symptoms of systemic illness³⁷ (TABLE 5³⁷).

Management of pain is best approached by its cause, with neurologic, rheumatologic (including myofascial pain and arthralgia), lymphatic, and genital causes most common.³⁷ Across all types of pain, complete relief is unlikely; functional goals provide a more effective target.

For neuropathic cancer pain, duloxetine is the only medication with evidence of benefit; anticonvulsant and topical medications are recommended on the basis of the findings of studies of noncancer pain.³⁸ There are few data on the value of treatments for cancer-related rheumatologic and lymphatic pain, although exercise has shown benefit in both types.³⁸ For dyspareunia and sexual dysfunction (common after gynecologic and nongynecologic cancers), vaginal lubricants and pelvic-floor physiotherapy have shown benefit.³⁹ There is significant overlap in psychiatric comorbidities, sleep, and pain, and addressing all of a patient’s problems can reduce pain and improve function.⁴⁰

Opioids are often prescribed for pain in cancer survivors. Cancer survivors have a higher rate of opioid prescribing compared with that of non-cancer patients, even 10 years after diagnosis.⁴¹ Guidelines of the Centers for Disease Control and Prevention for using opioids to manage chronic pain specifically exclude cancer patients.⁴² Regrettably, there is no evidence that opioids have long-term efficacy in chronic pain; in fact, evidence is accumulating that chronic opioid therapy exacerbates chronic pain.⁴³

Cognitive dysfunction is present in 17% to 75% of cancer survivors as memory disturbance, psychological disorder, sleep dysfunction, or impairment of executive functioning.⁴⁴ Cognitive deficits appear to be secondary to both cancer and treatment modalities⁴⁵; as many as one-third of patients have cognitive dysfunction prior to receiving chemotherapy.⁴⁶

Continue to: Chemotherapies that are more likely...

Chemotherapies that are more likely to cause cognitive symptoms include methotrexate, 5-fluorouracil, cyclophosphamide, and hormone antagonists.⁴⁷ More powerful regimens and repetitive chemotherapy regimens tend to cause more cognitive effects.⁴⁷

Cognitive training interventions show evidence of likely benefit,^44,48 leading to recommendations for self-treatment strategies, such as written lists, wordplay, crossword puzzles, jigsaw puzzles, playing a musical instrument, and new hobbies. Small studies suggest a benefit from cognitive behavioral therapy.^44,49 A study of breast cancer survivors showed that yoga led to improvement in patient-reported cognitive dysfunction.⁵⁰ Physical exercise yields cognitive benefit in healthy older adults and is supported by limited evidence in cancer survivors.⁵¹

There is no effective pharmacotherapy for cancer- and cancer chemotherapy-related cognitive dysfunction unless a treatable underlying cause is found.⁴⁴ Symptoms tend to subside with time after completion of chemotherapy, which might be reassuring to patients and families.⁴⁵

Psychiatric problems. The most common psychiatric issues in cancer survivors are anxiety and depression; the prevalence of anxiety is nearly double that of depression.⁵² Anxiety often presents as fear of a recurrence of cancer or a feeling of lack of control over present or future circumstances.⁵³ Screening for anxiety and depression is recommended at each visit, using standardized screening questionnaires.⁵⁴

A small study suggests that psychiatric treatment reduces the risk of early mortality.⁵⁵ Small studies also suggest that mindfulness-based therapy and cognitive behavioral therapy delivered by telehealth offer benefit.⁵⁶ A meta-analysis shows that exercise interventions improve depression and anxiety in breast cancer patients.⁵⁷

Continue to: There are few studies of pharmacotherapy...

There are few studies of pharmacotherapy of anxiety or depression in cancer survivors⁵⁶; it is known that cancer survivors are nearly twice as likely as the general population to be taking medical therapy for anxiety and depression.⁵⁸ A Cochrane systematic review of 7 small studies showed uncertain improvement in depressive symptoms in patients with cancer from antidepressant medication; however, an earlier systematic review did show benefit.^59,60

Second malignancies are dangerous; 55% of patients die of the second cancer, compared to only 13% of their initial cancer.

In a trial of patients without depression who were being treated for head and neck cancer, escitalopram, 20 mg/d, reduced the risk of subsequent depression compared with placebo.⁶¹ A study of 420 breast cancer survivors showed that 300 mg/d and 900 mg/d dosages of gabapentin were both superior to placebo, and nearly equivalent to each other, at reducing anxiety scores.⁶² In both studies, however, the evidence is nonetheless insufficient to make specific recommendations about these medications.

Cardiac risk. The risk of cardiovascular morbidity in cancer survivors is, in fact, higher than the risk of recurrence of cancer.⁶³ Cancer survivors have 5 times the risk of heart failure and 10 times the risk of coronary artery disease and cerebrovascular disease than patients without cancer.⁶³ Most of this risk is incurred because of the physiologic effects of chemotherapy and radiation.

Among chemotherapeutic agents, anthracyclines, such as doxorubicin, cause the most rapid and striking myocyte damage. This damage is dose-dependent and nearly irreversible, with 98% of injury occurring within the first year of chemotherapy.⁶⁴ More than one half of cancer patients taking an anthracycline have cardiac dysfunction on imaging; 5% will be in overt heart failure 10 to 20 years, or longer, after chemotherapy.⁶³ Following monitoring at 1 year post-therapy, regular cardiac imaging is not recommended in the absence of symptoms.⁶²

Because other cardiotoxic chemotherapeutic agents cause partially reversible damage, imaging is not recommended in the absence of symptoms in patients taking those agents.⁶⁴

Continue to: Radiation therapy to the chest leads...

Radiation therapy to the chest leads to many cardiac complications, including cardiomyopathy, valvular disease, pericardial disease, and arrhythmias. Development of cardiomyopathy can be delayed 20 to 30 years after radiation; screening echocardiography is therefore recommended every 5 to 10 years after radiation therapy.⁶⁵ Recent adjustments to the dosages and delivery of radiation therapy should reduce cardiac damage, but will require decades to validate.⁶³

Evidence is accumulating that chronic opioid therapy exacerbates chronic pain.

For patients at risk of cardiovascular disease prior to treatment of cancer, there is evidence to support preventive treatment with angiotensin II-receptor antagonists, beta-blockers, and statins to prevent cardiomyopathy.⁶³ Treatment of diagnosed cardiomyopathy and heart failure follows standard guidelines, with significant emphasis on aerobic exercise and smoking cessation.⁶³

Cancer survivorship care: Your critical role

Cancer survivors constitute a large population who frequent the practices of primary care physicians. Primary care visits provide an opportunity to monitor key elements of survivorship, including surveillance of the current cancer and screening for second cancers. Similar to what is seen with diabetes and coronary artery disease, cancer increases cardiac risk, which requires preventive care and chronic management. FPs are well placed to treat common issues in cancer survivors—issues that mirror concerns seen in the general population.

CORRESPONDENCE
Michael J. Arnold, MD, CDR, USN, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; [email protected].

ACKNOWLEDGEMENT
Kristian Sanchack, MD, and James Higgins, DO, assisted with the editing of the manuscript.

Cancer survivors represent a rapidly increasing population. In 1971, there were 3 million cancer survivors; this number increased to 15.5 million in 2016 and will reach 20 million by 2026.¹TABLE 1¹ shows the percentage of survivors by type of cancer. Cancer survivors tend to be older,* comprising nearly 1 of every 5 people older than 65 years.²

The Institute of Medicine (IOM) identified 3 key characteristics of cancer survivors³:

• Trajectories of survivorship are variable; many cancer patients have periods of relative health between episodes of their disease.
• Survivors require careful cancer monitoring; in addition to the risk that their primary cancer will recur, they have an elevated risk for another, second cancer.
• Both cancer and its treatments increase the risk of other medical and psychiatric problems.

Family physicians (FPs) have optimal skills for navigating the chronic risks and health concerns of the well cancer survivor. This article reviews the primary care management of the functional cancer survivor, focusing on the management of chronic conditions and preventive care.

Survivorship follows any of 6 paths

Cancer survivorship is increasing in importance as treatment has steadily reduced mortality. Six trajectories of cancer survivors have been identified¹:

• living cancer-free after treatment with minimal effects
• living cancer-free but suffering serious treatment complications
• Suffering late recurrence
• Developing a second cancer
• Living with intermittent cancer recurrences
• Living with cancer continuously.

Only patients in the last 2 groups are likely to be managed primarily by oncologists.

Survivors look to their FPs for ongoing care

Cancer survivors routinely see their primary care physician after initial treatment. A study of 30,000 Canadian breast cancer survivors demonstrated that follow-up care was limited to an oncologist in only 2%; 84% saw a primary care provider and an oncologist; and 14% saw a primary care provider only.⁴ A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily⁵; in that study, primary care physicians delivered more preventive care than oncologists did.⁵ Similar to what is done in other chronic conditions, the various effects of cancer are best managed as a whole.

The IOM recommends that cancer survivor care comprise 4 elements²:

1. coordination between oncologist and primary care physician
2. surveillance for recurrence or spread of existing cancer
3. screening for new cancer
4. intervention for the effects of cancer and treatment.

Continue to: The following discussion summarizes...

The following discussion summarizes evidence and recommendations for each element of the IOM recommendations for survivor care.

