INTRODUCTION

Sickle cell disease is the most common inherited blood disorder in the world. It affects more than 100,000 individuals in the United States, and millions more worldwide.¹ Sickle cell disease is most commonly found in individuals of African heritage, but the disease also occurs in Hispanics and people of Middle Eastern and subcontinent Indian heritage.² The distribution of the sickle hemoglobin (hemoglobin S [HbS]) allele overlaps with the distribution of malaria; HbS carriers, or individuals with sickle cell trait, have protection against malaria,³ and are not considered to have sickle cell disease.

Sickle cell disease is a severe monogenic disorder marked by significant morbidity and mortality, affecting every organ in the body.⁴ The term sickle cell disease refers to all genotypes that cause sickling; the most common are the homozygous hemoglobin SS (HbSS) and compound heterozygotes hemoglobin SC (HbSC), hemoglobin S–β⁰-thalassemia (HbSβ⁰), and hemoglobin S–β⁺-thalassemia (HbSβ⁺), although HbS and several rarer hemoglobin variants such as HbSO(Arab) and HbSD(Punjab) can also cause sickle cell disease. The term sickle cell anemia refers exclusively to the most severe genotypes, HbSS and HbSβ⁰.⁵ Common sickling genotypes along with their relative clinical severity are shown in Table 1.^6–11

This article reviews the pathophysiology of sickle cell disease, common clinical complications, and available therapies. A complex case which illustrates diagnostic and management challenges is presented as well.

PATHOPHYSIOLOGY

HbS is the result of a substitution of valine for glutamic acid in the sixth amino acid of the β-globin chain.¹² The change from a hydrophilic to a hydrophobic amino acid causes the hemoglobin molecules to stack, or polymerize, when deoxygenated. This rigid rod of hemoglobin distorts the cell, producing the characteristic crescent or sickle shape that gives the disease its name.¹³ Polymerization of hemoglobin within the cell is promoted by dehydration, which increases the concentration of HbS.^13,14 Polymerization occurs when hemoglobin is in the deoxygenated state.¹³

The sickle red blood cell is abnormal; it is rigid and dense, and lacks the deformability needed to navigate the microvasculature.¹⁵ Blockages of blood flow result in painful vaso-occlusion that is the hallmark of the disease, and that also can cause damage to the spleen, kidneys, and liver.¹⁶ The sickle red cell is also fragile, with a lifespan of only 20 days compared to the 120-day lifespan of a normal red blood cell.¹³ Frequent hemolysis results in anemia and the release of free hemoglobin, which both scavenges nitric oxide and impairs the production of more nitric oxide, which is essential for vasodilatation.¹⁷ This contributes to vascular dysfunction and an increased risk for stroke.¹⁸ If untreated, the natural course of sickle cell anemia is mortality in early childhood in most cases.¹⁹ Common chronic and acute sickle cell disease–related complications and recommended therapies, based on 2014 National Institutes of Health guidelines, are shown in Table 2 and Table 3.²⁰

One of the most challenging aspects of sickle cell disease is its clinical variability. While in general, HbSS and HbSβ⁰ are the most severe genotypes, there are patients with HbSC and HbSb⁺ who have significant sickle-cell–related complications, and may have a more severe clinical course than a HbSS patient.²¹ A great deal of this clinical variability cannot be explained, but some can be attributed to endogenous fetal hemoglobin (HbF) levels.^22–24 The importance of HbF levels in sickle cell disease was first noted by a pediatrician in the 1940s.²⁵ She observed that sickle cell disease complications in children under the age of 1 were rare, and attributed it to the presence of HbF.²⁵ HbF levels decline more slowly in individuals with hemoglobinopathies, reaching their nadir after the age of 5 rather than within 6 months of birth in individuals without hemoglobinopathies.²⁶ HbF levels remain elevated lifelong in most sickle cell disease patients, especially those with the HbSS and HbSβ⁰ genotypes. Levels of HbF vary widely between individuals, from zero to 20% to 30%, with a median of 10%.^26–28 Individuals who produce more HbF have a milder course, in general.²⁴ An association between the 4 β-globin haplotypes and HbF levels has been reported in the past,^27,29 but more sophisticated next-generation sequencing has revealed causal variants in BCL11A and HBS1L-MYB that contribute approximately 50% of the observed variability in HbF levels.^30–33

Co-inheritance of α-thalassemia also modifies disease course; less available α-globin chains results in a lower hemoglobin concentration within the cell. Paradoxically, this results in a higher overall hemoglobin level, as there is a reduction in polymerization, and therefore sickling due to lower HbS concentrations in the cell. Patients therefore are less anemic, reducing the risk of stroke in childhood,^34,35 but blood viscosity may be higher, resulting in more frequent pain crises and increased risk³⁶ of avascular necrosis.^34,35,37 It is often helpful to think of sickle cell patients as falling into 1 of 2 groups: high hemolysis/low hemoglobin and high viscosity/high hemoglobin. Individuals with high rates of hemolysis are at greater risk for stroke, pulmonary hypertension, and acute chest syndrome (ACS). Higher rates of hemolysis result in higher levels of free hemoglobin, which scavenges nitric oxide. This leads to the vascular damage and dysfunction that contributes to the associated clinical complications. This phenotype is most commonly seen in HbSS and HbSβ⁰.³⁸ High hemoglobin/high viscosity phenotypes are most often found in HbSC patients and in sickle cell anemia with α-thalassemia coinheritance.^39–42

TREATMENT OPTIONS

In high-resource countries with newborn screening, the initiation of penicillin prophylaxis has dramatically altered the natural history of the disease, allowing the majority of patients to reach adulthood.⁴³ Penicillin prophylaxis is usually discontinued at age 5 years; however, individuals who have undergone surgical splenectomy or have had pneumococcal sepsis on penicillin prophylaxis may remain on penicillin to age 18 or beyond.²⁰

Another advance in sickle cell care is screening for stroke risk through transcranial Doppler ultrasound (TCD).^44–47 This screening tool has reduced the incidence of childhood stroke from 10% by age 11 to 1%. TCDs typically cannot be performed after the age of 16 due to changes in the skull. Individuals found to have abnormal (elevated) TCD velocities are placed on chronic transfusion therapy for primary stroke prevention. They may remain on monthly chronic transfusions, with the goal of suppressing the percentage of HbS to 30% to 50% indefinitely. A clinical trial (STOPII) designed to determine if pediatric sickle cell disease patients on chronic transfusion therapy for primary stroke prevention could be safely taken off transfusion therapy was discontinued early due to an excess of strokes and conversion to abnormal TCD velocities in the untransfused arm.⁴⁴ Individuals who have experienced an ischemic stroke have a 70% risk of another stroke, and must remain on chronic transfusion therapy indefinitely. Chronic transfusion reduces their stroke risk to 13%.

The only widely used pharmacologic therapy for sickle cell disease is hydroxyurea.^12,48–50 A significant portion of the benefit of hydroxyurea stems from its induction of HbF.⁵¹ HbF does not sickle, and it interrupts the polymerization of HbS in the cell, if present in high enough concentrations.⁵⁰ The level of HbF needed to achieve clinical improvement is not known, but in vitro assays suggest 20% HbF is needed to prevent sickling.^52,53 However, endogenous and hydroxyurea-induced HbF is not distributed evenly through the red cells, so sickling is possible regardless of the level of HbF induced.^54,55 Hydroxyurea likely has other disease-modifying effects as well, including reduction of white blood cell count and reticulocyte count and reduction of red cell adhesion to the endothelium.^56–58 Clinical criteria for initiation of hydroxyurea in adult sickle cell disease patients are shown in Table 4.²⁰ Hydroxyurea is given daily and is dosed to maximum tolerated dose for the individual by following the absolute neutrophil count (ANC). The goal ANC is between 2000 and 4000/µL. At times, absolute reticulocyte count (ARC) can be dose-limiting; goal ARC is greater than 70,000/µL.⁵⁹ Platelet counts may be reduced as well, especially in HbSC patients.^60,61

The only curative therapy for sickle cell disease is hematopoietic stem cell transplant.⁶² Transplant use is limited by availability of matched sibling donors,⁶² and even at experienced centers transplant carries a small risk for mortality, graft rejection, and graft-versus-host disease. Furthermore, consensus on disease complications for which transplant is recommended is also lacking.^63–65 Clinical trials of gene therapy for sickle cell disease and thalassemia are ongoing.⁶⁶

COMPLICATIONS AND DISEASE-SPECIFIC THERAPIES

CASE PRESENTATION

A 26-year-old African-American man who works as a school bus driver presents to an academic center’s emergency department complaining of pain in his left leg, similar to prior pain events. He is described as having sickle cell trait, although no hemoglobin profile is available in his chart. He describes the pain as dull and aching, 10/10 in intensity. A complete blood count (CBC) is obtained; it reveals a hemoglobin of 14.5 g/dL, white blood cell (WBC) count of 5600/µL, and platelet count of 344,000/µL. His CBC is also notable for a mean corpuscular volume (MCV) of 72 fL, a mean corpuscular hemoglobin concentration (MCHC) of 37 g/dL, and a red blood cell distribution width (RDW) of 12. Slide review of a peripheral blood smear shows 2+ target cells (Figure).

The patient is given 6 mg of morphine, which provides some relief of his pain, and is discharged with a prescription for hydrocodone bitartrate/acetaminophen 5/325 mg. The diagnosis given is musculoskeletal pain, and he is instructed to follow-up with a primary care physician. His past medical history is significant for 4 or 5 visits to the emergency department per year in the past 4 years. Prior to 4 years ago, he rarely required medical attention.

• What laboratory and clinical features might lead you to question the diagnosis of sickle cell trait in this patient?

The patient’s hemoglobin is within normal range, which is consistent with sickle cell trait; however, he is microcytic, with a normal RDW. It is possible to be mildly microcytic in the early stages of iron deficiency, prior to the development of anemia, but the RDW would typically be elevated, demonstrating the presence of newer, smaller cells produced under conditions of iron deficiency.⁶⁷ It is also possible that his microcytosis with a normal RDW could represent sickle cell trait with co-inheritance of β-thalassemia. Up to 30% of African Americans have β-thalassemia,² and 1 in 10 have sickle cell trait.⁶⁸ However, a high MCHC, indicating the presence of dense cells, and target cells noted on slide review are most consistent with HbSC.⁹ HbSC patients, especially males, can have hemoglobin levels in the normal range.⁴ The biggest inconsistency with the diagnosis of sickle cell trait is his history of frequent pain events. Individuals with sickle cell trait rarely present with pain crises, except under extreme conditions of dehydration or high altitude.⁶⁸ Sickle cell trait is generally regarded as a benign condition, although a study of U.S. military recruits found a 30-fold higher risk of sudden death during basic training in persons with sickle cell trait.⁶⁹ Additional sickle cell trait–related complications include hematuria, risk of splenic sequestration or infarct under extreme conditions and high altitude, and a rare and usually fatal renal malignancy, renal medullary carcinoma, which is vanishingly rare in individuals without sickle cell trait.^70,71 Although the patient reported having sickle cell trait, this diagnosis should have been verified with a hemoglobin panel, given his atypical presentation.²⁰

In sickle cell disease, vaso-occlusive pain events can be common, often beginning in early childhood.¹⁷ This disease complication accounts for 95% of all adult sickle cell disease hospitalizations.⁷² There is a great deal of variability in pain symptoms between individuals, and within individuals at various times in their lives:⁷³ 30% have no pain events, 50% have occasional events, and 20% have monthly or more frequent events that require hospitalization.⁷⁴ The frequency and severity of pain events are modulated by HbF levels, β-thalassemia status, genotypes, therapies like hydroxyurea, or in rare cases, chronic transfusion therapy.²³ Personal factors, such as psychosocial stressors, also contribute to the frequency of pain events.⁷⁵ Pain event triggers include exposure to cold water, windy or cold weather, temperature changes, and extreme temperatures.^76–79 Patient age also contributes to pain event frequency. Many patients see an increase in pain event frequency in their late 20s, and a marked decrease in their 40s.^23,73 More than 3 pain events per year is associated with reduced life expectancy.²³

Acute management of pain episodes involves nonsteroidal anti-inflammatory drugs, oral opioids, and when hospitalization is required, intravenous opioids, often delivered via patient-controlled analgesia (PCA) pumps.⁷⁹ As sickle cell disease patients become teenagers and young adults, some experience an increased frequency of pain episodes, with fewer pain-free days, or a failure to return to baseline before the next pain crisis occurs.^80,81 This is characteristic of emerging chronic pain.⁸² Chronic pain is a significant problem in adult patients with sickle cell disease, with up to 85% reporting pain on most days.^72,80 The development of chronic pain may be reduced by early and aggressive treatment of acute pain events, as well as use of hydroxyurea to reduce the number of pain events. Many adult sickle cell patients with chronic pain are treated with daily opioids.²⁰ Given the significant side effects of chronic opioid use—sedation, respiratory depression, itching, nausea, and impairment of function and quality of life—non-opioid therapies are under investigation.⁸³ Many chronic pain patients have symptoms of neuropathic pain, and may benefit from neuropathic agents like gabapentin, both to reduce opioid use and to more effectively treat chronic neuropathic pain, which is known to respond poorly to opioids.^84–86

• Is the patient’s peripheral blood smear consistent with a diagnosis of sickle cell trait?

Several target cells are visible, which is not typical of sickle cell trait, but may be seen in HbSC or thalassemia. The finding of an intracellular crystal is pathognomonic for HbSC or HbCC. HbC polymerizes in high oxygen conditions, opposite of HbS, which polymerizes in low oxygen conditions.⁹

CASE CONTINUED

The patient’s family history is significant for a sister who died at age 3 from sickle cell–related complications, and a sister with sickle cell trait who had a cholecystectomy for gallstones at age 22. His father died at age 38 due to unknown causes. The sickle cell trait status of his parents is unknown. His mother is alive, and has hypertension.