Implementing the 4 elements of cancer survivor care

1. Coordinate care through a unified survivorship care plan

The IOM has noted that the needs of cancer survivors are rarely met²; communication between oncology and primary care is often deficient during transition of care. The IOM has recommended that oncologists provide a survivorship care plan that details the cancer (ie, tumor characteristics), the type of treatment (ie, enrollment in a clinical trial; medical, surgical, or radiation), support services, and follow-up recommendations for the primary care provider. (Examples of elements of a survivorship care plan can be found at www.mskcc.org/hcp-education-training/survivorship/survivorship-care-plan⁶ and http://sma.org/southern-medical-journal/article/cancer-survivors-history-physical/⁷).

Regrettably, survivorship care plans have been rarely and poorly employed. Studies show that fewer than one-half of oncologists provide a plan, and that when they do, the plan often lacks recommended information.^8,9 Survivorship care plans may soon become common practice, however; the Commission on Cancer of the American College of Surgeons has required their use in all certified cancer centers since 2015.¹⁰

2. Provide surveillance of existing cancer

Cancer follow-up is challenging after the initial treatment phase. Although there are many conflicting guidelines for surveillance after cancer, guidelines of the National Comprehensive Cancer Network (NCCN) (summarized in TABLE 2¹¹ for the 10 most common cancers in survivors) are the ones generally accepted.^12,13

Although individual surveillance recommendations are based on limited evidence, studies confirm the importance of surveillance. A systematic review showed that surveillance mammography after breast cancer reduces breast cancer mortality by 36%.¹⁴ A study showed that bladder cancer recurrence diagnosed by surveillance instead of by symptoms led to a 35% increase in 5-year survival.¹⁵

Continue to: Yet adherence to cancer surveillance...

Yet adherence to cancer surveillance recommendations is poor. A study of patients with colon cancer demonstrated that only 12% met all recommended surveillance guidelines.¹⁶ A study of patients with bladder cancer after radical cystectomy showed that only 9% met recommended surveillance more than 2 years after diagnosis.¹⁷ Those dismal statistics may be the result of provider oversight—not patient reluctance.

In the colon cancer study, for example, compliance with follow-up colonoscopy was 80% but compliance with carcinoembryonic antigen testing was only 22%.¹⁶ In the bladder cancer study, follow-up urine cytology was obtained in only 23% of patients, although 75% completed recommended imaging.¹⁷

Although surveillance remains the oncologist’s responsibility, visits to the FP provide an opportunity to review surveillance and order needed laboratory testing and other studies, including imaging.

3. Screen for new cancers

The risk of a second cancer is elevated for cancer survivors compared with the risk of a primary cancer in the healthy general population; some survivors have a lifetime risk of a second cancer as high as 36%.¹⁸ Risk varies by cancer type (TABLE 3¹⁹). Some of this variation is due to the impact of smoking: Smoking-related cancers have the highest risk of second malignancy.¹⁹ Genetic predisposition to malignant transformation is also theorized to contribute to increased risk. Second malignancies are dangerous; 55% of patients die of the second cancer compared with only 13% of their initial cancer.¹⁹

A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily.

Studies show that cancer survivors display varying adherence with recommended screening for second cancers. In a study of Latina cancer survivors, depressive symptoms were associated with lower screening compliance.²⁰ A study of survivors of hematologic cancer showed a low rate of cancer screening and high fear of cancer recurrence—suggesting avoidance due to fear.²¹ Other studies, however, show similar or increased compliance with screening in cancer survivors.^22,23 A meta-analysis of 19 studies determined that, overall, cancer survivors receive 25% to 38% more recommended screening than the general population.²⁴

Continue to: Few guidelines exist to guide FPs...

Few guidelines exist to guide FPs in adjusting screening for the cancer survivor. For women who received radiation therapy for a tumor in the chest, for example, the recommendation offered by several groups is to start breast cancer screening 8 to 10 years after treatment or by 30 years of age, and to consider combining magnetic resonance imaging and mammography.²⁵ Recommendations for breast cancer screening do not account for a history of other gynecologic cancers unless genetic markers are present.²⁵ On the other hand, the impact of a history of cancer on the risk of prostate cancer and on screening decisions has not been studied,²⁶ and cervical cancer screening guidelines, which recommend that screening continue after 65 years of age for patients who are immunocompromised, do not address a history of other cancer.²⁷

4. Manage the effects of both the cancer and the treatment

Medical issues faced by cancer survivors are familiar to FPs, but there are some specific recommendations regarding evaluation and treatment that stand in contrast to what would be considered for a healthy, or non-cancer, patient. For example, each chemotherapeutic agent has characteristic adverse effects; TABLE 4⁷ lists the principal adverse effects of common agents and recommendations for testing when these problems develop. Common long-term problems in cancer survivors include fatigue, chronic pain, cognitive dysfunction, psychiatric illness, and cardiovascular disease. Although these symptoms and manifestations are common, the physician must be careful: New or changing symptoms could signal the spread or recurrence of disease. Fear of recurrence can lead patients to exaggerate or minimize symptoms.

Fatigue is the most common symptom seen in cancer survivors during treatment and following remission.²⁸ More than 40% of cancer survivors report significant fatigue.²⁹ Although fatigue is concerning for cancer recurrence, other causes are common in cancer survivors. Both depression and anxiety commonly present with worsened fatigue.³⁰ Sleep disturbances are common, even without a psychiatric diagnosis.³¹ Effects of treatment, including nausea, anemia, heart failure, and medication adverse effects can cause or worsen fatigue. Pain is associated with fatigue, but to a lesser extent than are depression, anxiety, and nausea.³²

Pharmacotherapy of cancer-related fatigue is challenging. Psychostimulants have been most studied. A recent systematic review shows that methylphenidate produces mild or moderate improvement in fatigue, whereas modafanil has minimal effectiveness.³³ Antidepressants have not been shown to relieve fatigue.³³

A recent meta-analysis showed that nonpharmaceutical treatments for cancer-related fatigue are more effective than pharmacotherapy. In this review, both exercise and pharmacotherapy had a mild-to-moderate effect on fatigue.³⁵ Exercise is best studied in this regard, and has shown the most consistent results.³¹

Continue to: Chronic pain

Chronic pain. Pain is common in cancer survivors: As many as 40% experience pain for years after initial therapy.³⁶ Treatment of some cancers—eg, thoracotomy (80%), amputation (50%-80%), neck dissection (52%), and surgical management of breast cancer (63%)—increase the likelihood of chronic pain.³⁷ Reports of pain in cancer survivors that should be considered red flags that might signal recurrence of cancer include new or worsening pain; pain worse at night or when recumbent; new neurologic symptoms; and general symptoms of systemic illness³⁷ (TABLE 5³⁷).

Management of pain is best approached by its cause, with neurologic, rheumatologic (including myofascial pain and arthralgia), lymphatic, and genital causes most common.³⁷ Across all types of pain, complete relief is unlikely; functional goals provide a more effective target.

For neuropathic cancer pain, duloxetine is the only medication with evidence of benefit; anticonvulsant and topical medications are recommended on the basis of the findings of studies of noncancer pain.³⁸ There are few data on the value of treatments for cancer-related rheumatologic and lymphatic pain, although exercise has shown benefit in both types.³⁸ For dyspareunia and sexual dysfunction (common after gynecologic and nongynecologic cancers), vaginal lubricants and pelvic-floor physiotherapy have shown benefit.³⁹ There is significant overlap in psychiatric comorbidities, sleep, and pain, and addressing all of a patient’s problems can reduce pain and improve function.⁴⁰

Opioids are often prescribed for pain in cancer survivors. Cancer survivors have a higher rate of opioid prescribing compared with that of non-cancer patients, even 10 years after diagnosis.⁴¹ Guidelines of the Centers for Disease Control and Prevention for using opioids to manage chronic pain specifically exclude cancer patients.⁴² Regrettably, there is no evidence that opioids have long-term efficacy in chronic pain; in fact, evidence is accumulating that chronic opioid therapy exacerbates chronic pain.⁴³

Cognitive dysfunction is present in 17% to 75% of cancer survivors as memory disturbance, psychological disorder, sleep dysfunction, or impairment of executive functioning.⁴⁴ Cognitive deficits appear to be secondary to both cancer and treatment modalities⁴⁵; as many as one-third of patients have cognitive dysfunction prior to receiving chemotherapy.⁴⁶

Continue to: Chemotherapies that are more likely...

Chemotherapies that are more likely to cause cognitive symptoms include methotrexate, 5-fluorouracil, cyclophosphamide, and hormone antagonists.⁴⁷ More powerful regimens and repetitive chemotherapy regimens tend to cause more cognitive effects.⁴⁷

Cognitive training interventions show evidence of likely benefit,^44,48 leading to recommendations for self-treatment strategies, such as written lists, wordplay, crossword puzzles, jigsaw puzzles, playing a musical instrument, and new hobbies. Small studies suggest a benefit from cognitive behavioral therapy.^44,49 A study of breast cancer survivors showed that yoga led to improvement in patient-reported cognitive dysfunction.⁵⁰ Physical exercise yields cognitive benefit in healthy older adults and is supported by limited evidence in cancer survivors.⁵¹

There is no effective pharmacotherapy for cancer- and cancer chemotherapy-related cognitive dysfunction unless a treatable underlying cause is found.⁴⁴ Symptoms tend to subside with time after completion of chemotherapy, which might be reassuring to patients and families.⁴⁵

Psychiatric problems. The most common psychiatric issues in cancer survivors are anxiety and depression; the prevalence of anxiety is nearly double that of depression.⁵² Anxiety often presents as fear of a recurrence of cancer or a feeling of lack of control over present or future circumstances.⁵³ Screening for anxiety and depression is recommended at each visit, using standardized screening questionnaires.⁵⁴

A small study suggests that psychiatric treatment reduces the risk of early mortality.⁵⁵ Small studies also suggest that mindfulness-based therapy and cognitive behavioral therapy delivered by telehealth offer benefit.⁵⁶ A meta-analysis shows that exercise interventions improve depression and anxiety in breast cancer patients.⁵⁷

Continue to: There are few studies of pharmacotherapy...