• Is the medical history of this patient’s family members consistent with sickle cell trait?

It is unlikely that sickle cell trait would result in early death in childhood, or in gallstones at age 22. Gallstones in early adulthood is a common presentation for HbSC patients not diagnosed by newborn screening.⁸⁷ Any hemolytic condition can lead to the formation of hemoglobin-containing pigmented gallstones, biliary sludge, and obstruction of the gallbladder. In the presence of right-sided abdominal pain, a serum bilirubin level of more than 4 mg/dL should lead to measurement of direct bilirubin; if greater than 10% of total, imaging of the gallbladder should be obtained. In sickle cell disease, 30% of patients will have gallstones by 18 years of age. The low hemolysis/high viscosity phenotype patients are typically older at diagnosis. Co-inheritance of Gilbert syndrome and sickle cell disease is not uncommon, and can result in formation of gallstones at a young age; Gilbert syndrome alone typically results in gallstones in mid-life.⁸⁸

 

 

CASE CONTINUED

Two months later, the patient presents again to the emergency department with the same complaint of leg pain, as well as abdominal pain. His hemoglobin is 12.5 g/dL, and his platelet count is 134,000/µL. His pain is not improved with 3 doses of morphine 6 mg intravenously, and he is admitted to the medicine service. A hemoglobin profile is obtained, revealing 52% HbS, 45% HbC, and 1.5% HbF, consistent with HbSC. In sickle cell trait, the hemoglobin profile is 60% HbA and 40% HbS (available α-globin prefers to pair with a normal β-globin, so the ratio of HbA to HbS is 60:40, not 50:50).

On the second hospital day, the patient’s hemoglobin drops to 7.2 g/dL and his platelet count decreases to 44,000/µL. His abdomen is distended and diffusely tender. The internist transfuses him with 2 units of packed red blood cells (PRBC), after which his hemoglobin increases to 11 g/dL, while his platelet count increases to 112,000/µL. Following the transfusion, his abdominal pain resolves, as does his anemia and thrombocytopenia.

• What caused this patient’s anemia and thrombocytopenia?

High on the differential diagnosis is a splenic sequestration. Acute splenic sequestration occurs when red cells are trapped in the splenic sinuses. Massive splenic enlargement may occur over several hours.^89,90 Unrecognized splenic sequestration has a high mortality rate from severe anemia and splenic rupture.⁹⁰ Splenic sequestration must be ruled out in a sickle cell patient with abdominal pain accompanied by dropping platelet and red cell counts, especially in milder subtypes that often have splenic function preserved into adolescence and adulthood. Sickle cell anemia patients usually become functionally asplenic in early childhood.^89,91,92 The rise in hemoglobin, more than would be expected from 2 units of PRBC, plus the improvement in platelet count without a platelet transfusion observed in the case patient strongly supports the diagnosis of splenic sequestration.

Splenic sequestration can occur in any sickle cell patient whose spleen has not fibrosed. Splenic sequestration in adulthood is not uncommon in HbSC patients, who often have preserved splenic function into adulthood.^93–95

Clinical signs of splenic sequestration include a rapid drop in hemoglobin, rise in reticulocyte count, a tender, enlarged spleen, and, in severe cases, hypovolemia.^89,93 It is treated with prompt blood transfusion, but care must be taken not to overtransfuse the patient, as the spleen can trap several grams of hemoglobin, which may be released upon transfusion, potentially causing life-threatening hyperviscosity.⁸⁹ Hemoglobin levels must be checked following transfusion in suspected splenic sequestration, and “mini transfusions” of 5 mL/kg are recommended in sickle cell disease patients who are hemodynamically stable.²⁰

Hepatic sequestration may also occur, but it is much less common than splenic sequestration.⁹⁶ Other conditions on the differential diagnosis include thrombotic thrombocytopenic purpura, which would be unlikely to respond to a transfusion. ACS can cause a drop in hemoglobin, and is treated with simple or exchange transfusions.⁹⁷ ACS is less likely without respiratory symptoms or oxygen requirement, and usually is not associated with thrombocytopenia. Sepsis may also cause anemia and thrombocytopenia, but again would not likely respond to a simple transfusion. The patient’s response to transfusion is consistent with a sequestering event, not a destructive event as in the case of sepsis.

CASE CONTINUED

Imaging reveals a grossly enlarged spleen, which is having a mass effect on the left kidney. The patient is started on hydroxyurea therapy at 500 mg 3 times daily. Discharge instructions include following up with his primary care physician, continuing hydroxyurea therapy, and receiving yearly dilated eye exams to evaluate for proliferative sickle retinopathy.

• Are these discharge instructions complete?

Splenic sequestration has a 50% recurrence rate.⁹⁸ In very young children, watchful waiting or chronic transfusion may be implemented to preserve the immunologic function of the spleen and reduce the risk of sepsis.⁸⁹ Splenectomy after a single episode of sequestration in adults is a matter of debate, with experts advising both watchful waiting⁹⁹ and splenectomy after recovery from the first sequestering event.¹⁰⁰ The patient should have been informed of the risk for recurrence, and the signs and symptoms of splenic sequestration as well as the need for emergency medical attention should have been discussed. Splenic sequestration may be milder in adults than in children, but fatal sequestrations have been reported.^95,101–103

Proliferative sickle cell retinopathy is a high viscosity/high hemoglobin complication that may occur more frequently in HbSC than HbSS, with an incidence of 33% in HbSC.^42,104 Spontaneous regression of retinopathy occurs in approximately 32% of eyes, and laser or scatter photocoagulation is an effective intervention.¹⁰⁵

• Would the patient need to be transfused prior to splenectomy?

Preoperative transfusion therapy is standard of care for HbSS patients undergoing general anesthesia. The TRAP study found that simple “top off” transfusion to a hemoglobin of 10 g/dL was as effective at preventing postoperative sickle cell–related complications as exchange transfusion to HbS of 30% or less, and had fewer transfusion-related complications like alloimmunization.¹⁰⁶ There is little data regarding preoperative transfusions in HbSC disease. A retrospective study suggests that HbSC patients undergoing abdominal surgeries should be transfused.¹⁰⁷ The higher hemoglobin level of the typical HbSC patient necessitates exchange transfusion to avoid hyperviscosity.

• Is hydroxyurea therapy indicated in this patient?

• Has it been dosed appropriately?

If the patient had the HbSS subtype, hydroxyurea would be clearly indicated, given his frequent pain events.²⁰ HbSC patients may be placed on hydroxyurea on a case-by-case basis, but evidence for its efficacy in this sickle cell subtype is lacking.¹⁰⁸ Large clinical trials like the Multi-Center Study of Hydroxyurea (MSH) that established the safety and efficacy of hydroxyurea in sickle cell anemia excluded HbSC and HbSβ⁺ patients.¹⁰⁹ These mild to moderate subtypes produce less HbF at baseline, and typically have a minimal to modest rise in HbF on hydroxyurea.¹¹⁰ In sickle cell anemia, hydroxyurea is titrated to maximum tolerated dose, defined as an ANC of 2000 to 4000/µL and an ARC of 70,000/µL or higher.⁵³ Because of their lower levels of chronic inflammation and lower reticulocyte counts due to higher hemoglobin levels, many HbSC and HbSβ⁺ patients have values in that range before initiating hydroxyurea therapy.⁹ Cytopenias, particularly of platelets in HbSC, occur at low doses of hydroxyurea.¹¹¹

Of note, although the half-life of hydroxyurea would suggest that 3 times daily dosing is indicated, daily dosing has been found to have equal response and is preferred. Another concern is the monitoring of this myelosuppressive medication. This patient has repeatedly failed to obtain a primary care physician or a hematologist, and hydroxyurea requires laboratory monitoring at least every 2 months, especially in a HbSC patient with a very large spleen who is at significant risk for thrombocytopenia and neutropenia.⁹

CASE CONTINUED

A week after discharge from his admission for abdominal pain diagnosed as splenic sequestration, the patient presents again to the emergency department with abdominal pain which he reports is his typical sickle cell pain. Hemoglobin is 13.8 g/dL, platelet count is 388,000/µL, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are both 10 times their prior value. Creatinine is 1.2 mg/dL (0.75 mg/dL on his prior admission), and total bilirubin is 3 mg/dL, with 0.3 mg/dL direct bilirubin. He undergoes an ultrasound exam of his gallbladder, which reveals sludge and a possible gallstone. There is no evidence of cholecystitis. General surgery performs a laparoscopic cholecystectomy.

• Was this cholecystectomy necessary?

In patients with sickle cell disease, symptomatic gallstones and gallbladder sludge should be observed; recurrent abdominal pain without a significant change in bilirubin may not be due to gallstones or sludge, and therefore may not be relieved by cholecystectomy.^112,113 In sickle cell disease, 40% of patients with gallbladder sludge do not develop gallstones.⁸⁷ The patient’s bilirubin level was at baseline, and there was no increase in the direct (conjugated) fraction. Watchful waiting would have been appropriate, with cholecystectomy being performed if he experienced recurrent symptoms associated with fatty foods accompanied by an elevation in direct bilirubin.

More concerning and deserving of investigation was his elevated liver enzymes. Patients with sickle cell disease may experience recurrent ischemia and reperfusion injuries in the liver, which is called right upper quadrant syndrome. On autopsy of 70 sickle cell patients, 91% had hepatomegaly and 34% had focal necrosis.¹¹⁴ AST is often elevated in sickle cell disease, as it is affected by hemolysis. In this patient, both AST and ALT are elevated, consistent with a hepatocellular disorder. His abdominal pain and ALT rise may be a sign of a hepatic crisis.¹¹⁵ Rapid resolution of ALT elevation in a matter of days suggests a vaso-occlusive, inflammatory event that is self- limiting. Prolonged AST elevation requires further investigation, with consideration of autoimmune hepatitis, viral hepatitis, or iron overload. Iron overload is unlikely in this patient given his lifetime history of only 1 transfusion. Hepatic iron overload typically occurs in sickle cell disease after a minimum of 10 transfusions.¹¹⁵

CASE CONTINUED

The patient is discharged on the day after the procedure, with instructions to continue his hydroxyurea.

• Should the patient resume hydroxyurea therapy?

Hydroxyurea is hepatically cleared and thus it should be held until his liver function tests normalize.¹⁰⁶

CASE CONTINUED

Two months later, the patient presents to the emergency department with abdominal pain that moves to his left leg. A CBC is obtained, showing a hemoglobin of 11.8 g/dL and a platelet count of 144,000/µL. He is given 2 doses of morphine 6 mg intravenously, and reports that his leg pain is now a 4/10. He is discharged home with a prescription for hydrocodone/acetaminophen.

• Is the emergency department evaluation sufficient?

This patient remains at high risk for splenic sequestration,⁹³ with a hemoglobin 2 g lower than it was 2 months ago and platelets less than half. This decline could be consistent with early splenic sequestration.²⁰ Additionally, he had elevated liver function tests on a recent admission, as well as rising creatinine, without evidence of resolution. It is not appropriate to discharge him without checking a chemistry and liver panel, and abdominal imaging should be considered. The best plan would be to admit him for observation, given his risk for splenic sequestration, and consult surgery for an elective splenectomy if he has a second episode of splenic sequestration 2 months after the first.¹⁰⁰ His abdominal pain that migrates to his left leg could be due to his massive splenomegaly compressing his left kidney, as noted on imaging during his recent admission for splenic sequestration

CASE CONTINUED

An hour after discharge from the emergency department, EMS is called to his home for intractable pain. He is found lying on the floor, and reports excruciating left leg pain. He is brought to the closest hospital, a community hospital that he has not visited previously. There, he is admitted for hydration and pain control and placed on hydromorphone 2 mg every 4 hours as needed for pain. His hemoglobin is 10.8 g/dL, and platelets are 121,000/µL. A chemistry panel is remarkable for a creatinine level of 1.5 mg/dL and a potassium level of 3.2 mEq/L. Liver function tests are not obtained. After 3 doses of hydromorphone, he falls asleep. He is not in a monitored bed, and intravenous fluids, while ordered, are not started. At 6:30 AM the day after admission, he cannot be aroused on a routine vital sign check; he has an SpO₂ of 60%, a blood pressure of 80/60 mm Hg, and heart rate of 148 beats/min. A rapid response is called, and naloxone is administered along with oxygen by face mask and several fluid boluses. His systolic blood pressure increases to 100 mm Hg from a low of 70 mm Hg. His SpO₂ increases to 92%, and he is arousable and alert, although he reports 10/10 leg pain. His abdomen is noted to be distended and tender.

• What may have contributed to his clinical condition?

The patient is opioid tolerant and has received equivalent doses of opioids in the past without excess sedation. He may have liver dysfunction making him unable to metabolize opioids effectively. His hemoglobin and platelets continue to decline, raising concern for splenic sequestration versus sepsis. Failure to place him on a monitor allowed his hypoxia to continue for an unknown amount of time, placing him at high risk for developing ACS. Lack of intravenous hydration while he was too sedated to drink likely exacerbated his sickling.

 

 

CASE CONTINUED

At 9:20 AM, a CBC is obtained and reveals a hemoglobin of 4.8 g/dL and a platelet count of 44,000/µL. Two units of stat O negative blood are administered, and preparations are made to administer an exchange transfusion. A liver panel is obtained 3 hours later, which reveals an AST level of 1200 U/L and an ALT level of 1050 U/L. His bilirubin is 10 mg/dL, and his lactate dehydrogenase level is 1800 U/L. His urine is dark and is positive for bilirubin and ketones. He is transferred to the intensive care unit. A chest X-ray shows pulmonary congestion. Hematology/oncology is consulted.

He receives a 7-unit red blood cell exchange, which reduces his HbS to 11%. He continues to be hypotensive, and requires norepinephrine to support his blood pressure. Antibiotic therapy is started. His creatinine concentration rises to 2.3 mg/dL, potassium is 7.8 mEq/L, and bicarbonate is 12 mEq/L. He is placed on hemodialysis.

Computed tomography of the chest and abdomen reveals lower posterior lung infiltrates and a grossly enlarged spleen. He requires intubation. He is given a diagnosis of ACS in addition to kidney failure, liver failure, and “sickle crisis.” He continues to require daily to twice daily transfusions to maintain a hemoglobin of 7 to 9 g/dL, and his abdominal distension increases. As his condition worsens, surgery is consulted to discuss a liver transplant. He is deemed to not be a surgical candidate, and he passes away 6 days after entering the hospital. The immediate cause of death is listed as vaso-occlusive crisis, with ACS and sickle crisis listed as contributors.

• Are the causes of death accurate and complete?

If vaso-occlusive crisis is used to indicate a pain event, it is not an accurate cause of death. Pain is one of the most distressing complications of sickle cell disease, and frequent pain events are associated with early mortality,^4,80 but they are not in themselves fatal. ACS is the number one cause of death in sickle cell disease,⁴ and it likely contributed to this patient’s death. Sickle crisis is a vague term that should not be used in this context. Causes of death should include splenic sequestration and multisystem organ failure. Multisystem organ failure in sickle cell disease often responds to aggressive transfusion therapy, which this patient received.^116–118

CONCLUSION

Sickle cell disease is a complex chronic disease that impacts almost every organ system in the body. Clinicians may be inclined to attribute most pain in a patient with sickle cell disease to a simple vaso-occlusive crisis, treat them for this, and not investigate further. As the case presented here demonstrates, failure to identify the actual life-threatening process occurring in a patient with sickle cell disease presenting with pain can result in preventable early mortality. Clinicians must approach a sickle cell patient reporting pain in a thoughtful manner, and consider a complete differential diagnosis, including both sickle cell disease complications and those unrelated to sickle cell disease. Knowledge of the disease courses of the different sickle cell genotypes is essential, and must go beyond a superficial hierarchy of severity, but rather include an understanding of the complications each genotype is most prone to, and at what ages. Complete laboratory assessment, including a comprehensive metabolic panel, should be performed on all admitted patients, not just a complete blood count. Treating pain with high-dose opioids, while appropriate in an uncomplicated pain crisis, can lead to ACS or even respiratory failure in a patient with uninvestigated liver and kidney dysfunction. The most important lesson to remember is that even the sickle cell disease patient who has been given the unfortunate and pejorative label of “frequent flyer” by some providers has the potential for rapid deterioration into multisystem organ failure and death.

INTRODUCTION

Sickle cell disease is the most common inherited blood disorder in the world. It affects more than 100,000 individuals in the United States, and millions more worldwide.¹ Sickle cell disease is most commonly found in individuals of African heritage, but the disease also occurs in Hispanics and people of Middle Eastern and subcontinent Indian heritage.² The distribution of the sickle hemoglobin (hemoglobin S [HbS]) allele overlaps with the distribution of malaria; HbS carriers, or individuals with sickle cell trait, have protection against malaria,³ and are not considered to have sickle cell disease.

Sickle cell disease is a severe monogenic disorder marked by significant morbidity and mortality, affecting every organ in the body.⁴ The term sickle cell disease refers to all genotypes that cause sickling; the most common are the homozygous hemoglobin SS (HbSS) and compound heterozygotes hemoglobin SC (HbSC), hemoglobin S–β⁰-thalassemia (HbSβ⁰), and hemoglobin S–β⁺-thalassemia (HbSβ⁺), although HbS and several rarer hemoglobin variants such as HbSO(Arab) and HbSD(Punjab) can also cause sickle cell disease. The term sickle cell anemia refers exclusively to the most severe genotypes, HbSS and HbSβ⁰.⁵ Common sickling genotypes along with their relative clinical severity are shown in Table 1.^6–11

This article reviews the pathophysiology of sickle cell disease, common clinical complications, and available therapies. A complex case which illustrates diagnostic and management challenges is presented as well.

PATHOPHYSIOLOGY

HbS is the result of a substitution of valine for glutamic acid in the sixth amino acid of the β-globin chain.¹² The change from a hydrophilic to a hydrophobic amino acid causes the hemoglobin molecules to stack, or polymerize, when deoxygenated. This rigid rod of hemoglobin distorts the cell, producing the characteristic crescent or sickle shape that gives the disease its name.¹³ Polymerization of hemoglobin within the cell is promoted by dehydration, which increases the concentration of HbS.^13,14 Polymerization occurs when hemoglobin is in the deoxygenated state.¹³

The sickle red blood cell is abnormal; it is rigid and dense, and lacks the deformability needed to navigate the microvasculature.¹⁵ Blockages of blood flow result in painful vaso-occlusion that is the hallmark of the disease, and that also can cause damage to the spleen, kidneys, and liver.¹⁶ The sickle red cell is also fragile, with a lifespan of only 20 days compared to the 120-day lifespan of a normal red blood cell.¹³ Frequent hemolysis results in anemia and the release of free hemoglobin, which both scavenges nitric oxide and impairs the production of more nitric oxide, which is essential for vasodilatation.¹⁷ This contributes to vascular dysfunction and an increased risk for stroke.¹⁸ If untreated, the natural course of sickle cell anemia is mortality in early childhood in most cases.¹⁹ Common chronic and acute sickle cell disease–related complications and recommended therapies, based on 2014 National Institutes of Health guidelines, are shown in Table 2 and Table 3.²⁰

One of the most challenging aspects of sickle cell disease is its clinical variability. While in general, HbSS and HbSβ⁰ are the most severe genotypes, there are patients with HbSC and HbSb⁺ who have significant sickle-cell–related complications, and may have a more severe clinical course than a HbSS patient.²¹ A great deal of this clinical variability cannot be explained, but some can be attributed to endogenous fetal hemoglobin (HbF) levels.^22–24 The importance of HbF levels in sickle cell disease was first noted by a pediatrician in the 1940s.²⁵ She observed that sickle cell disease complications in children under the age of 1 were rare, and attributed it to the presence of HbF.²⁵ HbF levels decline more slowly in individuals with hemoglobinopathies, reaching their nadir after the age of 5 rather than within 6 months of birth in individuals without hemoglobinopathies.²⁶ HbF levels remain elevated lifelong in most sickle cell disease patients, especially those with the HbSS and HbSβ⁰ genotypes. Levels of HbF vary widely between individuals, from zero to 20% to 30%, with a median of 10%.^26–28 Individuals who produce more HbF have a milder course, in general.²⁴ An association between the 4 β-globin haplotypes and HbF levels has been reported in the past,^27,29 but more sophisticated next-generation sequencing has revealed causal variants in BCL11A and HBS1L-MYB that contribute approximately 50% of the observed variability in HbF levels.^30–33

Co-inheritance of α-thalassemia also modifies disease course; less available α-globin chains results in a lower hemoglobin concentration within the cell. Paradoxically, this results in a higher overall hemoglobin level, as there is a reduction in polymerization, and therefore sickling due to lower HbS concentrations in the cell. Patients therefore are less anemic, reducing the risk of stroke in childhood,^34,35 but blood viscosity may be higher, resulting in more frequent pain crises and increased risk³⁶ of avascular necrosis.^34,35,37 It is often helpful to think of sickle cell patients as falling into 1 of 2 groups: high hemolysis/low hemoglobin and high viscosity/high hemoglobin. Individuals with high rates of hemolysis are at greater risk for stroke, pulmonary hypertension, and acute chest syndrome (ACS). Higher rates of hemolysis result in higher levels of free hemoglobin, which scavenges nitric oxide. This leads to the vascular damage and dysfunction that contributes to the associated clinical complications. This phenotype is most commonly seen in HbSS and HbSβ⁰.³⁸ High hemoglobin/high viscosity phenotypes are most often found in HbSC patients and in sickle cell anemia with α-thalassemia coinheritance.^39–42

TREATMENT OPTIONS

In high-resource countries with newborn screening, the initiation of penicillin prophylaxis has dramatically altered the natural history of the disease, allowing the majority of patients to reach adulthood.⁴³ Penicillin prophylaxis is usually discontinued at age 5 years; however, individuals who have undergone surgical splenectomy or have had pneumococcal sepsis on penicillin prophylaxis may remain on penicillin to age 18 or beyond.²⁰

Another advance in sickle cell care is screening for stroke risk through transcranial Doppler ultrasound (TCD).^44–47 This screening tool has reduced the incidence of childhood stroke from 10% by age 11 to 1%. TCDs typically cannot be performed after the age of 16 due to changes in the skull. Individuals found to have abnormal (elevated) TCD velocities are placed on chronic transfusion therapy for primary stroke prevention. They may remain on monthly chronic transfusions, with the goal of suppressing the percentage of HbS to 30% to 50% indefinitely. A clinical trial (STOPII) designed to determine if pediatric sickle cell disease patients on chronic transfusion therapy for primary stroke prevention could be safely taken off transfusion therapy was discontinued early due to an excess of strokes and conversion to abnormal TCD velocities in the untransfused arm.⁴⁴ Individuals who have experienced an ischemic stroke have a 70% risk of another stroke, and must remain on chronic transfusion therapy indefinitely. Chronic transfusion reduces their stroke risk to 13%.

The only widely used pharmacologic therapy for sickle cell disease is hydroxyurea.^12,48–50 A significant portion of the benefit of hydroxyurea stems from its induction of HbF.⁵¹ HbF does not sickle, and it interrupts the polymerization of HbS in the cell, if present in high enough concentrations.⁵⁰ The level of HbF needed to achieve clinical improvement is not known, but in vitro assays suggest 20% HbF is needed to prevent sickling.^52,53 However, endogenous and hydroxyurea-induced HbF is not distributed evenly through the red cells, so sickling is possible regardless of the level of HbF induced.^54,55 Hydroxyurea likely has other disease-modifying effects as well, including reduction of white blood cell count and reticulocyte count and reduction of red cell adhesion to the endothelium.^56–58 Clinical criteria for initiation of hydroxyurea in adult sickle cell disease patients are shown in Table 4.²⁰ Hydroxyurea is given daily and is dosed to maximum tolerated dose for the individual by following the absolute neutrophil count (ANC). The goal ANC is between 2000 and 4000/µL. At times, absolute reticulocyte count (ARC) can be dose-limiting; goal ARC is greater than 70,000/µL.⁵⁹ Platelet counts may be reduced as well, especially in HbSC patients.^60,61

The only curative therapy for sickle cell disease is hematopoietic stem cell transplant.⁶² Transplant use is limited by availability of matched sibling donors,⁶² and even at experienced centers transplant carries a small risk for mortality, graft rejection, and graft-versus-host disease. Furthermore, consensus on disease complications for which transplant is recommended is also lacking.^63–65 Clinical trials of gene therapy for sickle cell disease and thalassemia are ongoing.⁶⁶

COMPLICATIONS AND DISEASE-SPECIFIC THERAPIES

CASE PRESENTATION

A 26-year-old African-American man who works as a school bus driver presents to an academic center’s emergency department complaining of pain in his left leg, similar to prior pain events. He is described as having sickle cell trait, although no hemoglobin profile is available in his chart. He describes the pain as dull and aching, 10/10 in intensity. A complete blood count (CBC) is obtained; it reveals a hemoglobin of 14.5 g/dL, white blood cell (WBC) count of 5600/µL, and platelet count of 344,000/µL. His CBC is also notable for a mean corpuscular volume (MCV) of 72 fL, a mean corpuscular hemoglobin concentration (MCHC) of 37 g/dL, and a red blood cell distribution width (RDW) of 12. Slide review of a peripheral blood smear shows 2+ target cells (Figure).

The patient is given 6 mg of morphine, which provides some relief of his pain, and is discharged with a prescription for hydrocodone bitartrate/acetaminophen 5/325 mg. The diagnosis given is musculoskeletal pain, and he is instructed to follow-up with a primary care physician. His past medical history is significant for 4 or 5 visits to the emergency department per year in the past 4 years. Prior to 4 years ago, he rarely required medical attention.

• What laboratory and clinical features might lead you to question the diagnosis of sickle cell trait in this patient?