There are few studies of pharmacotherapy of anxiety or depression in cancer survivors⁵⁶; it is known that cancer survivors are nearly twice as likely as the general population to be taking medical therapy for anxiety and depression.⁵⁸ A Cochrane systematic review of 7 small studies showed uncertain improvement in depressive symptoms in patients with cancer from antidepressant medication; however, an earlier systematic review did show benefit.^59,60

Second malignancies are dangerous; 55% of patients die of the second cancer, compared to only 13% of their initial cancer.

In a trial of patients without depression who were being treated for head and neck cancer, escitalopram, 20 mg/d, reduced the risk of subsequent depression compared with placebo.⁶¹ A study of 420 breast cancer survivors showed that 300 mg/d and 900 mg/d dosages of gabapentin were both superior to placebo, and nearly equivalent to each other, at reducing anxiety scores.⁶² In both studies, however, the evidence is nonetheless insufficient to make specific recommendations about these medications.

Cardiac risk. The risk of cardiovascular morbidity in cancer survivors is, in fact, higher than the risk of recurrence of cancer.⁶³ Cancer survivors have 5 times the risk of heart failure and 10 times the risk of coronary artery disease and cerebrovascular disease than patients without cancer.⁶³ Most of this risk is incurred because of the physiologic effects of chemotherapy and radiation.

Among chemotherapeutic agents, anthracyclines, such as doxorubicin, cause the most rapid and striking myocyte damage. This damage is dose-dependent and nearly irreversible, with 98% of injury occurring within the first year of chemotherapy.⁶⁴ More than one half of cancer patients taking an anthracycline have cardiac dysfunction on imaging; 5% will be in overt heart failure 10 to 20 years, or longer, after chemotherapy.⁶³ Following monitoring at 1 year post-therapy, regular cardiac imaging is not recommended in the absence of symptoms.⁶²

Because other cardiotoxic chemotherapeutic agents cause partially reversible damage, imaging is not recommended in the absence of symptoms in patients taking those agents.⁶⁴

Continue to: Radiation therapy to the chest leads...

Radiation therapy to the chest leads to many cardiac complications, including cardiomyopathy, valvular disease, pericardial disease, and arrhythmias. Development of cardiomyopathy can be delayed 20 to 30 years after radiation; screening echocardiography is therefore recommended every 5 to 10 years after radiation therapy.⁶⁵ Recent adjustments to the dosages and delivery of radiation therapy should reduce cardiac damage, but will require decades to validate.⁶³

Evidence is accumulating that chronic opioid therapy exacerbates chronic pain.

For patients at risk of cardiovascular disease prior to treatment of cancer, there is evidence to support preventive treatment with angiotensin II-receptor antagonists, beta-blockers, and statins to prevent cardiomyopathy.⁶³ Treatment of diagnosed cardiomyopathy and heart failure follows standard guidelines, with significant emphasis on aerobic exercise and smoking cessation.⁶³

Cancer survivorship care: Your critical role

Cancer survivors constitute a large population who frequent the practices of primary care physicians. Primary care visits provide an opportunity to monitor key elements of survivorship, including surveillance of the current cancer and screening for second cancers. Similar to what is seen with diabetes and coronary artery disease, cancer increases cardiac risk, which requires preventive care and chronic management. FPs are well placed to treat common issues in cancer survivors—issues that mirror concerns seen in the general population.

CORRESPONDENCE
Michael J. Arnold, MD, CDR, USN, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; [email protected].

ACKNOWLEDGEMENT
Kristian Sanchack, MD, and James Higgins, DO, assisted with the editing of the manuscript.

Cancer survivors represent a rapidly increasing population. In 1971, there were 3 million cancer survivors; this number increased to 15.5 million in 2016 and will reach 20 million by 2026.¹TABLE 1¹ shows the percentage of survivors by type of cancer. Cancer survivors tend to be older,* comprising nearly 1 of every 5 people older than 65 years.²

The Institute of Medicine (IOM) identified 3 key characteristics of cancer survivors³:

• Trajectories of survivorship are variable; many cancer patients have periods of relative health between episodes of their disease.
• Survivors require careful cancer monitoring; in addition to the risk that their primary cancer will recur, they have an elevated risk for another, second cancer.
• Both cancer and its treatments increase the risk of other medical and psychiatric problems.

Family physicians (FPs) have optimal skills for navigating the chronic risks and health concerns of the well cancer survivor. This article reviews the primary care management of the functional cancer survivor, focusing on the management of chronic conditions and preventive care.

Survivorship follows any of 6 paths

Cancer survivorship is increasing in importance as treatment has steadily reduced mortality. Six trajectories of cancer survivors have been identified¹:

• living cancer-free after treatment with minimal effects
• living cancer-free but suffering serious treatment complications
• Suffering late recurrence
• Developing a second cancer
• Living with intermittent cancer recurrences
• Living with cancer continuously.

Only patients in the last 2 groups are likely to be managed primarily by oncologists.

Survivors look to their FPs for ongoing care

Cancer survivors routinely see their primary care physician after initial treatment. A study of 30,000 Canadian breast cancer survivors demonstrated that follow-up care was limited to an oncologist in only 2%; 84% saw a primary care provider and an oncologist; and 14% saw a primary care provider only.⁴ A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily⁵; in that study, primary care physicians delivered more preventive care than oncologists did.⁵ Similar to what is done in other chronic conditions, the various effects of cancer are best managed as a whole.

The IOM recommends that cancer survivor care comprise 4 elements²:

1. coordination between oncologist and primary care physician
2. surveillance for recurrence or spread of existing cancer
3. screening for new cancer
4. intervention for the effects of cancer and treatment.

Continue to: The following discussion summarizes...

The following discussion summarizes evidence and recommendations for each element of the IOM recommendations for survivor care.

Implementing the 4 elements of cancer survivor care

1. Coordinate care through a unified survivorship care plan

The IOM has noted that the needs of cancer survivors are rarely met²; communication between oncology and primary care is often deficient during transition of care. The IOM has recommended that oncologists provide a survivorship care plan that details the cancer (ie, tumor characteristics), the type of treatment (ie, enrollment in a clinical trial; medical, surgical, or radiation), support services, and follow-up recommendations for the primary care provider. (Examples of elements of a survivorship care plan can be found at www.mskcc.org/hcp-education-training/survivorship/survivorship-care-plan⁶ and http://sma.org/southern-medical-journal/article/cancer-survivors-history-physical/⁷).

Regrettably, survivorship care plans have been rarely and poorly employed. Studies show that fewer than one-half of oncologists provide a plan, and that when they do, the plan often lacks recommended information.^8,9 Survivorship care plans may soon become common practice, however; the Commission on Cancer of the American College of Surgeons has required their use in all certified cancer centers since 2015.¹⁰

2. Provide surveillance of existing cancer

Cancer follow-up is challenging after the initial treatment phase. Although there are many conflicting guidelines for surveillance after cancer, guidelines of the National Comprehensive Cancer Network (NCCN) (summarized in TABLE 2¹¹ for the 10 most common cancers in survivors) are the ones generally accepted.^12,13

Although individual surveillance recommendations are based on limited evidence, studies confirm the importance of surveillance. A systematic review showed that surveillance mammography after breast cancer reduces breast cancer mortality by 36%.¹⁴ A study showed that bladder cancer recurrence diagnosed by surveillance instead of by symptoms led to a 35% increase in 5-year survival.¹⁵

Continue to: Yet adherence to cancer surveillance...

Yet adherence to cancer surveillance recommendations is poor. A study of patients with colon cancer demonstrated that only 12% met all recommended surveillance guidelines.¹⁶ A study of patients with bladder cancer after radical cystectomy showed that only 9% met recommended surveillance more than 2 years after diagnosis.¹⁷ Those dismal statistics may be the result of provider oversight—not patient reluctance.

In the colon cancer study, for example, compliance with follow-up colonoscopy was 80% but compliance with carcinoembryonic antigen testing was only 22%.¹⁶ In the bladder cancer study, follow-up urine cytology was obtained in only 23% of patients, although 75% completed recommended imaging.¹⁷

Although surveillance remains the oncologist’s responsibility, visits to the FP provide an opportunity to review surveillance and order needed laboratory testing and other studies, including imaging.

3. Screen for new cancers

The risk of a second cancer is elevated for cancer survivors compared with the risk of a primary cancer in the healthy general population; some survivors have a lifetime risk of a second cancer as high as 36%.¹⁸ Risk varies by cancer type (TABLE 3¹⁹). Some of this variation is due to the impact of smoking: Smoking-related cancers have the highest risk of second malignancy.¹⁹ Genetic predisposition to malignant transformation is also theorized to contribute to increased risk. Second malignancies are dangerous; 55% of patients die of the second cancer compared with only 13% of their initial cancer.¹⁹

A study of colorectal cancer survivors showed that primary care visits increased in each of the 5 years after diagnosis, during which time oncology visits decreased steadily.