The patient’s hemoglobin is within normal range, which is consistent with sickle cell trait; however, he is microcytic, with a normal RDW. It is possible to be mildly microcytic in the early stages of iron deficiency, prior to the development of anemia, but the RDW would typically be elevated, demonstrating the presence of newer, smaller cells produced under conditions of iron deficiency.⁶⁷ It is also possible that his microcytosis with a normal RDW could represent sickle cell trait with co-inheritance of β-thalassemia. Up to 30% of African Americans have β-thalassemia,² and 1 in 10 have sickle cell trait.⁶⁸ However, a high MCHC, indicating the presence of dense cells, and target cells noted on slide review are most consistent with HbSC.⁹ HbSC patients, especially males, can have hemoglobin levels in the normal range.⁴ The biggest inconsistency with the diagnosis of sickle cell trait is his history of frequent pain events. Individuals with sickle cell trait rarely present with pain crises, except under extreme conditions of dehydration or high altitude.⁶⁸ Sickle cell trait is generally regarded as a benign condition, although a study of U.S. military recruits found a 30-fold higher risk of sudden death during basic training in persons with sickle cell trait.⁶⁹ Additional sickle cell trait–related complications include hematuria, risk of splenic sequestration or infarct under extreme conditions and high altitude, and a rare and usually fatal renal malignancy, renal medullary carcinoma, which is vanishingly rare in individuals without sickle cell trait.^70,71 Although the patient reported having sickle cell trait, this diagnosis should have been verified with a hemoglobin panel, given his atypical presentation.²⁰

In sickle cell disease, vaso-occlusive pain events can be common, often beginning in early childhood.¹⁷ This disease complication accounts for 95% of all adult sickle cell disease hospitalizations.⁷² There is a great deal of variability in pain symptoms between individuals, and within individuals at various times in their lives:⁷³ 30% have no pain events, 50% have occasional events, and 20% have monthly or more frequent events that require hospitalization.⁷⁴ The frequency and severity of pain events are modulated by HbF levels, β-thalassemia status, genotypes, therapies like hydroxyurea, or in rare cases, chronic transfusion therapy.²³ Personal factors, such as psychosocial stressors, also contribute to the frequency of pain events.⁷⁵ Pain event triggers include exposure to cold water, windy or cold weather, temperature changes, and extreme temperatures.^76–79 Patient age also contributes to pain event frequency. Many patients see an increase in pain event frequency in their late 20s, and a marked decrease in their 40s.^23,73 More than 3 pain events per year is associated with reduced life expectancy.²³

Acute management of pain episodes involves nonsteroidal anti-inflammatory drugs, oral opioids, and when hospitalization is required, intravenous opioids, often delivered via patient-controlled analgesia (PCA) pumps.⁷⁹ As sickle cell disease patients become teenagers and young adults, some experience an increased frequency of pain episodes, with fewer pain-free days, or a failure to return to baseline before the next pain crisis occurs.^80,81 This is characteristic of emerging chronic pain.⁸² Chronic pain is a significant problem in adult patients with sickle cell disease, with up to 85% reporting pain on most days.^72,80 The development of chronic pain may be reduced by early and aggressive treatment of acute pain events, as well as use of hydroxyurea to reduce the number of pain events. Many adult sickle cell patients with chronic pain are treated with daily opioids.²⁰ Given the significant side effects of chronic opioid use—sedation, respiratory depression, itching, nausea, and impairment of function and quality of life—non-opioid therapies are under investigation.⁸³ Many chronic pain patients have symptoms of neuropathic pain, and may benefit from neuropathic agents like gabapentin, both to reduce opioid use and to more effectively treat chronic neuropathic pain, which is known to respond poorly to opioids.^84–86

• Is the patient’s peripheral blood smear consistent with a diagnosis of sickle cell trait?

Several target cells are visible, which is not typical of sickle cell trait, but may be seen in HbSC or thalassemia. The finding of an intracellular crystal is pathognomonic for HbSC or HbCC. HbC polymerizes in high oxygen conditions, opposite of HbS, which polymerizes in low oxygen conditions.⁹

CASE CONTINUED

The patient’s family history is significant for a sister who died at age 3 from sickle cell–related complications, and a sister with sickle cell trait who had a cholecystectomy for gallstones at age 22. His father died at age 38 due to unknown causes. The sickle cell trait status of his parents is unknown. His mother is alive, and has hypertension.

• Is the medical history of this patient’s family members consistent with sickle cell trait?

It is unlikely that sickle cell trait would result in early death in childhood, or in gallstones at age 22. Gallstones in early adulthood is a common presentation for HbSC patients not diagnosed by newborn screening.⁸⁷ Any hemolytic condition can lead to the formation of hemoglobin-containing pigmented gallstones, biliary sludge, and obstruction of the gallbladder. In the presence of right-sided abdominal pain, a serum bilirubin level of more than 4 mg/dL should lead to measurement of direct bilirubin; if greater than 10% of total, imaging of the gallbladder should be obtained. In sickle cell disease, 30% of patients will have gallstones by 18 years of age. The low hemolysis/high viscosity phenotype patients are typically older at diagnosis. Co-inheritance of Gilbert syndrome and sickle cell disease is not uncommon, and can result in formation of gallstones at a young age; Gilbert syndrome alone typically results in gallstones in mid-life.⁸⁸

 

 

CASE CONTINUED

Two months later, the patient presents again to the emergency department with the same complaint of leg pain, as well as abdominal pain. His hemoglobin is 12.5 g/dL, and his platelet count is 134,000/µL. His pain is not improved with 3 doses of morphine 6 mg intravenously, and he is admitted to the medicine service. A hemoglobin profile is obtained, revealing 52% HbS, 45% HbC, and 1.5% HbF, consistent with HbSC. In sickle cell trait, the hemoglobin profile is 60% HbA and 40% HbS (available α-globin prefers to pair with a normal β-globin, so the ratio of HbA to HbS is 60:40, not 50:50).

On the second hospital day, the patient’s hemoglobin drops to 7.2 g/dL and his platelet count decreases to 44,000/µL. His abdomen is distended and diffusely tender. The internist transfuses him with 2 units of packed red blood cells (PRBC), after which his hemoglobin increases to 11 g/dL, while his platelet count increases to 112,000/µL. Following the transfusion, his abdominal pain resolves, as does his anemia and thrombocytopenia.

• What caused this patient’s anemia and thrombocytopenia?

High on the differential diagnosis is a splenic sequestration. Acute splenic sequestration occurs when red cells are trapped in the splenic sinuses. Massive splenic enlargement may occur over several hours.^89,90 Unrecognized splenic sequestration has a high mortality rate from severe anemia and splenic rupture.⁹⁰ Splenic sequestration must be ruled out in a sickle cell patient with abdominal pain accompanied by dropping platelet and red cell counts, especially in milder subtypes that often have splenic function preserved into adolescence and adulthood. Sickle cell anemia patients usually become functionally asplenic in early childhood.^89,91,92 The rise in hemoglobin, more than would be expected from 2 units of PRBC, plus the improvement in platelet count without a platelet transfusion observed in the case patient strongly supports the diagnosis of splenic sequestration.

Splenic sequestration can occur in any sickle cell patient whose spleen has not fibrosed. Splenic sequestration in adulthood is not uncommon in HbSC patients, who often have preserved splenic function into adulthood.^93–95

Clinical signs of splenic sequestration include a rapid drop in hemoglobin, rise in reticulocyte count, a tender, enlarged spleen, and, in severe cases, hypovolemia.^89,93 It is treated with prompt blood transfusion, but care must be taken not to overtransfuse the patient, as the spleen can trap several grams of hemoglobin, which may be released upon transfusion, potentially causing life-threatening hyperviscosity.⁸⁹ Hemoglobin levels must be checked following transfusion in suspected splenic sequestration, and “mini transfusions” of 5 mL/kg are recommended in sickle cell disease patients who are hemodynamically stable.²⁰

Hepatic sequestration may also occur, but it is much less common than splenic sequestration.⁹⁶ Other conditions on the differential diagnosis include thrombotic thrombocytopenic purpura, which would be unlikely to respond to a transfusion. ACS can cause a drop in hemoglobin, and is treated with simple or exchange transfusions.⁹⁷ ACS is less likely without respiratory symptoms or oxygen requirement, and usually is not associated with thrombocytopenia. Sepsis may also cause anemia and thrombocytopenia, but again would not likely respond to a simple transfusion. The patient’s response to transfusion is consistent with a sequestering event, not a destructive event as in the case of sepsis.

CASE CONTINUED

Imaging reveals a grossly enlarged spleen, which is having a mass effect on the left kidney. The patient is started on hydroxyurea therapy at 500 mg 3 times daily. Discharge instructions include following up with his primary care physician, continuing hydroxyurea therapy, and receiving yearly dilated eye exams to evaluate for proliferative sickle retinopathy.

• Are these discharge instructions complete?

Splenic sequestration has a 50% recurrence rate.⁹⁸ In very young children, watchful waiting or chronic transfusion may be implemented to preserve the immunologic function of the spleen and reduce the risk of sepsis.⁸⁹ Splenectomy after a single episode of sequestration in adults is a matter of debate, with experts advising both watchful waiting⁹⁹ and splenectomy after recovery from the first sequestering event.¹⁰⁰ The patient should have been informed of the risk for recurrence, and the signs and symptoms of splenic sequestration as well as the need for emergency medical attention should have been discussed. Splenic sequestration may be milder in adults than in children, but fatal sequestrations have been reported.^95,101–103

Proliferative sickle cell retinopathy is a high viscosity/high hemoglobin complication that may occur more frequently in HbSC than HbSS, with an incidence of 33% in HbSC.^42,104 Spontaneous regression of retinopathy occurs in approximately 32% of eyes, and laser or scatter photocoagulation is an effective intervention.¹⁰⁵

• Would the patient need to be transfused prior to splenectomy?

Preoperative transfusion therapy is standard of care for HbSS patients undergoing general anesthesia. The TRAP study found that simple “top off” transfusion to a hemoglobin of 10 g/dL was as effective at preventing postoperative sickle cell–related complications as exchange transfusion to HbS of 30% or less, and had fewer transfusion-related complications like alloimmunization.¹⁰⁶ There is little data regarding preoperative transfusions in HbSC disease. A retrospective study suggests that HbSC patients undergoing abdominal surgeries should be transfused.¹⁰⁷ The higher hemoglobin level of the typical HbSC patient necessitates exchange transfusion to avoid hyperviscosity.

• Is hydroxyurea therapy indicated in this patient?

• Has it been dosed appropriately?

If the patient had the HbSS subtype, hydroxyurea would be clearly indicated, given his frequent pain events.²⁰ HbSC patients may be placed on hydroxyurea on a case-by-case basis, but evidence for its efficacy in this sickle cell subtype is lacking.¹⁰⁸ Large clinical trials like the Multi-Center Study of Hydroxyurea (MSH) that established the safety and efficacy of hydroxyurea in sickle cell anemia excluded HbSC and HbSβ⁺ patients.¹⁰⁹ These mild to moderate subtypes produce less HbF at baseline, and typically have a minimal to modest rise in HbF on hydroxyurea.¹¹⁰ In sickle cell anemia, hydroxyurea is titrated to maximum tolerated dose, defined as an ANC of 2000 to 4000/µL and an ARC of 70,000/µL or higher.⁵³ Because of their lower levels of chronic inflammation and lower reticulocyte counts due to higher hemoglobin levels, many HbSC and HbSβ⁺ patients have values in that range before initiating hydroxyurea therapy.⁹ Cytopenias, particularly of platelets in HbSC, occur at low doses of hydroxyurea.¹¹¹

Of note, although the half-life of hydroxyurea would suggest that 3 times daily dosing is indicated, daily dosing has been found to have equal response and is preferred. Another concern is the monitoring of this myelosuppressive medication. This patient has repeatedly failed to obtain a primary care physician or a hematologist, and hydroxyurea requires laboratory monitoring at least every 2 months, especially in a HbSC patient with a very large spleen who is at significant risk for thrombocytopenia and neutropenia.⁹

CASE CONTINUED

A week after discharge from his admission for abdominal pain diagnosed as splenic sequestration, the patient presents again to the emergency department with abdominal pain which he reports is his typical sickle cell pain. Hemoglobin is 13.8 g/dL, platelet count is 388,000/µL, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are both 10 times their prior value. Creatinine is 1.2 mg/dL (0.75 mg/dL on his prior admission), and total bilirubin is 3 mg/dL, with 0.3 mg/dL direct bilirubin. He undergoes an ultrasound exam of his gallbladder, which reveals sludge and a possible gallstone. There is no evidence of cholecystitis. General surgery performs a laparoscopic cholecystectomy.

• Was this cholecystectomy necessary?

In patients with sickle cell disease, symptomatic gallstones and gallbladder sludge should be observed; recurrent abdominal pain without a significant change in bilirubin may not be due to gallstones or sludge, and therefore may not be relieved by cholecystectomy.^112,113 In sickle cell disease, 40% of patients with gallbladder sludge do not develop gallstones.⁸⁷ The patient’s bilirubin level was at baseline, and there was no increase in the direct (conjugated) fraction. Watchful waiting would have been appropriate, with cholecystectomy being performed if he experienced recurrent symptoms associated with fatty foods accompanied by an elevation in direct bilirubin.

More concerning and deserving of investigation was his elevated liver enzymes. Patients with sickle cell disease may experience recurrent ischemia and reperfusion injuries in the liver, which is called right upper quadrant syndrome. On autopsy of 70 sickle cell patients, 91% had hepatomegaly and 34% had focal necrosis.¹¹⁴ AST is often elevated in sickle cell disease, as it is affected by hemolysis. In this patient, both AST and ALT are elevated, consistent with a hepatocellular disorder. His abdominal pain and ALT rise may be a sign of a hepatic crisis.¹¹⁵ Rapid resolution of ALT elevation in a matter of days suggests a vaso-occlusive, inflammatory event that is self- limiting. Prolonged AST elevation requires further investigation, with consideration of autoimmune hepatitis, viral hepatitis, or iron overload. Iron overload is unlikely in this patient given his lifetime history of only 1 transfusion. Hepatic iron overload typically occurs in sickle cell disease after a minimum of 10 transfusions.¹¹⁵

CASE CONTINUED

The patient is discharged on the day after the procedure, with instructions to continue his hydroxyurea.

• Should the patient resume hydroxyurea therapy?

Hydroxyurea is hepatically cleared and thus it should be held until his liver function tests normalize.¹⁰⁶

CASE CONTINUED

Two months later, the patient presents to the emergency department with abdominal pain that moves to his left leg. A CBC is obtained, showing a hemoglobin of 11.8 g/dL and a platelet count of 144,000/µL. He is given 2 doses of morphine 6 mg intravenously, and reports that his leg pain is now a 4/10. He is discharged home with a prescription for hydrocodone/acetaminophen.

• Is the emergency department evaluation sufficient?

This patient remains at high risk for splenic sequestration,⁹³ with a hemoglobin 2 g lower than it was 2 months ago and platelets less than half. This decline could be consistent with early splenic sequestration.²⁰ Additionally, he had elevated liver function tests on a recent admission, as well as rising creatinine, without evidence of resolution. It is not appropriate to discharge him without checking a chemistry and liver panel, and abdominal imaging should be considered. The best plan would be to admit him for observation, given his risk for splenic sequestration, and consult surgery for an elective splenectomy if he has a second episode of splenic sequestration 2 months after the first.¹⁰⁰ His abdominal pain that migrates to his left leg could be due to his massive splenomegaly compressing his left kidney, as noted on imaging during his recent admission for splenic sequestration

CASE CONTINUED

An hour after discharge from the emergency department, EMS is called to his home for intractable pain. He is found lying on the floor, and reports excruciating left leg pain. He is brought to the closest hospital, a community hospital that he has not visited previously. There, he is admitted for hydration and pain control and placed on hydromorphone 2 mg every 4 hours as needed for pain. His hemoglobin is 10.8 g/dL, and platelets are 121,000/µL. A chemistry panel is remarkable for a creatinine level of 1.5 mg/dL and a potassium level of 3.2 mEq/L. Liver function tests are not obtained. After 3 doses of hydromorphone, he falls asleep. He is not in a monitored bed, and intravenous fluids, while ordered, are not started. At 6:30 AM the day after admission, he cannot be aroused on a routine vital sign check; he has an SpO₂ of 60%, a blood pressure of 80/60 mm Hg, and heart rate of 148 beats/min. A rapid response is called, and naloxone is administered along with oxygen by face mask and several fluid boluses. His systolic blood pressure increases to 100 mm Hg from a low of 70 mm Hg. His SpO₂ increases to 92%, and he is arousable and alert, although he reports 10/10 leg pain. His abdomen is noted to be distended and tender.

• What may have contributed to his clinical condition?

The patient is opioid tolerant and has received equivalent doses of opioids in the past without excess sedation. He may have liver dysfunction making him unable to metabolize opioids effectively. His hemoglobin and platelets continue to decline, raising concern for splenic sequestration versus sepsis. Failure to place him on a monitor allowed his hypoxia to continue for an unknown amount of time, placing him at high risk for developing ACS. Lack of intravenous hydration while he was too sedated to drink likely exacerbated his sickling.

 

 

CASE CONTINUED

At 9:20 AM, a CBC is obtained and reveals a hemoglobin of 4.8 g/dL and a platelet count of 44,000/µL. Two units of stat O negative blood are administered, and preparations are made to administer an exchange transfusion. A liver panel is obtained 3 hours later, which reveals an AST level of 1200 U/L and an ALT level of 1050 U/L. His bilirubin is 10 mg/dL, and his lactate dehydrogenase level is 1800 U/L. His urine is dark and is positive for bilirubin and ketones. He is transferred to the intensive care unit. A chest X-ray shows pulmonary congestion. Hematology/oncology is consulted.

He receives a 7-unit red blood cell exchange, which reduces his HbS to 11%. He continues to be hypotensive, and requires norepinephrine to support his blood pressure. Antibiotic therapy is started. His creatinine concentration rises to 2.3 mg/dL, potassium is 7.8 mEq/L, and bicarbonate is 12 mEq/L. He is placed on hemodialysis.

Computed tomography of the chest and abdomen reveals lower posterior lung infiltrates and a grossly enlarged spleen. He requires intubation. He is given a diagnosis of ACS in addition to kidney failure, liver failure, and “sickle crisis.” He continues to require daily to twice daily transfusions to maintain a hemoglobin of 7 to 9 g/dL, and his abdominal distension increases. As his condition worsens, surgery is consulted to discuss a liver transplant. He is deemed to not be a surgical candidate, and he passes away 6 days after entering the hospital. The immediate cause of death is listed as vaso-occlusive crisis, with ACS and sickle crisis listed as contributors.

• Are the causes of death accurate and complete?

If vaso-occlusive crisis is used to indicate a pain event, it is not an accurate cause of death. Pain is one of the most distressing complications of sickle cell disease, and frequent pain events are associated with early mortality,^4,80 but they are not in themselves fatal. ACS is the number one cause of death in sickle cell disease,⁴ and it likely contributed to this patient’s death. Sickle crisis is a vague term that should not be used in this context. Causes of death should include splenic sequestration and multisystem organ failure. Multisystem organ failure in sickle cell disease often responds to aggressive transfusion therapy, which this patient received.^116–118

CONCLUSION

Sickle cell disease is a complex chronic disease that impacts almost every organ system in the body. Clinicians may be inclined to attribute most pain in a patient with sickle cell disease to a simple vaso-occlusive crisis, treat them for this, and not investigate further. As the case presented here demonstrates, failure to identify the actual life-threatening process occurring in a patient with sickle cell disease presenting with pain can result in preventable early mortality. Clinicians must approach a sickle cell patient reporting pain in a thoughtful manner, and consider a complete differential diagnosis, including both sickle cell disease complications and those unrelated to sickle cell disease. Knowledge of the disease courses of the different sickle cell genotypes is essential, and must go beyond a superficial hierarchy of severity, but rather include an understanding of the complications each genotype is most prone to, and at what ages. Complete laboratory assessment, including a comprehensive metabolic panel, should be performed on all admitted patients, not just a complete blood count. Treating pain with high-dose opioids, while appropriate in an uncomplicated pain crisis, can lead to ACS or even respiratory failure in a patient with uninvestigated liver and kidney dysfunction. The most important lesson to remember is that even the sickle cell disease patient who has been given the unfortunate and pejorative label of “frequent flyer” by some providers has the potential for rapid deterioration into multisystem organ failure and death.

INTRODUCTION

Sickle cell disease is the most common inherited blood disorder in the world. It affects more than 100,000 individuals in the United States, and millions more worldwide.¹ Sickle cell disease is most commonly found in individuals of African heritage, but the disease also occurs in Hispanics and people of Middle Eastern and subcontinent Indian heritage.² The distribution of the sickle hemoglobin (hemoglobin S [HbS]) allele overlaps with the distribution of malaria; HbS carriers, or individuals with sickle cell trait, have protection against malaria,³ and are not considered to have sickle cell disease.

Sickle cell disease is a severe monogenic disorder marked by significant morbidity and mortality, affecting every organ in the body.⁴ The term sickle cell disease refers to all genotypes that cause sickling; the most common are the homozygous hemoglobin SS (HbSS) and compound heterozygotes hemoglobin SC (HbSC), hemoglobin S–β⁰-thalassemia (HbSβ⁰), and hemoglobin S–β⁺-thalassemia (HbSβ⁺), although HbS and several rarer hemoglobin variants such as HbSO(Arab) and HbSD(Punjab) can also cause sickle cell disease. The term sickle cell anemia refers exclusively to the most severe genotypes, HbSS and HbSβ⁰.⁵ Common sickling genotypes along with their relative clinical severity are shown in Table 1.^6–11

This article reviews the pathophysiology of sickle cell disease, common clinical complications, and available therapies. A complex case which illustrates diagnostic and management challenges is presented as well.

PATHOPHYSIOLOGY

HbS is the result of a substitution of valine for glutamic acid in the sixth amino acid of the β-globin chain.¹² The change from a hydrophilic to a hydrophobic amino acid causes the hemoglobin molecules to stack, or polymerize, when deoxygenated. This rigid rod of hemoglobin distorts the cell, producing the characteristic crescent or sickle shape that gives the disease its name.¹³ Polymerization of hemoglobin within the cell is promoted by dehydration, which increases the concentration of HbS.^13,14 Polymerization occurs when hemoglobin is in the deoxygenated state.¹³

The sickle red blood cell is abnormal; it is rigid and dense, and lacks the deformability needed to navigate the microvasculature.¹⁵ Blockages of blood flow result in painful vaso-occlusion that is the hallmark of the disease, and that also can cause damage to the spleen, kidneys, and liver.¹⁶ The sickle red cell is also fragile, with a lifespan of only 20 days compared to the 120-day lifespan of a normal red blood cell.¹³ Frequent hemolysis results in anemia and the release of free hemoglobin, which both scavenges nitric oxide and impairs the production of more nitric oxide, which is essential for vasodilatation.¹⁷ This contributes to vascular dysfunction and an increased risk for stroke.¹⁸ If untreated, the natural course of sickle cell anemia is mortality in early childhood in most cases.¹⁹ Common chronic and acute sickle cell disease–related complications and recommended therapies, based on 2014 National Institutes of Health guidelines, are shown in Table 2 and Table 3.²⁰

One of the most challenging aspects of sickle cell disease is its clinical variability. While in general, HbSS and HbSβ⁰ are the most severe genotypes, there are patients with HbSC and HbSb⁺ who have significant sickle-cell–related complications, and may have a more severe clinical course than a HbSS patient.²¹ A great deal of this clinical variability cannot be explained, but some can be attributed to endogenous fetal hemoglobin (HbF) levels.^22–24 The importance of HbF levels in sickle cell disease was first noted by a pediatrician in the 1940s.²⁵ She observed that sickle cell disease complications in children under the age of 1 were rare, and attributed it to the presence of HbF.²⁵ HbF levels decline more slowly in individuals with hemoglobinopathies, reaching their nadir after the age of 5 rather than within 6 months of birth in individuals without hemoglobinopathies.²⁶ HbF levels remain elevated lifelong in most sickle cell disease patients, especially those with the HbSS and HbSβ⁰ genotypes. Levels of HbF vary widely between individuals, from zero to 20% to 30%, with a median of 10%.^26–28 Individuals who produce more HbF have a milder course, in general.²⁴ An association between the 4 β-globin haplotypes and HbF levels has been reported in the past,^27,29 but more sophisticated next-generation sequencing has revealed causal variants in BCL11A and HBS1L-MYB that contribute approximately 50% of the observed variability in HbF levels.^30–33

Co-inheritance of α-thalassemia also modifies disease course; less available α-globin chains results in a lower hemoglobin concentration within the cell. Paradoxically, this results in a higher overall hemoglobin level, as there is a reduction in polymerization, and therefore sickling due to lower HbS concentrations in the cell. Patients therefore are less anemic, reducing the risk of stroke in childhood,^34,35 but blood viscosity may be higher, resulting in more frequent pain crises and increased risk³⁶ of avascular necrosis.^34,35,37 It is often helpful to think of sickle cell patients as falling into 1 of 2 groups: high hemolysis/low hemoglobin and high viscosity/high hemoglobin. Individuals with high rates of hemolysis are at greater risk for stroke, pulmonary hypertension, and acute chest syndrome (ACS). Higher rates of hemolysis result in higher levels of free hemoglobin, which scavenges nitric oxide. This leads to the vascular damage and dysfunction that contributes to the associated clinical complications. This phenotype is most commonly seen in HbSS and HbSβ⁰.³⁸ High hemoglobin/high viscosity phenotypes are most often found in HbSC patients and in sickle cell anemia with α-thalassemia coinheritance.^39–42

TREATMENT OPTIONS

In high-resource countries with newborn screening, the initiation of penicillin prophylaxis has dramatically altered the natural history of the disease, allowing the majority of patients to reach adulthood.⁴³ Penicillin prophylaxis is usually discontinued at age 5 years; however, individuals who have undergone surgical splenectomy or have had pneumococcal sepsis on penicillin prophylaxis may remain on penicillin to age 18 or beyond.²⁰

Another advance in sickle cell care is screening for stroke risk through transcranial Doppler ultrasound (TCD).^44–47 This screening tool has reduced the incidence of childhood stroke from 10% by age 11 to 1%. TCDs typically cannot be performed after the age of 16 due to changes in the skull. Individuals found to have abnormal (elevated) TCD velocities are placed on chronic transfusion therapy for primary stroke prevention. They may remain on monthly chronic transfusions, with the goal of suppressing the percentage of HbS to 30% to 50% indefinitely. A clinical trial (STOPII) designed to determine if pediatric sickle cell disease patients on chronic transfusion therapy for primary stroke prevention could be safely taken off transfusion therapy was discontinued early due to an excess of strokes and conversion to abnormal TCD velocities in the untransfused arm.⁴⁴ Individuals who have experienced an ischemic stroke have a 70% risk of another stroke, and must remain on chronic transfusion therapy indefinitely. Chronic transfusion reduces their stroke risk to 13%.

The only widely used pharmacologic therapy for sickle cell disease is hydroxyurea.^12,48–50 A significant portion of the benefit of hydroxyurea stems from its induction of HbF.⁵¹ HbF does not sickle, and it interrupts the polymerization of HbS in the cell, if present in high enough concentrations.⁵⁰ The level of HbF needed to achieve clinical improvement is not known, but in vitro assays suggest 20% HbF is needed to prevent sickling.^52,53 However, endogenous and hydroxyurea-induced HbF is not distributed evenly through the red cells, so sickling is possible regardless of the level of HbF induced.^54,55 Hydroxyurea likely has other disease-modifying effects as well, including reduction of white blood cell count and reticulocyte count and reduction of red cell adhesion to the endothelium.^56–58 Clinical criteria for initiation of hydroxyurea in adult sickle cell disease patients are shown in Table 4.²⁰ Hydroxyurea is given daily and is dosed to maximum tolerated dose for the individual by following the absolute neutrophil count (ANC). The goal ANC is between 2000 and 4000/µL. At times, absolute reticulocyte count (ARC) can be dose-limiting; goal ARC is greater than 70,000/µL.⁵⁹ Platelet counts may be reduced as well, especially in HbSC patients.^60,61

The only curative therapy for sickle cell disease is hematopoietic stem cell transplant.⁶² Transplant use is limited by availability of matched sibling donors,⁶² and even at experienced centers transplant carries a small risk for mortality, graft rejection, and graft-versus-host disease. Furthermore, consensus on disease complications for which transplant is recommended is also lacking.^63–65 Clinical trials of gene therapy for sickle cell disease and thalassemia are ongoing.⁶⁶

COMPLICATIONS AND DISEASE-SPECIFIC THERAPIES

CASE PRESENTATION

A 26-year-old African-American man who works as a school bus driver presents to an academic center’s emergency department complaining of pain in his left leg, similar to prior pain events. He is described as having sickle cell trait, although no hemoglobin profile is available in his chart. He describes the pain as dull and aching, 10/10 in intensity. A complete blood count (CBC) is obtained; it reveals a hemoglobin of 14.5 g/dL, white blood cell (WBC) count of 5600/µL, and platelet count of 344,000/µL. His CBC is also notable for a mean corpuscular volume (MCV) of 72 fL, a mean corpuscular hemoglobin concentration (MCHC) of 37 g/dL, and a red blood cell distribution width (RDW) of 12. Slide review of a peripheral blood smear shows 2+ target cells (Figure).