Studies show that cancer survivors display varying adherence with recommended screening for second cancers. In a study of Latina cancer survivors, depressive symptoms were associated with lower screening compliance.²⁰ A study of survivors of hematologic cancer showed a low rate of cancer screening and high fear of cancer recurrence—suggesting avoidance due to fear.²¹ Other studies, however, show similar or increased compliance with screening in cancer survivors.^22,23 A meta-analysis of 19 studies determined that, overall, cancer survivors receive 25% to 38% more recommended screening than the general population.²⁴

Continue to: Few guidelines exist to guide FPs...

Few guidelines exist to guide FPs in adjusting screening for the cancer survivor. For women who received radiation therapy for a tumor in the chest, for example, the recommendation offered by several groups is to start breast cancer screening 8 to 10 years after treatment or by 30 years of age, and to consider combining magnetic resonance imaging and mammography.²⁵ Recommendations for breast cancer screening do not account for a history of other gynecologic cancers unless genetic markers are present.²⁵ On the other hand, the impact of a history of cancer on the risk of prostate cancer and on screening decisions has not been studied,²⁶ and cervical cancer screening guidelines, which recommend that screening continue after 65 years of age for patients who are immunocompromised, do not address a history of other cancer.²⁷

4. Manage the effects of both the cancer and the treatment

Medical issues faced by cancer survivors are familiar to FPs, but there are some specific recommendations regarding evaluation and treatment that stand in contrast to what would be considered for a healthy, or non-cancer, patient. For example, each chemotherapeutic agent has characteristic adverse effects; TABLE 4⁷ lists the principal adverse effects of common agents and recommendations for testing when these problems develop. Common long-term problems in cancer survivors include fatigue, chronic pain, cognitive dysfunction, psychiatric illness, and cardiovascular disease. Although these symptoms and manifestations are common, the physician must be careful: New or changing symptoms could signal the spread or recurrence of disease. Fear of recurrence can lead patients to exaggerate or minimize symptoms.

Fatigue is the most common symptom seen in cancer survivors during treatment and following remission.²⁸ More than 40% of cancer survivors report significant fatigue.²⁹ Although fatigue is concerning for cancer recurrence, other causes are common in cancer survivors. Both depression and anxiety commonly present with worsened fatigue.³⁰ Sleep disturbances are common, even without a psychiatric diagnosis.³¹ Effects of treatment, including nausea, anemia, heart failure, and medication adverse effects can cause or worsen fatigue. Pain is associated with fatigue, but to a lesser extent than are depression, anxiety, and nausea.³²

Pharmacotherapy of cancer-related fatigue is challenging. Psychostimulants have been most studied. A recent systematic review shows that methylphenidate produces mild or moderate improvement in fatigue, whereas modafanil has minimal effectiveness.³³ Antidepressants have not been shown to relieve fatigue.³³

A recent meta-analysis showed that nonpharmaceutical treatments for cancer-related fatigue are more effective than pharmacotherapy. In this review, both exercise and pharmacotherapy had a mild-to-moderate effect on fatigue.³⁵ Exercise is best studied in this regard, and has shown the most consistent results.³¹

Continue to: Chronic pain

Chronic pain. Pain is common in cancer survivors: As many as 40% experience pain for years after initial therapy.³⁶ Treatment of some cancers—eg, thoracotomy (80%), amputation (50%-80%), neck dissection (52%), and surgical management of breast cancer (63%)—increase the likelihood of chronic pain.³⁷ Reports of pain in cancer survivors that should be considered red flags that might signal recurrence of cancer include new or worsening pain; pain worse at night or when recumbent; new neurologic symptoms; and general symptoms of systemic illness³⁷ (TABLE 5³⁷).

Management of pain is best approached by its cause, with neurologic, rheumatologic (including myofascial pain and arthralgia), lymphatic, and genital causes most common.³⁷ Across all types of pain, complete relief is unlikely; functional goals provide a more effective target.

For neuropathic cancer pain, duloxetine is the only medication with evidence of benefit; anticonvulsant and topical medications are recommended on the basis of the findings of studies of noncancer pain.³⁸ There are few data on the value of treatments for cancer-related rheumatologic and lymphatic pain, although exercise has shown benefit in both types.³⁸ For dyspareunia and sexual dysfunction (common after gynecologic and nongynecologic cancers), vaginal lubricants and pelvic-floor physiotherapy have shown benefit.³⁹ There is significant overlap in psychiatric comorbidities, sleep, and pain, and addressing all of a patient’s problems can reduce pain and improve function.⁴⁰

Opioids are often prescribed for pain in cancer survivors. Cancer survivors have a higher rate of opioid prescribing compared with that of non-cancer patients, even 10 years after diagnosis.⁴¹ Guidelines of the Centers for Disease Control and Prevention for using opioids to manage chronic pain specifically exclude cancer patients.⁴² Regrettably, there is no evidence that opioids have long-term efficacy in chronic pain; in fact, evidence is accumulating that chronic opioid therapy exacerbates chronic pain.⁴³

Cognitive dysfunction is present in 17% to 75% of cancer survivors as memory disturbance, psychological disorder, sleep dysfunction, or impairment of executive functioning.⁴⁴ Cognitive deficits appear to be secondary to both cancer and treatment modalities⁴⁵; as many as one-third of patients have cognitive dysfunction prior to receiving chemotherapy.⁴⁶

Continue to: Chemotherapies that are more likely...

Chemotherapies that are more likely to cause cognitive symptoms include methotrexate, 5-fluorouracil, cyclophosphamide, and hormone antagonists.⁴⁷ More powerful regimens and repetitive chemotherapy regimens tend to cause more cognitive effects.⁴⁷

Cognitive training interventions show evidence of likely benefit,^44,48 leading to recommendations for self-treatment strategies, such as written lists, wordplay, crossword puzzles, jigsaw puzzles, playing a musical instrument, and new hobbies. Small studies suggest a benefit from cognitive behavioral therapy.^44,49 A study of breast cancer survivors showed that yoga led to improvement in patient-reported cognitive dysfunction.⁵⁰ Physical exercise yields cognitive benefit in healthy older adults and is supported by limited evidence in cancer survivors.⁵¹

There is no effective pharmacotherapy for cancer- and cancer chemotherapy-related cognitive dysfunction unless a treatable underlying cause is found.⁴⁴ Symptoms tend to subside with time after completion of chemotherapy, which might be reassuring to patients and families.⁴⁵

Psychiatric problems. The most common psychiatric issues in cancer survivors are anxiety and depression; the prevalence of anxiety is nearly double that of depression.⁵² Anxiety often presents as fear of a recurrence of cancer or a feeling of lack of control over present or future circumstances.⁵³ Screening for anxiety and depression is recommended at each visit, using standardized screening questionnaires.⁵⁴

A small study suggests that psychiatric treatment reduces the risk of early mortality.⁵⁵ Small studies also suggest that mindfulness-based therapy and cognitive behavioral therapy delivered by telehealth offer benefit.⁵⁶ A meta-analysis shows that exercise interventions improve depression and anxiety in breast cancer patients.⁵⁷

Continue to: There are few studies of pharmacotherapy...

There are few studies of pharmacotherapy of anxiety or depression in cancer survivors⁵⁶; it is known that cancer survivors are nearly twice as likely as the general population to be taking medical therapy for anxiety and depression.⁵⁸ A Cochrane systematic review of 7 small studies showed uncertain improvement in depressive symptoms in patients with cancer from antidepressant medication; however, an earlier systematic review did show benefit.^59,60

Second malignancies are dangerous; 55% of patients die of the second cancer, compared to only 13% of their initial cancer.

In a trial of patients without depression who were being treated for head and neck cancer, escitalopram, 20 mg/d, reduced the risk of subsequent depression compared with placebo.⁶¹ A study of 420 breast cancer survivors showed that 300 mg/d and 900 mg/d dosages of gabapentin were both superior to placebo, and nearly equivalent to each other, at reducing anxiety scores.⁶² In both studies, however, the evidence is nonetheless insufficient to make specific recommendations about these medications.

Cardiac risk. The risk of cardiovascular morbidity in cancer survivors is, in fact, higher than the risk of recurrence of cancer.⁶³ Cancer survivors have 5 times the risk of heart failure and 10 times the risk of coronary artery disease and cerebrovascular disease than patients without cancer.⁶³ Most of this risk is incurred because of the physiologic effects of chemotherapy and radiation.

Among chemotherapeutic agents, anthracyclines, such as doxorubicin, cause the most rapid and striking myocyte damage. This damage is dose-dependent and nearly irreversible, with 98% of injury occurring within the first year of chemotherapy.⁶⁴ More than one half of cancer patients taking an anthracycline have cardiac dysfunction on imaging; 5% will be in overt heart failure 10 to 20 years, or longer, after chemotherapy.⁶³ Following monitoring at 1 year post-therapy, regular cardiac imaging is not recommended in the absence of symptoms.⁶²

Because other cardiotoxic chemotherapeutic agents cause partially reversible damage, imaging is not recommended in the absence of symptoms in patients taking those agents.⁶⁴

Continue to: Radiation therapy to the chest leads...

Radiation therapy to the chest leads to many cardiac complications, including cardiomyopathy, valvular disease, pericardial disease, and arrhythmias. Development of cardiomyopathy can be delayed 20 to 30 years after radiation; screening echocardiography is therefore recommended every 5 to 10 years after radiation therapy.⁶⁵ Recent adjustments to the dosages and delivery of radiation therapy should reduce cardiac damage, but will require decades to validate.⁶³

Evidence is accumulating that chronic opioid therapy exacerbates chronic pain.