The patient is given 6 mg of morphine, which provides some relief of his pain, and is discharged with a prescription for hydrocodone bitartrate/acetaminophen 5/325 mg. The diagnosis given is musculoskeletal pain, and he is instructed to follow-up with a primary care physician. His past medical history is significant for 4 or 5 visits to the emergency department per year in the past 4 years. Prior to 4 years ago, he rarely required medical attention.

• What laboratory and clinical features might lead you to question the diagnosis of sickle cell trait in this patient?

The patient’s hemoglobin is within normal range, which is consistent with sickle cell trait; however, he is microcytic, with a normal RDW. It is possible to be mildly microcytic in the early stages of iron deficiency, prior to the development of anemia, but the RDW would typically be elevated, demonstrating the presence of newer, smaller cells produced under conditions of iron deficiency.⁶⁷ It is also possible that his microcytosis with a normal RDW could represent sickle cell trait with co-inheritance of β-thalassemia. Up to 30% of African Americans have β-thalassemia,² and 1 in 10 have sickle cell trait.⁶⁸ However, a high MCHC, indicating the presence of dense cells, and target cells noted on slide review are most consistent with HbSC.⁹ HbSC patients, especially males, can have hemoglobin levels in the normal range.⁴ The biggest inconsistency with the diagnosis of sickle cell trait is his history of frequent pain events. Individuals with sickle cell trait rarely present with pain crises, except under extreme conditions of dehydration or high altitude.⁶⁸ Sickle cell trait is generally regarded as a benign condition, although a study of U.S. military recruits found a 30-fold higher risk of sudden death during basic training in persons with sickle cell trait.⁶⁹ Additional sickle cell trait–related complications include hematuria, risk of splenic sequestration or infarct under extreme conditions and high altitude, and a rare and usually fatal renal malignancy, renal medullary carcinoma, which is vanishingly rare in individuals without sickle cell trait.^70,71 Although the patient reported having sickle cell trait, this diagnosis should have been verified with a hemoglobin panel, given his atypical presentation.²⁰

In sickle cell disease, vaso-occlusive pain events can be common, often beginning in early childhood.¹⁷ This disease complication accounts for 95% of all adult sickle cell disease hospitalizations.⁷² There is a great deal of variability in pain symptoms between individuals, and within individuals at various times in their lives:⁷³ 30% have no pain events, 50% have occasional events, and 20% have monthly or more frequent events that require hospitalization.⁷⁴ The frequency and severity of pain events are modulated by HbF levels, β-thalassemia status, genotypes, therapies like hydroxyurea, or in rare cases, chronic transfusion therapy.²³ Personal factors, such as psychosocial stressors, also contribute to the frequency of pain events.⁷⁵ Pain event triggers include exposure to cold water, windy or cold weather, temperature changes, and extreme temperatures.^76–79 Patient age also contributes to pain event frequency. Many patients see an increase in pain event frequency in their late 20s, and a marked decrease in their 40s.^23,73 More than 3 pain events per year is associated with reduced life expectancy.²³

Acute management of pain episodes involves nonsteroidal anti-inflammatory drugs, oral opioids, and when hospitalization is required, intravenous opioids, often delivered via patient-controlled analgesia (PCA) pumps.⁷⁹ As sickle cell disease patients become teenagers and young adults, some experience an increased frequency of pain episodes, with fewer pain-free days, or a failure to return to baseline before the next pain crisis occurs.^80,81 This is characteristic of emerging chronic pain.⁸² Chronic pain is a significant problem in adult patients with sickle cell disease, with up to 85% reporting pain on most days.^72,80 The development of chronic pain may be reduced by early and aggressive treatment of acute pain events, as well as use of hydroxyurea to reduce the number of pain events. Many adult sickle cell patients with chronic pain are treated with daily opioids.²⁰ Given the significant side effects of chronic opioid use—sedation, respiratory depression, itching, nausea, and impairment of function and quality of life—non-opioid therapies are under investigation.⁸³ Many chronic pain patients have symptoms of neuropathic pain, and may benefit from neuropathic agents like gabapentin, both to reduce opioid use and to more effectively treat chronic neuropathic pain, which is known to respond poorly to opioids.^84–86

• Is the patient’s peripheral blood smear consistent with a diagnosis of sickle cell trait?

Several target cells are visible, which is not typical of sickle cell trait, but may be seen in HbSC or thalassemia. The finding of an intracellular crystal is pathognomonic for HbSC or HbCC. HbC polymerizes in high oxygen conditions, opposite of HbS, which polymerizes in low oxygen conditions.⁹

CASE CONTINUED

The patient’s family history is significant for a sister who died at age 3 from sickle cell–related complications, and a sister with sickle cell trait who had a cholecystectomy for gallstones at age 22. His father died at age 38 due to unknown causes. The sickle cell trait status of his parents is unknown. His mother is alive, and has hypertension.

• Is the medical history of this patient’s family members consistent with sickle cell trait?

It is unlikely that sickle cell trait would result in early death in childhood, or in gallstones at age 22. Gallstones in early adulthood is a common presentation for HbSC patients not diagnosed by newborn screening.⁸⁷ Any hemolytic condition can lead to the formation of hemoglobin-containing pigmented gallstones, biliary sludge, and obstruction of the gallbladder. In the presence of right-sided abdominal pain, a serum bilirubin level of more than 4 mg/dL should lead to measurement of direct bilirubin; if greater than 10% of total, imaging of the gallbladder should be obtained. In sickle cell disease, 30% of patients will have gallstones by 18 years of age. The low hemolysis/high viscosity phenotype patients are typically older at diagnosis. Co-inheritance of Gilbert syndrome and sickle cell disease is not uncommon, and can result in formation of gallstones at a young age; Gilbert syndrome alone typically results in gallstones in mid-life.⁸⁸

 

 

CASE CONTINUED

Two months later, the patient presents again to the emergency department with the same complaint of leg pain, as well as abdominal pain. His hemoglobin is 12.5 g/dL, and his platelet count is 134,000/µL. His pain is not improved with 3 doses of morphine 6 mg intravenously, and he is admitted to the medicine service. A hemoglobin profile is obtained, revealing 52% HbS, 45% HbC, and 1.5% HbF, consistent with HbSC. In sickle cell trait, the hemoglobin profile is 60% HbA and 40% HbS (available α-globin prefers to pair with a normal β-globin, so the ratio of HbA to HbS is 60:40, not 50:50).

On the second hospital day, the patient’s hemoglobin drops to 7.2 g/dL and his platelet count decreases to 44,000/µL. His abdomen is distended and diffusely tender. The internist transfuses him with 2 units of packed red blood cells (PRBC), after which his hemoglobin increases to 11 g/dL, while his platelet count increases to 112,000/µL. Following the transfusion, his abdominal pain resolves, as does his anemia and thrombocytopenia.

• What caused this patient’s anemia and thrombocytopenia?

High on the differential diagnosis is a splenic sequestration. Acute splenic sequestration occurs when red cells are trapped in the splenic sinuses. Massive splenic enlargement may occur over several hours.^89,90 Unrecognized splenic sequestration has a high mortality rate from severe anemia and splenic rupture.⁹⁰ Splenic sequestration must be ruled out in a sickle cell patient with abdominal pain accompanied by dropping platelet and red cell counts, especially in milder subtypes that often have splenic function preserved into adolescence and adulthood. Sickle cell anemia patients usually become functionally asplenic in early childhood.^89,91,92 The rise in hemoglobin, more than would be expected from 2 units of PRBC, plus the improvement in platelet count without a platelet transfusion observed in the case patient strongly supports the diagnosis of splenic sequestration.

Splenic sequestration can occur in any sickle cell patient whose spleen has not fibrosed. Splenic sequestration in adulthood is not uncommon in HbSC patients, who often have preserved splenic function into adulthood.^93–95

Clinical signs of splenic sequestration include a rapid drop in hemoglobin, rise in reticulocyte count, a tender, enlarged spleen, and, in severe cases, hypovolemia.^89,93 It is treated with prompt blood transfusion, but care must be taken not to overtransfuse the patient, as the spleen can trap several grams of hemoglobin, which may be released upon transfusion, potentially causing life-threatening hyperviscosity.⁸⁹ Hemoglobin levels must be checked following transfusion in suspected splenic sequestration, and “mini transfusions” of 5 mL/kg are recommended in sickle cell disease patients who are hemodynamically stable.²⁰

Hepatic sequestration may also occur, but it is much less common than splenic sequestration.⁹⁶ Other conditions on the differential diagnosis include thrombotic thrombocytopenic purpura, which would be unlikely to respond to a transfusion. ACS can cause a drop in hemoglobin, and is treated with simple or exchange transfusions.⁹⁷ ACS is less likely without respiratory symptoms or oxygen requirement, and usually is not associated with thrombocytopenia. Sepsis may also cause anemia and thrombocytopenia, but again would not likely respond to a simple transfusion. The patient’s response to transfusion is consistent with a sequestering event, not a destructive event as in the case of sepsis.

CASE CONTINUED

Imaging reveals a grossly enlarged spleen, which is having a mass effect on the left kidney. The patient is started on hydroxyurea therapy at 500 mg 3 times daily. Discharge instructions include following up with his primary care physician, continuing hydroxyurea therapy, and receiving yearly dilated eye exams to evaluate for proliferative sickle retinopathy.

• Are these discharge instructions complete?

Splenic sequestration has a 50% recurrence rate.⁹⁸ In very young children, watchful waiting or chronic transfusion may be implemented to preserve the immunologic function of the spleen and reduce the risk of sepsis.⁸⁹ Splenectomy after a single episode of sequestration in adults is a matter of debate, with experts advising both watchful waiting⁹⁹ and splenectomy after recovery from the first sequestering event.¹⁰⁰ The patient should have been informed of the risk for recurrence, and the signs and symptoms of splenic sequestration as well as the need for emergency medical attention should have been discussed. Splenic sequestration may be milder in adults than in children, but fatal sequestrations have been reported.^95,101–103

Proliferative sickle cell retinopathy is a high viscosity/high hemoglobin complication that may occur more frequently in HbSC than HbSS, with an incidence of 33% in HbSC.^42,104 Spontaneous regression of retinopathy occurs in approximately 32% of eyes, and laser or scatter photocoagulation is an effective intervention.¹⁰⁵

• Would the patient need to be transfused prior to splenectomy?

Preoperative transfusion therapy is standard of care for HbSS patients undergoing general anesthesia. The TRAP study found that simple “top off” transfusion to a hemoglobin of 10 g/dL was as effective at preventing postoperative sickle cell–related complications as exchange transfusion to HbS of 30% or less, and had fewer transfusion-related complications like alloimmunization.¹⁰⁶ There is little data regarding preoperative transfusions in HbSC disease. A retrospective study suggests that HbSC patients undergoing abdominal surgeries should be transfused.¹⁰⁷ The higher hemoglobin level of the typical HbSC patient necessitates exchange transfusion to avoid hyperviscosity.

• Is hydroxyurea therapy indicated in this patient?

• Has it been dosed appropriately?

If the patient had the HbSS subtype, hydroxyurea would be clearly indicated, given his frequent pain events.²⁰ HbSC patients may be placed on hydroxyurea on a case-by-case basis, but evidence for its efficacy in this sickle cell subtype is lacking.¹⁰⁸ Large clinical trials like the Multi-Center Study of Hydroxyurea (MSH) that established the safety and efficacy of hydroxyurea in sickle cell anemia excluded HbSC and HbSβ⁺ patients.¹⁰⁹ These mild to moderate subtypes produce less HbF at baseline, and typically have a minimal to modest rise in HbF on hydroxyurea.¹¹⁰ In sickle cell anemia, hydroxyurea is titrated to maximum tolerated dose, defined as an ANC of 2000 to 4000/µL and an ARC of 70,000/µL or higher.⁵³ Because of their lower levels of chronic inflammation and lower reticulocyte counts due to higher hemoglobin levels, many HbSC and HbSβ⁺ patients have values in that range before initiating hydroxyurea therapy.⁹ Cytopenias, particularly of platelets in HbSC, occur at low doses of hydroxyurea.¹¹¹

Of note, although the half-life of hydroxyurea would suggest that 3 times daily dosing is indicated, daily dosing has been found to have equal response and is preferred. Another concern is the monitoring of this myelosuppressive medication. This patient has repeatedly failed to obtain a primary care physician or a hematologist, and hydroxyurea requires laboratory monitoring at least every 2 months, especially in a HbSC patient with a very large spleen who is at significant risk for thrombocytopenia and neutropenia.⁹

CASE CONTINUED

A week after discharge from his admission for abdominal pain diagnosed as splenic sequestration, the patient presents again to the emergency department with abdominal pain which he reports is his typical sickle cell pain. Hemoglobin is 13.8 g/dL, platelet count is 388,000/µL, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are both 10 times their prior value. Creatinine is 1.2 mg/dL (0.75 mg/dL on his prior admission), and total bilirubin is 3 mg/dL, with 0.3 mg/dL direct bilirubin. He undergoes an ultrasound exam of his gallbladder, which reveals sludge and a possible gallstone. There is no evidence of cholecystitis. General surgery performs a laparoscopic cholecystectomy.

• Was this cholecystectomy necessary?

In patients with sickle cell disease, symptomatic gallstones and gallbladder sludge should be observed; recurrent abdominal pain without a significant change in bilirubin may not be due to gallstones or sludge, and therefore may not be relieved by cholecystectomy.^112,113 In sickle cell disease, 40% of patients with gallbladder sludge do not develop gallstones.⁸⁷ The patient’s bilirubin level was at baseline, and there was no increase in the direct (conjugated) fraction. Watchful waiting would have been appropriate, with cholecystectomy being performed if he experienced recurrent symptoms associated with fatty foods accompanied by an elevation in direct bilirubin.

More concerning and deserving of investigation was his elevated liver enzymes. Patients with sickle cell disease may experience recurrent ischemia and reperfusion injuries in the liver, which is called right upper quadrant syndrome. On autopsy of 70 sickle cell patients, 91% had hepatomegaly and 34% had focal necrosis.¹¹⁴ AST is often elevated in sickle cell disease, as it is affected by hemolysis. In this patient, both AST and ALT are elevated, consistent with a hepatocellular disorder. His abdominal pain and ALT rise may be a sign of a hepatic crisis.¹¹⁵ Rapid resolution of ALT elevation in a matter of days suggests a vaso-occlusive, inflammatory event that is self- limiting. Prolonged AST elevation requires further investigation, with consideration of autoimmune hepatitis, viral hepatitis, or iron overload. Iron overload is unlikely in this patient given his lifetime history of only 1 transfusion. Hepatic iron overload typically occurs in sickle cell disease after a minimum of 10 transfusions.¹¹⁵

CASE CONTINUED

The patient is discharged on the day after the procedure, with instructions to continue his hydroxyurea.

• Should the patient resume hydroxyurea therapy?

Hydroxyurea is hepatically cleared and thus it should be held until his liver function tests normalize.¹⁰⁶

CASE CONTINUED

Two months later, the patient presents to the emergency department with abdominal pain that moves to his left leg. A CBC is obtained, showing a hemoglobin of 11.8 g/dL and a platelet count of 144,000/µL. He is given 2 doses of morphine 6 mg intravenously, and reports that his leg pain is now a 4/10. He is discharged home with a prescription for hydrocodone/acetaminophen.

• Is the emergency department evaluation sufficient?

This patient remains at high risk for splenic sequestration,⁹³ with a hemoglobin 2 g lower than it was 2 months ago and platelets less than half. This decline could be consistent with early splenic sequestration.²⁰ Additionally, he had elevated liver function tests on a recent admission, as well as rising creatinine, without evidence of resolution. It is not appropriate to discharge him without checking a chemistry and liver panel, and abdominal imaging should be considered. The best plan would be to admit him for observation, given his risk for splenic sequestration, and consult surgery for an elective splenectomy if he has a second episode of splenic sequestration 2 months after the first.¹⁰⁰ His abdominal pain that migrates to his left leg could be due to his massive splenomegaly compressing his left kidney, as noted on imaging during his recent admission for splenic sequestration

CASE CONTINUED

An hour after discharge from the emergency department, EMS is called to his home for intractable pain. He is found lying on the floor, and reports excruciating left leg pain. He is brought to the closest hospital, a community hospital that he has not visited previously. There, he is admitted for hydration and pain control and placed on hydromorphone 2 mg every 4 hours as needed for pain. His hemoglobin is 10.8 g/dL, and platelets are 121,000/µL. A chemistry panel is remarkable for a creatinine level of 1.5 mg/dL and a potassium level of 3.2 mEq/L. Liver function tests are not obtained. After 3 doses of hydromorphone, he falls asleep. He is not in a monitored bed, and intravenous fluids, while ordered, are not started. At 6:30 AM the day after admission, he cannot be aroused on a routine vital sign check; he has an SpO₂ of 60%, a blood pressure of 80/60 mm Hg, and heart rate of 148 beats/min. A rapid response is called, and naloxone is administered along with oxygen by face mask and several fluid boluses. His systolic blood pressure increases to 100 mm Hg from a low of 70 mm Hg. His SpO₂ increases to 92%, and he is arousable and alert, although he reports 10/10 leg pain. His abdomen is noted to be distended and tender.

• What may have contributed to his clinical condition?

The patient is opioid tolerant and has received equivalent doses of opioids in the past without excess sedation. He may have liver dysfunction making him unable to metabolize opioids effectively. His hemoglobin and platelets continue to decline, raising concern for splenic sequestration versus sepsis. Failure to place him on a monitor allowed his hypoxia to continue for an unknown amount of time, placing him at high risk for developing ACS. Lack of intravenous hydration while he was too sedated to drink likely exacerbated his sickling.

 

 

CASE CONTINUED

At 9:20 AM, a CBC is obtained and reveals a hemoglobin of 4.8 g/dL and a platelet count of 44,000/µL. Two units of stat O negative blood are administered, and preparations are made to administer an exchange transfusion. A liver panel is obtained 3 hours later, which reveals an AST level of 1200 U/L and an ALT level of 1050 U/L. His bilirubin is 10 mg/dL, and his lactate dehydrogenase level is 1800 U/L. His urine is dark and is positive for bilirubin and ketones. He is transferred to the intensive care unit. A chest X-ray shows pulmonary congestion. Hematology/oncology is consulted.

He receives a 7-unit red blood cell exchange, which reduces his HbS to 11%. He continues to be hypotensive, and requires norepinephrine to support his blood pressure. Antibiotic therapy is started. His creatinine concentration rises to 2.3 mg/dL, potassium is 7.8 mEq/L, and bicarbonate is 12 mEq/L. He is placed on hemodialysis.

Computed tomography of the chest and abdomen reveals lower posterior lung infiltrates and a grossly enlarged spleen. He requires intubation. He is given a diagnosis of ACS in addition to kidney failure, liver failure, and “sickle crisis.” He continues to require daily to twice daily transfusions to maintain a hemoglobin of 7 to 9 g/dL, and his abdominal distension increases. As his condition worsens, surgery is consulted to discuss a liver transplant. He is deemed to not be a surgical candidate, and he passes away 6 days after entering the hospital. The immediate cause of death is listed as vaso-occlusive crisis, with ACS and sickle crisis listed as contributors.

• Are the causes of death accurate and complete?

If vaso-occlusive crisis is used to indicate a pain event, it is not an accurate cause of death. Pain is one of the most distressing complications of sickle cell disease, and frequent pain events are associated with early mortality,^4,80 but they are not in themselves fatal. ACS is the number one cause of death in sickle cell disease,⁴ and it likely contributed to this patient’s death. Sickle crisis is a vague term that should not be used in this context. Causes of death should include splenic sequestration and multisystem organ failure. Multisystem organ failure in sickle cell disease often responds to aggressive transfusion therapy, which this patient received.^116–118

CONCLUSION

Sickle cell disease is a complex chronic disease that impacts almost every organ system in the body. Clinicians may be inclined to attribute most pain in a patient with sickle cell disease to a simple vaso-occlusive crisis, treat them for this, and not investigate further. As the case presented here demonstrates, failure to identify the actual life-threatening process occurring in a patient with sickle cell disease presenting with pain can result in preventable early mortality. Clinicians must approach a sickle cell patient reporting pain in a thoughtful manner, and consider a complete differential diagnosis, including both sickle cell disease complications and those unrelated to sickle cell disease. Knowledge of the disease courses of the different sickle cell genotypes is essential, and must go beyond a superficial hierarchy of severity, but rather include an understanding of the complications each genotype is most prone to, and at what ages. Complete laboratory assessment, including a comprehensive metabolic panel, should be performed on all admitted patients, not just a complete blood count. Treating pain with high-dose opioids, while appropriate in an uncomplicated pain crisis, can lead to ACS or even respiratory failure in a patient with uninvestigated liver and kidney dysfunction. The most important lesson to remember is that even the sickle cell disease patient who has been given the unfortunate and pejorative label of “frequent flyer” by some providers has the potential for rapid deterioration into multisystem organ failure and death.

Over 20 million endoscopic procedures are performed in the United States annually. A small but significant number of patients undergoing these procedures will have valvular heart disease. Bacteremia can occur after endoscopic procedures, and this may carry an increased risk for the development of infective endocarditis in patients with valvular heart disease.

Throughout the 1980s to 2000s, based on expert opinion and the related American Heart Association (AHA) guidelines in 1997, many patients with valvular abnormalities would routinely receive antibiotics before endoscopy. There would be much anxiety among patients and providers to choose the right antibiotic and not to “miss” a patient with cardiac issues, especially those scheduled as open access. Antibiotics were stocked in GI labs, and questionnaires or intake forms inquired about cardiac history.

There are also significant implications for savings in costs and time as well as for reducing adverse events associated with antibiotics. Theoretically, the new guidelines also improved access to endoscopy as those patients who might have avoided procedures due to the perceived risk of endocarditis or the need for prophylactic antibiotics no longer had that concern.

After decades of pre-endoscopy prophylactic antibiotic use, clinical acceptance of the new guidelines took time. During training, I remember concerned looks from patients who had previously routinely received antibiotics. In addition, some consulting cardiologists and referring physicians were either not aware of the new guidelines or were not yet comfortable with the new recommendations, despite the fact that “brushing your teeth leads to more instances of bacteremia than endoscopy” was well known.

Despite the slow start, inappropriate use of prophylactic antibiotics was phased out, and postendoscopy endocarditis did not appear as a new problem, thereby confirming the wisdom of the new approach. This example shows how one article that appeared in the June 2007* issue of GI & Hepatology News introduced an important recommendation that resulted in a major shift in the practice of endoscopy.

Gyanprakash A. Ketwaroo, MD, MSc is an assistant professor in the division of gastroenterology and hepatology at Bayor College of Medicine, Houston, and an Associate Editor of GI & Hepatology News.

*This story was corrected on 1/10/16.

Over 20 million endoscopic procedures are performed in the United States annually. A small but significant number of patients undergoing these procedures will have valvular heart disease. Bacteremia can occur after endoscopic procedures, and this may carry an increased risk for the development of infective endocarditis in patients with valvular heart disease.

Throughout the 1980s to 2000s, based on expert opinion and the related American Heart Association (AHA) guidelines in 1997, many patients with valvular abnormalities would routinely receive antibiotics before endoscopy. There would be much anxiety among patients and providers to choose the right antibiotic and not to “miss” a patient with cardiac issues, especially those scheduled as open access. Antibiotics were stocked in GI labs, and questionnaires or intake forms inquired about cardiac history.

There are also significant implications for savings in costs and time as well as for reducing adverse events associated with antibiotics. Theoretically, the new guidelines also improved access to endoscopy as those patients who might have avoided procedures due to the perceived risk of endocarditis or the need for prophylactic antibiotics no longer had that concern.

After decades of pre-endoscopy prophylactic antibiotic use, clinical acceptance of the new guidelines took time. During training, I remember concerned looks from patients who had previously routinely received antibiotics. In addition, some consulting cardiologists and referring physicians were either not aware of the new guidelines or were not yet comfortable with the new recommendations, despite the fact that “brushing your teeth leads to more instances of bacteremia than endoscopy” was well known.

Despite the slow start, inappropriate use of prophylactic antibiotics was phased out, and postendoscopy endocarditis did not appear as a new problem, thereby confirming the wisdom of the new approach. This example shows how one article that appeared in the June 2007* issue of GI & Hepatology News introduced an important recommendation that resulted in a major shift in the practice of endoscopy.

Gyanprakash A. Ketwaroo, MD, MSc is an assistant professor in the division of gastroenterology and hepatology at Bayor College of Medicine, Houston, and an Associate Editor of GI & Hepatology News.

*This story was corrected on 1/10/16.

Over 20 million endoscopic procedures are performed in the United States annually. A small but significant number of patients undergoing these procedures will have valvular heart disease. Bacteremia can occur after endoscopic procedures, and this may carry an increased risk for the development of infective endocarditis in patients with valvular heart disease.

Throughout the 1980s to 2000s, based on expert opinion and the related American Heart Association (AHA) guidelines in 1997, many patients with valvular abnormalities would routinely receive antibiotics before endoscopy. There would be much anxiety among patients and providers to choose the right antibiotic and not to “miss” a patient with cardiac issues, especially those scheduled as open access. Antibiotics were stocked in GI labs, and questionnaires or intake forms inquired about cardiac history.

There are also significant implications for savings in costs and time as well as for reducing adverse events associated with antibiotics. Theoretically, the new guidelines also improved access to endoscopy as those patients who might have avoided procedures due to the perceived risk of endocarditis or the need for prophylactic antibiotics no longer had that concern.

After decades of pre-endoscopy prophylactic antibiotic use, clinical acceptance of the new guidelines took time. During training, I remember concerned looks from patients who had previously routinely received antibiotics. In addition, some consulting cardiologists and referring physicians were either not aware of the new guidelines or were not yet comfortable with the new recommendations, despite the fact that “brushing your teeth leads to more instances of bacteremia than endoscopy” was well known.

Despite the slow start, inappropriate use of prophylactic antibiotics was phased out, and postendoscopy endocarditis did not appear as a new problem, thereby confirming the wisdom of the new approach. This example shows how one article that appeared in the June 2007* issue of GI & Hepatology News introduced an important recommendation that resulted in a major shift in the practice of endoscopy.

Gyanprakash A. Ketwaroo, MD, MSc is an assistant professor in the division of gastroenterology and hepatology at Bayor College of Medicine, Houston, and an Associate Editor of GI & Hepatology News.