For patients at risk of cardiovascular disease prior to treatment of cancer, there is evidence to support preventive treatment with angiotensin II-receptor antagonists, beta-blockers, and statins to prevent cardiomyopathy.⁶³ Treatment of diagnosed cardiomyopathy and heart failure follows standard guidelines, with significant emphasis on aerobic exercise and smoking cessation.⁶³

Cancer survivorship care: Your critical role

Cancer survivors constitute a large population who frequent the practices of primary care physicians. Primary care visits provide an opportunity to monitor key elements of survivorship, including surveillance of the current cancer and screening for second cancers. Similar to what is seen with diabetes and coronary artery disease, cancer increases cardiac risk, which requires preventive care and chronic management. FPs are well placed to treat common issues in cancer survivors—issues that mirror concerns seen in the general population.

CORRESPONDENCE
Michael J. Arnold, MD, CDR, USN, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; [email protected].

ACKNOWLEDGEMENT
Kristian Sanchack, MD, and James Higgins, DO, assisted with the editing of the manuscript.

SAN DIEGO – In patients with atrial fibrillation and stable coronary artery disease, a randomized trial of oral anticoagulation alone versus an anticoagulant plus a single antiplatelet agent failed to establish noninferiority of the single-agent approach. The trial could not demonstrate its primary endpoint of all-cause death, myocardial infarction, stroke, or systemic embolism.

But a secondary endpoint that included major bleeding did demonstrate equivalence, leading the researchers to suggest that oral anticoagulation (OAC) alone may be sufficient in most patients.

“Combined OAC and single antiplatelet therapy is unlikely to provide net clinical benefit over OAC alone. Thus, OAC alone might be reasonable for AF [atrial fibrillation] patients beyond 1 year after coronary stenting,” Yukiko Nakano, MD, of Kyoto (Japan) University Graduate School of Medicine, said during a press conference at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation. The report was simultaneously published Sept. 24 in Circulation (doi: 10.1161/CIRCULATIONAHA.118.036768).

Jim Kling/MDedge News

The study was stopped prematurely because of insufficient recruitment, which may have contributed to the failed primary endpoint. It’s a shortcoming that befalls many such studies, perhaps because cardiologists tend to be set in their ways when it comes to treatment of patients after a stent implant. “Cardiologists just think they know the answer, and they don’t want to expose their patients (to a clinical trial). They say, ‘I have my patients on whatever regimen. It seems to be working, and they’re not bleeding, so I don’t want to change it.’ This study suggests that we probably can stop one of the two (antiplatelet drugs) and get by with a single agent, and in this case they got by with no agent (in the monotherapy arm),” said C. Michael Gibson, MD, chief of clinical research in the division of cardiology at Beth Israel Deaconess Medical Center, Boston, who was a discussant at the press conference.

The study recruited 696 patients who were receiving OAC plus single antiplatelet therapy (SAPT) 1 year after receiving a stent. They were randomized 1:1 to continue combined therapy or to stop SAPT and then followed for a median of 2.5 years. A total of 74% of patients who received OAC alone were taking warfarin, while 26% were taking a direct oral anticoagulant. The SAPT group took aspirin or clopidogrel.

Overall, 15.7% of OAC patients experienced the primary endpoint, compared with 13.6% of the combined group (noninferiority P = .20). None of the individual components of the primary endpoint were statistically significantly different between the groups. International Society on Thrombosis and Haemostasis major bleeding and Thrombolysis in Myocardial Infarction major bleeding trended in favor of OAC alone. The secondary endpoint (primary endpoint plus major bleeding) achieved noninferiority, occurring in 19.5% of the OAC group and 19.4% of the combined therapy group (noninferiority P = .016; superiority P = .96).

Daiichi-Sankyo funded the trial. Dr. Nakano had no conflicts of interest. Dr. Gibson reported numerous financial ties to pharmaceutical companies, including Daiichi-Sankyo.

SAN DIEGO – In patients with atrial fibrillation and stable coronary artery disease, a randomized trial of oral anticoagulation alone versus an anticoagulant plus a single antiplatelet agent failed to establish noninferiority of the single-agent approach. The trial could not demonstrate its primary endpoint of all-cause death, myocardial infarction, stroke, or systemic embolism.

But a secondary endpoint that included major bleeding did demonstrate equivalence, leading the researchers to suggest that oral anticoagulation (OAC) alone may be sufficient in most patients.

“Combined OAC and single antiplatelet therapy is unlikely to provide net clinical benefit over OAC alone. Thus, OAC alone might be reasonable for AF [atrial fibrillation] patients beyond 1 year after coronary stenting,” Yukiko Nakano, MD, of Kyoto (Japan) University Graduate School of Medicine, said during a press conference at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation. The report was simultaneously published Sept. 24 in Circulation (doi: 10.1161/CIRCULATIONAHA.118.036768).

Jim Kling/MDedge News

The study was stopped prematurely because of insufficient recruitment, which may have contributed to the failed primary endpoint. It’s a shortcoming that befalls many such studies, perhaps because cardiologists tend to be set in their ways when it comes to treatment of patients after a stent implant. “Cardiologists just think they know the answer, and they don’t want to expose their patients (to a clinical trial). They say, ‘I have my patients on whatever regimen. It seems to be working, and they’re not bleeding, so I don’t want to change it.’ This study suggests that we probably can stop one of the two (antiplatelet drugs) and get by with a single agent, and in this case they got by with no agent (in the monotherapy arm),” said C. Michael Gibson, MD, chief of clinical research in the division of cardiology at Beth Israel Deaconess Medical Center, Boston, who was a discussant at the press conference.

The study recruited 696 patients who were receiving OAC plus single antiplatelet therapy (SAPT) 1 year after receiving a stent. They were randomized 1:1 to continue combined therapy or to stop SAPT and then followed for a median of 2.5 years. A total of 74% of patients who received OAC alone were taking warfarin, while 26% were taking a direct oral anticoagulant. The SAPT group took aspirin or clopidogrel.

Overall, 15.7% of OAC patients experienced the primary endpoint, compared with 13.6% of the combined group (noninferiority P = .20). None of the individual components of the primary endpoint were statistically significantly different between the groups. International Society on Thrombosis and Haemostasis major bleeding and Thrombolysis in Myocardial Infarction major bleeding trended in favor of OAC alone. The secondary endpoint (primary endpoint plus major bleeding) achieved noninferiority, occurring in 19.5% of the OAC group and 19.4% of the combined therapy group (noninferiority P = .016; superiority P = .96).

Daiichi-Sankyo funded the trial. Dr. Nakano had no conflicts of interest. Dr. Gibson reported numerous financial ties to pharmaceutical companies, including Daiichi-Sankyo.

SAN DIEGO – In patients with atrial fibrillation and stable coronary artery disease, a randomized trial of oral anticoagulation alone versus an anticoagulant plus a single antiplatelet agent failed to establish noninferiority of the single-agent approach. The trial could not demonstrate its primary endpoint of all-cause death, myocardial infarction, stroke, or systemic embolism.

But a secondary endpoint that included major bleeding did demonstrate equivalence, leading the researchers to suggest that oral anticoagulation (OAC) alone may be sufficient in most patients.

“Combined OAC and single antiplatelet therapy is unlikely to provide net clinical benefit over OAC alone. Thus, OAC alone might be reasonable for AF [atrial fibrillation] patients beyond 1 year after coronary stenting,” Yukiko Nakano, MD, of Kyoto (Japan) University Graduate School of Medicine, said during a press conference at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation. The report was simultaneously published Sept. 24 in Circulation (doi: 10.1161/CIRCULATIONAHA.118.036768).

Jim Kling/MDedge News

The study was stopped prematurely because of insufficient recruitment, which may have contributed to the failed primary endpoint. It’s a shortcoming that befalls many such studies, perhaps because cardiologists tend to be set in their ways when it comes to treatment of patients after a stent implant. “Cardiologists just think they know the answer, and they don’t want to expose their patients (to a clinical trial). They say, ‘I have my patients on whatever regimen. It seems to be working, and they’re not bleeding, so I don’t want to change it.’ This study suggests that we probably can stop one of the two (antiplatelet drugs) and get by with a single agent, and in this case they got by with no agent (in the monotherapy arm),” said C. Michael Gibson, MD, chief of clinical research in the division of cardiology at Beth Israel Deaconess Medical Center, Boston, who was a discussant at the press conference.

The study recruited 696 patients who were receiving OAC plus single antiplatelet therapy (SAPT) 1 year after receiving a stent. They were randomized 1:1 to continue combined therapy or to stop SAPT and then followed for a median of 2.5 years. A total of 74% of patients who received OAC alone were taking warfarin, while 26% were taking a direct oral anticoagulant. The SAPT group took aspirin or clopidogrel.

Overall, 15.7% of OAC patients experienced the primary endpoint, compared with 13.6% of the combined group (noninferiority P = .20). None of the individual components of the primary endpoint were statistically significantly different between the groups. International Society on Thrombosis and Haemostasis major bleeding and Thrombolysis in Myocardial Infarction major bleeding trended in favor of OAC alone. The secondary endpoint (primary endpoint plus major bleeding) achieved noninferiority, occurring in 19.5% of the OAC group and 19.4% of the combined therapy group (noninferiority P = .016; superiority P = .96).

Daiichi-Sankyo funded the trial. Dr. Nakano had no conflicts of interest. Dr. Gibson reported numerous financial ties to pharmaceutical companies, including Daiichi-Sankyo.

Synthetic cannabinoids laced with superwarfarin were behind a recent outbreak of severe coagulopathy in Illinois.

In most cases, vitamin K replacement therapy alleviated symptoms, but four patients died after developing intracranial bleeding, said Amar H. Kelkar, MD, of the University of Illinois at Peoria.

Experts continue to look for how and why superwarfarin ended up in synthetic cannabinoids, whose street names include spice and K2, wrote Dr. Kelkar and his associates. Their report is in the New England Journal of Medicine.

Starting in March 2018, more than 150 patients across Illinois presented to hospitals with bleeding diathesis that involved persistent coagulopathy, the investigators explained. Early inquiries revealed that patients had consumed synthetic cannabinoids. Serum tests identified vitamin K antagonists, including brodifacoum, bromadiolone, and difenacoum. During arrests of suspected distributors, police confiscated synthetic cannabinoids that also tested positive for brodifacoum.

To help characterize the outbreak, the investigators reviewed admissions to Saint Francis Medical Center in Peoria, Ill., between March 28 and April 21, 2018. They identified 34 cases in which patients with vitamin K–dependent factor coagulopathy reported recent exposure to synthetic cannabinoids.

Fifteen of these patients underwent confirmatory anticoagulant testing, which universally confirmed superwarfarin poisoning. Brodifacoum was detected in all patients, difenacoum in five patients, bromadiolone in two patients, and warfarin in one patient.

Common presenting symptoms included gross hematuria (56% of patients) and abdominal pain (47%). Computed tomography identified renal abnormalities in 12 patients.

All patients received oral vitamin K₁ (phytonadione). Red cell transfusions, fresh-frozen plasma infusions, and 4-factor prothrombin complex concentrate, or a combination of these treatments, were also used in some patients.

Among the four confirmed deaths in this outbreak, one occurred in a patient in this case series. The patient, a 37-year-old woman presenting to the emergency department with markedly reduced consciousness, was reported by her friends to have recently used synthetic cannabinoids and methamphetamine. She had no personal or family history of coagulopathy.

Computed tomography of the head without contrast material revealed severe acute intraparenchymal hemorrhage of the right basal nuclei and insula with intraventricular extension, a 10-mm left-sided midline shift, and herniation.

She met criteria for brain death 15 hours after hospital admission despite treatment with 10 mg of intravenous vitamin K₁, four units of fresh frozen plasma, and 2,300 units of Kcentra.

Treating these patients after hospital discharge was difficult because of a lack of consensus guidelines and access to follow-up care, Dr. Kelkar and his associates noted. Some patients were quoted $24,000 to $34,000 per month for oral vitamin K1 therapy, which also made caring for them difficult and highlighted the need for confirmatory laboratory testing of suspected cases of superwarfarin poisoning.

Dr. Kelkar reported having no conflicts of interest. Two coinvestigators reported relationships outside the submitted work with Shire, CSL Behring, HEMA Biologics, and other companies.

SOURCE: Kelkar AH et al. N Engl J Med. 2018;379:1216-23.

Synthetic cannabinoids laced with superwarfarin were behind a recent outbreak of severe coagulopathy in Illinois.

In most cases, vitamin K replacement therapy alleviated symptoms, but four patients died after developing intracranial bleeding, said Amar H. Kelkar, MD, of the University of Illinois at Peoria.

Experts continue to look for how and why superwarfarin ended up in synthetic cannabinoids, whose street names include spice and K2, wrote Dr. Kelkar and his associates. Their report is in the New England Journal of Medicine.

Starting in March 2018, more than 150 patients across Illinois presented to hospitals with bleeding diathesis that involved persistent coagulopathy, the investigators explained. Early inquiries revealed that patients had consumed synthetic cannabinoids. Serum tests identified vitamin K antagonists, including brodifacoum, bromadiolone, and difenacoum. During arrests of suspected distributors, police confiscated synthetic cannabinoids that also tested positive for brodifacoum.

To help characterize the outbreak, the investigators reviewed admissions to Saint Francis Medical Center in Peoria, Ill., between March 28 and April 21, 2018. They identified 34 cases in which patients with vitamin K–dependent factor coagulopathy reported recent exposure to synthetic cannabinoids.

Fifteen of these patients underwent confirmatory anticoagulant testing, which universally confirmed superwarfarin poisoning. Brodifacoum was detected in all patients, difenacoum in five patients, bromadiolone in two patients, and warfarin in one patient.

Common presenting symptoms included gross hematuria (56% of patients) and abdominal pain (47%). Computed tomography identified renal abnormalities in 12 patients.

All patients received oral vitamin K₁ (phytonadione). Red cell transfusions, fresh-frozen plasma infusions, and 4-factor prothrombin complex concentrate, or a combination of these treatments, were also used in some patients.

Among the four confirmed deaths in this outbreak, one occurred in a patient in this case series. The patient, a 37-year-old woman presenting to the emergency department with markedly reduced consciousness, was reported by her friends to have recently used synthetic cannabinoids and methamphetamine. She had no personal or family history of coagulopathy.

Computed tomography of the head without contrast material revealed severe acute intraparenchymal hemorrhage of the right basal nuclei and insula with intraventricular extension, a 10-mm left-sided midline shift, and herniation.

She met criteria for brain death 15 hours after hospital admission despite treatment with 10 mg of intravenous vitamin K₁, four units of fresh frozen plasma, and 2,300 units of Kcentra.

Treating these patients after hospital discharge was difficult because of a lack of consensus guidelines and access to follow-up care, Dr. Kelkar and his associates noted. Some patients were quoted $24,000 to $34,000 per month for oral vitamin K1 therapy, which also made caring for them difficult and highlighted the need for confirmatory laboratory testing of suspected cases of superwarfarin poisoning.

Dr. Kelkar reported having no conflicts of interest. Two coinvestigators reported relationships outside the submitted work with Shire, CSL Behring, HEMA Biologics, and other companies.

SOURCE: Kelkar AH et al. N Engl J Med. 2018;379:1216-23.

Synthetic cannabinoids laced with superwarfarin were behind a recent outbreak of severe coagulopathy in Illinois.

In most cases, vitamin K replacement therapy alleviated symptoms, but four patients died after developing intracranial bleeding, said Amar H. Kelkar, MD, of the University of Illinois at Peoria.

Experts continue to look for how and why superwarfarin ended up in synthetic cannabinoids, whose street names include spice and K2, wrote Dr. Kelkar and his associates. Their report is in the New England Journal of Medicine.

Starting in March 2018, more than 150 patients across Illinois presented to hospitals with bleeding diathesis that involved persistent coagulopathy, the investigators explained. Early inquiries revealed that patients had consumed synthetic cannabinoids. Serum tests identified vitamin K antagonists, including brodifacoum, bromadiolone, and difenacoum. During arrests of suspected distributors, police confiscated synthetic cannabinoids that also tested positive for brodifacoum.

To help characterize the outbreak, the investigators reviewed admissions to Saint Francis Medical Center in Peoria, Ill., between March 28 and April 21, 2018. They identified 34 cases in which patients with vitamin K–dependent factor coagulopathy reported recent exposure to synthetic cannabinoids.

Fifteen of these patients underwent confirmatory anticoagulant testing, which universally confirmed superwarfarin poisoning. Brodifacoum was detected in all patients, difenacoum in five patients, bromadiolone in two patients, and warfarin in one patient.

Common presenting symptoms included gross hematuria (56% of patients) and abdominal pain (47%). Computed tomography identified renal abnormalities in 12 patients.

All patients received oral vitamin K₁ (phytonadione). Red cell transfusions, fresh-frozen plasma infusions, and 4-factor prothrombin complex concentrate, or a combination of these treatments, were also used in some patients.

Among the four confirmed deaths in this outbreak, one occurred in a patient in this case series. The patient, a 37-year-old woman presenting to the emergency department with markedly reduced consciousness, was reported by her friends to have recently used synthetic cannabinoids and methamphetamine. She had no personal or family history of coagulopathy.

Computed tomography of the head without contrast material revealed severe acute intraparenchymal hemorrhage of the right basal nuclei and insula with intraventricular extension, a 10-mm left-sided midline shift, and herniation.

She met criteria for brain death 15 hours after hospital admission despite treatment with 10 mg of intravenous vitamin K₁, four units of fresh frozen plasma, and 2,300 units of Kcentra.

Treating these patients after hospital discharge was difficult because of a lack of consensus guidelines and access to follow-up care, Dr. Kelkar and his associates noted. Some patients were quoted $24,000 to $34,000 per month for oral vitamin K1 therapy, which also made caring for them difficult and highlighted the need for confirmatory laboratory testing of suspected cases of superwarfarin poisoning.

Dr. Kelkar reported having no conflicts of interest. Two coinvestigators reported relationships outside the submitted work with Shire, CSL Behring, HEMA Biologics, and other companies.

SOURCE: Kelkar AH et al. N Engl J Med. 2018;379:1216-23.

From the Columbia University Medical Center, New York, NY (Dr. Falchi), and the University of Texas MD Anderson Cancer Center, Houston, TX (Dr. Verstovsek).

ABSTRACT

• Objective: To review the clinical aspects and current practices in the management of polycythemia vera (PV) and essential thrombocythemia (ET).
• Methods: Review of the literature.
• Results: PV and ET are rare chronic myeloid disorders. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/acute myeloid leukemia (AML) transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, interferons, or anagrelide (for patients with ET). Ruxolitinib was recently approved for PV after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment of leukemic transformation of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis and AML.
• Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near-normal quality of life. Transformation into myelofibrosis or AML cannot be prevented by current therapies, however. Treatment results with MPN LT are generally poor and novel strategies are needed to improve outcomes.

Key words: myeloproliferative neoplasms; myelofibrosis; leukemic transformation.

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes [1,2]. Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML) [3]. Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other symptoms associated with the disease [4]. No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF) [5,6] has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8].

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life [9]. Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention [13]. The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females [14]. Given the long course and low mortality associated with these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17].

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF [5,6,18,19]. JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway [5,6,18,19]. More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12 [20–22]. The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor [23–25], or the calreticulin (CALR) gene [26,27], which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis [28]. Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN. These are not exclusive of each other (ie, patients may have many at the same time) and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others [29]. The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification [30] are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors [30]. Clinically, both PV and ET generally remain asymptomatic for a long time. PV tends to be more symptomatic than ET and can present with debilitating constitutional symptoms (fatigue, night sweats, and weight loss), microvascular symptoms (headache, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, and pruritus) [31], or macrovascular accidents (larger vein thrombosis, stroke, or myocardial ischemia) [32]. ET is often diagnosed incidentally, but patients can suffer from similar general symptoms and vascular complications. Causes of secondary absolute erythrocytosis (altitude, chronic hypoxemia, heavy smoking, cardiomyopathy, use of corticosteroids, erythropoietin, or other anabolic hormones, familial or congenital forms) or thrombocytosis (iron deficiency, acute blood loss, trauma or injury, acute coronary syndrome, systemic autoimmune disorders, chronic kidney failure, other malignancies, splenectomy) should be considered and appropriately excluded. Once the diagnosis is made, symptom assessment tools such as the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [33] or the abbreviated version, the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], are generally used to assess patients’ symptom burden and response to treatment in everyday practice.

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation (LT) are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group [35] and the presence of other factors (see below).

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present, the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk [36]. In addition, high hematocrit [37] and high white blood cell (WBC) count [38], but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis [39]. Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal [40].

Traditionally, in ET patients, the thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event) [41,42]. Many [41,43–46], but not all [47–51], studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk [52]. Moreover, the impact of the JAK2 mutation on vascular events persists over time [53], particularly in patients with high or unstable mutation burden [54]. Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below) [55].

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events [56–59], as can splenomegaly [60] and baseline or persistent leukocytosis [61–63]. Thrombocytosis has been correlated with thrombotic risk in some studies [64–68], whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/μL (due to acquired von Willebrand syndrome) [51,61,63,68,69].

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance, as compared to JAK2 mutations [26,27,70–72]. The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations [73]. The presence of the mutation per se does not appear to affect the thrombotic risk [74–76]. Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation [73,77–79].

Venous thromboembolism (VTE) in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems [80]. Risk factors for unusual VTE include younger age [81], female gender (especially with concomitant use of oral contraceptive pills) [82], and splenomegaly/splenectomy [83]. JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic VTE has varied [80]. In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients [84]. Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic VTE. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic VTE is not recommended, as its prevalence in this group is low (< 3%) [85,86].

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms [55,87]. Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin [88]. Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In that study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis [38].

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Frontline cytoreductive therapies include hydroxyurea or interferon (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV [90]. In a small trial, hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone [91]. Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone [92], respectively, although an independent role for hydroxyurea in LT was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [93]. Approximately 70% of patients will have a sustained response to hydroxyurea [94], while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death [95].

IFN-alfa is a pleiotropic antitumor agent that has found application in many types of malignancies [96] and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases [97,98], albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations [99]. A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN-alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability [100]. Pilot phase 2 trials of PEG-IFN-alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in most patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of 20% to 30% [101–103]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN-alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN-alfa in the management of patients with high-risk PV or ET. In two phase 2 studies of PEG-IFN-alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases [105,106]. A new, longer-acting formulation of PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is also undergoing clinical development [107,108].

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.

Very Low- and Low-Risk ET

Individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model [55,87]. The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 10³/μL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA) [109]. Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.

Intermediate-Risk ET

This category includes patients older than 60 years, but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.

High-Risk ET

For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in most patients [110]. In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 10³/μL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs [64].

Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (n = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events [111]. As a result of this study, hydroxyurea is often preferred to anagrelide as frontline therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (n = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate [112]. The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET and the former utilizing Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.

Interferons were studied in ET in parallel with PV. PEG-IFN-alfa-2a proved effective in patients with ET, with responses observed in 80% of patients [103]. PEG-IFN- alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases [105,106,113]. Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk [114]. Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3) [94].

Approach to Patients Refractory to or Intolerant of First-line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain the hematocrit below < 45%, the platelet count > 400 × 10³/μL, and a WBC count > 10,000/μL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of LT [93,115,116]. IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea [7]. Following promising results of a phase 2 trial [117], ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (n = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms [118]. In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of these studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population [120]. Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting [121,122]. Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat [123].

Disease Evolution

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4. Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries [124]. The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In patients with PV, risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 10³/μL, and WBC count > 30,000/μL are associated with worse outcomes [125]. In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. The management of post-PV/post-ET myelofibrosis recapitulates that of PMF.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines LT. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase [126]. In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of LT has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 DNMT3, IDH1/2, and TP53 [127].

Clinical risk factors for LT include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, IFN, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of LT is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for MPN LT. Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others [128]. Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is applicable only to a minority of patients with chemosensitive disease and good performance status [130]. Notable experimental approaches to MPN LT include hypomethylating agents, such as decitabine [131] or azacytidine [132], with or without ruxolitinib [133–135].

PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve outcomes.

Corresponding author: Lorenzo Falchi, MD, Columbia University Medical Center, New York, NY.

Financial disclosures: None.

From the Columbia University Medical Center, New York, NY (Dr. Falchi), and the University of Texas MD Anderson Cancer Center, Houston, TX (Dr. Verstovsek).

ABSTRACT

• Objective: To review the clinical aspects and current practices in the management of polycythemia vera (PV) and essential thrombocythemia (ET).
• Methods: Review of the literature.
• Results: PV and ET are rare chronic myeloid disorders. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/acute myeloid leukemia (AML) transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, interferons, or anagrelide (for patients with ET). Ruxolitinib was recently approved for PV after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment of leukemic transformation of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis and AML.
• Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near-normal quality of life. Transformation into myelofibrosis or AML cannot be prevented by current therapies, however. Treatment results with MPN LT are generally poor and novel strategies are needed to improve outcomes.

Key words: myeloproliferative neoplasms; myelofibrosis; leukemic transformation.

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes [1,2]. Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML) [3]. Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other symptoms associated with the disease [4]. No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF) [5,6] has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8].

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life [9]. Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention [13]. The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females [14]. Given the long course and low mortality associated with these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17].

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF [5,6,18,19]. JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway [5,6,18,19]. More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12 [20–22]. The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor [23–25], or the calreticulin (CALR) gene [26,27], which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis [28]. Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN. These are not exclusive of each other (ie, patients may have many at the same time) and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others [29]. The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification [30] are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors [30]. Clinically, both PV and ET generally remain asymptomatic for a long time. PV tends to be more symptomatic than ET and can present with debilitating constitutional symptoms (fatigue, night sweats, and weight loss), microvascular symptoms (headache, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, and pruritus) [31], or macrovascular accidents (larger vein thrombosis, stroke, or myocardial ischemia) [32]. ET is often diagnosed incidentally, but patients can suffer from similar general symptoms and vascular complications. Causes of secondary absolute erythrocytosis (altitude, chronic hypoxemia, heavy smoking, cardiomyopathy, use of corticosteroids, erythropoietin, or other anabolic hormones, familial or congenital forms) or thrombocytosis (iron deficiency, acute blood loss, trauma or injury, acute coronary syndrome, systemic autoimmune disorders, chronic kidney failure, other malignancies, splenectomy) should be considered and appropriately excluded. Once the diagnosis is made, symptom assessment tools such as the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [33] or the abbreviated version, the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], are generally used to assess patients’ symptom burden and response to treatment in everyday practice.

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation (LT) are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group [35] and the presence of other factors (see below).

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present, the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk [36]. In addition, high hematocrit [37] and high white blood cell (WBC) count [38], but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis [39]. Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal [40].

Traditionally, in ET patients, the thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event) [41,42]. Many [41,43–46], but not all [47–51], studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk [52]. Moreover, the impact of the JAK2 mutation on vascular events persists over time [53], particularly in patients with high or unstable mutation burden [54]. Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below) [55].

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events [56–59], as can splenomegaly [60] and baseline or persistent leukocytosis [61–63]. Thrombocytosis has been correlated with thrombotic risk in some studies [64–68], whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/μL (due to acquired von Willebrand syndrome) [51,61,63,68,69].

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance, as compared to JAK2 mutations [26,27,70–72]. The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations [73]. The presence of the mutation per se does not appear to affect the thrombotic risk [74–76]. Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation [73,77–79].

Venous thromboembolism (VTE) in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems [80]. Risk factors for unusual VTE include younger age [81], female gender (especially with concomitant use of oral contraceptive pills) [82], and splenomegaly/splenectomy [83]. JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic VTE has varied [80]. In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients [84]. Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic VTE. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic VTE is not recommended, as its prevalence in this group is low (< 3%) [85,86].

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms [55,87]. Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin [88]. Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In that study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis [38].

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Frontline cytoreductive therapies include hydroxyurea or interferon (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV [90]. In a small trial, hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone [91]. Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone [92], respectively, although an independent role for hydroxyurea in LT was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [93]. Approximately 70% of patients will have a sustained response to hydroxyurea [94], while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death [95].

IFN-alfa is a pleiotropic antitumor agent that has found application in many types of malignancies [96] and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases [97,98], albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations [99]. A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN-alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability [100]. Pilot phase 2 trials of PEG-IFN-alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in most patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of 20% to 30% [101–103]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN-alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN-alfa in the management of patients with high-risk PV or ET. In two phase 2 studies of PEG-IFN-alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases [105,106]. A new, longer-acting formulation of PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is also undergoing clinical development [107,108].

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.

Very Low- and Low-Risk ET

Individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model [55,87]. The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 10³/μL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA) [109]. Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.

Intermediate-Risk ET

This category includes patients older than 60 years, but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.

High-Risk ET

For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in most patients [110]. In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 10³/μL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs [64].

Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (n = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events [111]. As a result of this study, hydroxyurea is often preferred to anagrelide as frontline therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (n = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate [112]. The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET and the former utilizing Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.

Interferons were studied in ET in parallel with PV. PEG-IFN-alfa-2a proved effective in patients with ET, with responses observed in 80% of patients [103]. PEG-IFN- alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases [105,106,113]. Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk [114]. Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3) [94].

Approach to Patients Refractory to or Intolerant of First-line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain the hematocrit below < 45%, the platelet count > 400 × 10³/μL, and a WBC count > 10,000/μL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of LT [93,115,116]. IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea [7]. Following promising results of a phase 2 trial [117], ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (n = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms [118]. In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of these studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population [120]. Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting [121,122]. Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat [123].

Disease Evolution

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4. Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries [124]. The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In patients with PV, risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 10³/μL, and WBC count > 30,000/μL are associated with worse outcomes [125]. In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. The management of post-PV/post-ET myelofibrosis recapitulates that of PMF.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines LT. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase [126]. In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of LT has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 DNMT3, IDH1/2, and TP53 [127].

Clinical risk factors for LT include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, IFN, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of LT is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for MPN LT. Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others [128]. Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is applicable only to a minority of patients with chemosensitive disease and good performance status [130]. Notable experimental approaches to MPN LT include hypomethylating agents, such as decitabine [131] or azacytidine [132], with or without ruxolitinib [133–135].

PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve outcomes.

Corresponding author: Lorenzo Falchi, MD, Columbia University Medical Center, New York, NY.

Financial disclosures: None.

From the Columbia University Medical Center, New York, NY (Dr. Falchi), and the University of Texas MD Anderson Cancer Center, Houston, TX (Dr. Verstovsek).

ABSTRACT

• Objective: To review the clinical aspects and current practices in the management of polycythemia vera (PV) and essential thrombocythemia (ET).
• Methods: Review of the literature.
• Results: PV and ET are rare chronic myeloid disorders. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/acute myeloid leukemia (AML) transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, interferons, or anagrelide (for patients with ET). Ruxolitinib was recently approved for PV after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment of leukemic transformation of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis and AML.
• Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near-normal quality of life. Transformation into myelofibrosis or AML cannot be prevented by current therapies, however. Treatment results with MPN LT are generally poor and novel strategies are needed to improve outcomes.

Key words: myeloproliferative neoplasms; myelofibrosis; leukemic transformation.

Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes [1,2]. Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML) [3]. Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other symptoms associated with the disease [4]. No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF) [5,6] has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8].

Epidemiology

PV and ET are typically diagnosed in the fifth to seventh decade of life [9]. Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention [13]. The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females [14]. Given the long course and low mortality associated with these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17].

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF [5,6,18,19]. JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway [5,6,18,19]. More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12 [20–22]. The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor [23–25], or the calreticulin (CALR) gene [26,27], which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis [28]. Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN. These are not exclusive of each other (ie, patients may have many at the same time) and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others [29]. The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification [30] are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors [30]. Clinically, both PV and ET generally remain asymptomatic for a long time. PV tends to be more symptomatic than ET and can present with debilitating constitutional symptoms (fatigue, night sweats, and weight loss), microvascular symptoms (headache, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, and pruritus) [31], or macrovascular accidents (larger vein thrombosis, stroke, or myocardial ischemia) [32]. ET is often diagnosed incidentally, but patients can suffer from similar general symptoms and vascular complications. Causes of secondary absolute erythrocytosis (altitude, chronic hypoxemia, heavy smoking, cardiomyopathy, use of corticosteroids, erythropoietin, or other anabolic hormones, familial or congenital forms) or thrombocytosis (iron deficiency, acute blood loss, trauma or injury, acute coronary syndrome, systemic autoimmune disorders, chronic kidney failure, other malignancies, splenectomy) should be considered and appropriately excluded. Once the diagnosis is made, symptom assessment tools such as the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [33] or the abbreviated version, the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], are generally used to assess patients’ symptom burden and response to treatment in everyday practice.

Risk Stratification

Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation (LT) are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group [35] and the presence of other factors (see below).

The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present, the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk [36]. In addition, high hematocrit [37] and high white blood cell (WBC) count [38], but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis [39]. Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal [40].

Traditionally, in ET patients, the thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event) [41,42]. Many [41,43–46], but not all [47–51], studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk [52]. Moreover, the impact of the JAK2 mutation on vascular events persists over time [53], particularly in patients with high or unstable mutation burden [54]. Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below) [55].

Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events [56–59], as can splenomegaly [60] and baseline or persistent leukocytosis [61–63]. Thrombocytosis has been correlated with thrombotic risk in some studies [64–68], whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 10³/μL (due to acquired von Willebrand syndrome) [51,61,63,68,69].

CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance, as compared to JAK2 mutations [26,27,70–72]. The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations [73]. The presence of the mutation per se does not appear to affect the thrombotic risk [74–76]. Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation [73,77–79].

Venous thromboembolism (VTE) in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems [80]. Risk factors for unusual VTE include younger age [81], female gender (especially with concomitant use of oral contraceptive pills) [82], and splenomegaly/splenectomy [83]. JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic VTE has varied [80]. In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients [84]. Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic VTE. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic VTE is not recommended, as its prevalence in this group is low (< 3%) [85,86].

Risk-Adapted Therapy

Low-Risk PV

All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms [55,87]. Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin [88]. Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In that study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis [38].

High-Risk PV

Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Frontline cytoreductive therapies include hydroxyurea or interferon (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV [90]. In a small trial, hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone [91]. Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone [92], respectively, although an independent role for hydroxyurea in LT was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [93]. Approximately 70% of patients will have a sustained response to hydroxyurea [94], while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death [95].

IFN-alfa is a pleiotropic antitumor agent that has found application in many types of malignancies [96] and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases [97,98], albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations [99]. A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN-alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability [100]. Pilot phase 2 trials of PEG-IFN-alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in most patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of 20% to 30% [101–103]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN-alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN-alfa in the management of patients with high-risk PV or ET. In two phase 2 studies of PEG-IFN-alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases [105,106]. A new, longer-acting formulation of PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is also undergoing clinical development [107,108].

The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.

Very Low- and Low-Risk ET

Individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model [55,87]. The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 10³/μL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA) [109]. Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.

Intermediate-Risk ET

This category includes patients older than 60 years, but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.

High-Risk ET

For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in most patients [110]. In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 10³/μL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs [64].

Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (n = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events [111]. As a result of this study, hydroxyurea is often preferred to anagrelide as frontline therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (n = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate [112]. The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET and the former utilizing Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.

Interferons were studied in ET in parallel with PV. PEG-IFN-alfa-2a proved effective in patients with ET, with responses observed in 80% of patients [103]. PEG-IFN- alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases [105,106,113]. Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.

The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.

Assessing Response to Therapy

For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk [114]. Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3) [94].

Approach to Patients Refractory to or Intolerant of First-line Therapy

According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain the hematocrit below < 45%, the platelet count > 400 × 10³/μL, and a WBC count > 10,000/μL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of LT [93,115,116]. IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.

Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea [7]. Following promising results of a phase 2 trial [117], ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (n = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms [118]. In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of these studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population [120]. Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting [121,122]. Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.

Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat [123].

Disease Evolution

Post-PV/Post-ET Myelofibrosis

Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4. Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries [124]. The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In patients with PV, risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 10³/μL, and WBC count > 30,000/μL are associated with worse outcomes [125]. In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. The management of post-PV/post-ET myelofibrosis recapitulates that of PMF.

Leukemic Transformation

The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines LT. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase [126]. In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of LT has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 DNMT3, IDH1/2, and TP53 [127].

Clinical risk factors for LT include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, IFN, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of LT is uniformly poor and patient survival rarely exceeds 6 months.

There is no standard of care for MPN LT. Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others [128]. Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is applicable only to a minority of patients with chemosensitive disease and good performance status [130]. Notable experimental approaches to MPN LT include hypomethylating agents, such as decitabine [131] or azacytidine [132], with or without ruxolitinib [133–135].

PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve outcomes.

Corresponding author: Lorenzo Falchi, MD, Columbia University Medical Center, New York, NY.

Financial disclosures: None.

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Xavier_S/Thinkstock

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.

Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Xavier_S/Thinkstock

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.

Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Xavier_S/Thinkstock

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.

Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.

Study Overview

Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.

Design. International randomized phase 3 trial.

Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.

Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.

Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.

Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.

Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).

Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.

Commentary

Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].

In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.

Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.

Applications for Clinical Practice

The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.

Design. International randomized phase 3 trial.

Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.

Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.

Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.

Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.

Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).

Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.

Commentary

Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].

In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.

Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.

Applications for Clinical Practice

The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.

Design. International randomized phase 3 trial.

Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.

Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.

Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.

Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.

Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).

Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.

Commentary

Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].

In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.

Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.

Applications for Clinical Practice

The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.

—Daniel Isaac, DO, MS