*This story was corrected on 1/10/16.

One-year survival without liver transplant was far more likely when transjugular intrahepatic portosystemic shunts (TIPS) with covered stents were used to treat cirrhosis with recurrent ascites, instead of ongoing large-volume paracenteses with albumin, in a 62-patient randomized trial from France.

“TIPS with covered stents ... should therefore be preferred to LVP [large-volume paracenteses] with volume expansion... These findings support TIPS as the first-line intervention,” said investigators led by gastroenterologist Christophe Bureau, MD, of Toulouse (France) University in the January issue of Gastroenterology (doi: 10.1053/j.gastro.2016.09.016).

All 62 patients had at least two LVPs prior to the study; 29 were then randomized to covered transjugular intrahepatic portosystemic shunt (TIPS), and 33 to LVP and albumin as needed. All the patients were on a low-salt diet.

Twenty-seven TIPS patients (93%) were alive without a liver transplant at 1 year, versus 17 (52%) in the LVP group (P = .003). TIPS patients had a total of 32 paracenteses in the first year, versus 320 in the LVP group. Six paracentesis patients (18%) had portal hypertension–related bleeding, and six had hernia-related complications; none of the TIPS patients had either. LVP patients spent a mean of 35 days in the hospital, versus 17 days for the TIPS group (P = .04). The probability of remaining free of encephalopathy at 1 year was the same in both groups, at 65%.

It has been shown before that TIPS has the edge on LVP for reducing recurrence of tense ascites. However, early studies used uncovered stents and, due to their almost 80% risk of dysfunction, they did not show a significant benefit for survival. As a result, repeated paracenteses have been recommended as first-line treatment, with TIPS held in reserve for patients who need very frequent LVP.

Polytetrafluoroethylene-covered stents appear to have changed the equation, “owing to a substantial decrease in the rate of shunt dysfunction,” the investigators said.

The French results are a bit better than previous reports of covered TIPS. “This could be related to greater experience with the TIPS procedure;” there were no technical failures. The study also mostly included patients younger than 65 years with Child-Pugh class B disease and no prior encephalopathy – favorable factors that also may have contributed to the results. However, “we believe that the use of covered stents was the main determinant of the observed improvement in outcomes... TIPS with uncovered stent[s] should not be considered effective or recommended any longer for the long-term treatment of” portal hypertension, they said.

Cirrhosis in the trial was due almost entirely to alcohol abuse. About three-quarters of both groups reported abstinence while enrolled. The mean age was 56 years, and the majority of subjects were men.

The work was funded by the French Ministry of Health and supported by Gore, maker of the covered stent used in the study. Dr. Bureau and another author are Gore consultants.

[email protected]

One-year survival without liver transplant was far more likely when transjugular intrahepatic portosystemic shunts (TIPS) with covered stents were used to treat cirrhosis with recurrent ascites, instead of ongoing large-volume paracenteses with albumin, in a 62-patient randomized trial from France.

“TIPS with covered stents ... should therefore be preferred to LVP [large-volume paracenteses] with volume expansion... These findings support TIPS as the first-line intervention,” said investigators led by gastroenterologist Christophe Bureau, MD, of Toulouse (France) University in the January issue of Gastroenterology (doi: 10.1053/j.gastro.2016.09.016).

All 62 patients had at least two LVPs prior to the study; 29 were then randomized to covered transjugular intrahepatic portosystemic shunt (TIPS), and 33 to LVP and albumin as needed. All the patients were on a low-salt diet.

Twenty-seven TIPS patients (93%) were alive without a liver transplant at 1 year, versus 17 (52%) in the LVP group (P = .003). TIPS patients had a total of 32 paracenteses in the first year, versus 320 in the LVP group. Six paracentesis patients (18%) had portal hypertension–related bleeding, and six had hernia-related complications; none of the TIPS patients had either. LVP patients spent a mean of 35 days in the hospital, versus 17 days for the TIPS group (P = .04). The probability of remaining free of encephalopathy at 1 year was the same in both groups, at 65%.

It has been shown before that TIPS has the edge on LVP for reducing recurrence of tense ascites. However, early studies used uncovered stents and, due to their almost 80% risk of dysfunction, they did not show a significant benefit for survival. As a result, repeated paracenteses have been recommended as first-line treatment, with TIPS held in reserve for patients who need very frequent LVP.

Polytetrafluoroethylene-covered stents appear to have changed the equation, “owing to a substantial decrease in the rate of shunt dysfunction,” the investigators said.

The French results are a bit better than previous reports of covered TIPS. “This could be related to greater experience with the TIPS procedure;” there were no technical failures. The study also mostly included patients younger than 65 years with Child-Pugh class B disease and no prior encephalopathy – favorable factors that also may have contributed to the results. However, “we believe that the use of covered stents was the main determinant of the observed improvement in outcomes... TIPS with uncovered stent[s] should not be considered effective or recommended any longer for the long-term treatment of” portal hypertension, they said.

Cirrhosis in the trial was due almost entirely to alcohol abuse. About three-quarters of both groups reported abstinence while enrolled. The mean age was 56 years, and the majority of subjects were men.

The work was funded by the French Ministry of Health and supported by Gore, maker of the covered stent used in the study. Dr. Bureau and another author are Gore consultants.

[email protected]

One-year survival without liver transplant was far more likely when transjugular intrahepatic portosystemic shunts (TIPS) with covered stents were used to treat cirrhosis with recurrent ascites, instead of ongoing large-volume paracenteses with albumin, in a 62-patient randomized trial from France.

“TIPS with covered stents ... should therefore be preferred to LVP [large-volume paracenteses] with volume expansion... These findings support TIPS as the first-line intervention,” said investigators led by gastroenterologist Christophe Bureau, MD, of Toulouse (France) University in the January issue of Gastroenterology (doi: 10.1053/j.gastro.2016.09.016).

All 62 patients had at least two LVPs prior to the study; 29 were then randomized to covered transjugular intrahepatic portosystemic shunt (TIPS), and 33 to LVP and albumin as needed. All the patients were on a low-salt diet.

Twenty-seven TIPS patients (93%) were alive without a liver transplant at 1 year, versus 17 (52%) in the LVP group (P = .003). TIPS patients had a total of 32 paracenteses in the first year, versus 320 in the LVP group. Six paracentesis patients (18%) had portal hypertension–related bleeding, and six had hernia-related complications; none of the TIPS patients had either. LVP patients spent a mean of 35 days in the hospital, versus 17 days for the TIPS group (P = .04). The probability of remaining free of encephalopathy at 1 year was the same in both groups, at 65%.

It has been shown before that TIPS has the edge on LVP for reducing recurrence of tense ascites. However, early studies used uncovered stents and, due to their almost 80% risk of dysfunction, they did not show a significant benefit for survival. As a result, repeated paracenteses have been recommended as first-line treatment, with TIPS held in reserve for patients who need very frequent LVP.

Polytetrafluoroethylene-covered stents appear to have changed the equation, “owing to a substantial decrease in the rate of shunt dysfunction,” the investigators said.

The French results are a bit better than previous reports of covered TIPS. “This could be related to greater experience with the TIPS procedure;” there were no technical failures. The study also mostly included patients younger than 65 years with Child-Pugh class B disease and no prior encephalopathy – favorable factors that also may have contributed to the results. However, “we believe that the use of covered stents was the main determinant of the observed improvement in outcomes... TIPS with uncovered stent[s] should not be considered effective or recommended any longer for the long-term treatment of” portal hypertension, they said.

Cirrhosis in the trial was due almost entirely to alcohol abuse. About three-quarters of both groups reported abstinence while enrolled. The mean age was 56 years, and the majority of subjects were men.

The work was funded by the French Ministry of Health and supported by Gore, maker of the covered stent used in the study. Dr. Bureau and another author are Gore consultants.

[email protected]

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Guillermo Garcia-Manero, MD
Photo courtesy of
MD Anderson Cancer Center

SAN DIEGO—Neither a 2-drug combination nor a 3-drug combination is superior to 7+3 chemotherapy in younger patients with previously untreated acute myeloid leukemia (AML), according to a phase 3 trial.

Treatment

with idarubicin and high-dose cytarabine (IA), with or without

vorinostat (V), was no more effective than standard cytarabine plus

daunorubicin (7+3) in this trial.

In fact, among patients with favorable cytogenetics, outcomes with IA or IA+V were inferior to outcomes with 7+3.

Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2016 ASH Annual Meeting (abstract 901*).

In a phase 2 trial, Dr Garcia-Manero and his colleagues found that IA+V produced a high response rate (85%) in patients with previously untreated AML or high-risk myelodysplastic syndromes.

So the researchers conducted a phase 3 study (SWOG S1203) to determine if IA or IA+V could improve outcomes for younger AML patients when compared to 7+3.

Treatment

Induction therapy was as follows:

• 7+3 arm—daunorubicin** at 90 mg/m² once daily on days 1 to 3 with cytarabine at 100 mg/m² once daily on days 1 to 7.
• IA arm—idarubicin at 12 mg/m² once daily on days 1 to 3 with cytarabine at 1.5 gm/m² once daily on days 1 to 4.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 12 mg/m² once daily on days 4 to 6, and cytarabine at 1.5 gm/m² once daily on days 4 to 7. 

Consolidation was as follows:

• 7+3 arm—standard high-dose cytarabine at 3 gm/m² over 3 hours every 12 hours x 6 doses for 1 to 4 cycles, depending on transplant availability.
• IA arm—idarubicin at 8 mg/m² once daily on days 1 to 2 with cytarabine at 0.75 mg/m² for 3 days on days 1 to 3 for 4 cycles.
• IA+V arm—vorinostat at 500 mg orally 3 times a day on days 1 to 3, idarubicin at 8 mg/m² once daily on days 4 to 5, and cytarabine at 0.75 gm/m² once daily on days 4 to 6.

The number of consolidation cycles varied depending on transplant indication. In all, 43% of patients (n=317) proceeded to allogeneic transplant. (Details on these patients were presented at ASH as abstract 1166.)

Patients in the IA+V arm also received maintenance with vorinostat at 300 mg 3 times a day for 14 days every 28 days. 

**There was a shortage of daunorubicin during this trial. So if daunorubicin was not available, patients received idarubicin at 12 mg/m² once daily on days 1 to 3. Dr Garcia-Manero could not provide data on how many patients assigned to daunorubicin actually received idarubicin.

Patients

There were a total of 738 eligible patients—261 in the 7+3 arm, 261 in the IA arm, and 216 in the IA+V arm. Dr Garcia-Manero said baseline characteristics were well balanced among the arms.

Overall, the median age was 49 (range, 18-60), 49% of patients were female, and 13% had a performance status of 2-3.

Thirteen percent of patients had favorable cytogenetics, 22% had high-risk cytogenetics, 16% had FLT3-ITD, and 21% had mutated NPM1.

Results

The complete response rates were 62% overall, 63% for 7+3, 64% for IA, and 60% for IA+V (P=0.58).

The rates of complete response with incomplete count recovery were 15%, 13%, 16%, and 17%, respectively. The failure rates were 23%, 25%, 21%, and 23%, respectively.

The rate of mortality within 30 days was 4% overall, 3% for 7+3, 6% for IA, and 4% for IA+V (P=0.013). The rate of mortality within 60 days was 7%, 5%, 9%, and 9%, respectively (P=0.097).

The rate of event-free survival was 42% overall, 43% for 7+3, 43% for IA, and 40% for IA+V.

There was no significant difference in event-free survival between IA+V and IA (P=0.66), IA+V and 7+3 (P=0.91), or IA and 7+3 (P=0.76). 
 
The rate of overall survival (OS) was 62% overall, 62% for 7+3, 63% for IA, and 59% for IA+V.

There was no significant difference in OS between IA+V and IA (P=0.6), IA+V and 7+3 (P=0.67), or IA and 7+3 (P=0.92). 

Among patients with favorable cytogenetics, there was no significant difference in OS between IA and IA+V (P=0.8). However, patients who received IA (P=0.011) or IA+V (P=0.012) had significantly better OS than patients who received 7+3.

There were more grade 5 adverse events (AEs) in the IA (n=19) and IA+V arms (n=16) than in the 7+3 arm (n=6).

Grade 5 AEs in the 7+3 arm were classified as follows: cardiac disorder (n=1), gastrointestinal disorder (n=1), general disorders (n=2), hepatobiliary disorder (n=1), and respiratory/thoracic/mediastinal disorder (n=1).

Grade 5 AEs in the IA arm included cardiac disorders (n=3), gastrointestinal disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), respiratory/thoracic/mediastinal disorders (n=4), and vascular disorder (n=1).

Grade 5 AEs in the IA+V arm included cardiac disorder (n=1), general disorders (n=2), infections and infestations (n=7), nervous system disorder (n=1), and respiratory/thoracic/mediastinal disorders (n=5).

“In newly diagnosed adults with AML ages 18 to 60, neither IA [plus] vorinostat nor IA were superior to standard 7+3,” Dr Garcia-Manero said in closing.

“Indeed, 7+3 was superior to IA and IA [plus] vorinostat for those patients with favorable cytogenetics, reinforcing the need for high-dose ara-C during the consolidation phase. Newer studies with other combinations, including, perhaps, nucleoside analogues, monoclonal antibodies, or targeted agents are needed.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.

MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.

The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.

What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.

“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.

Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).

“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”

Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).

In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.

“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”

Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.

Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.

CRS with CTL019

Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.

“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”

The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.

“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”

Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.

The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.

“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.

Studying CRS

IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.

He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.

With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.

“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.

To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.

The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.

The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.

“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”

The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.

“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.

The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.

“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.

To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.

The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.

On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.

Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.

The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.

Nanostring profiling

The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.

They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.

“There was a clear separation in cytokine production in this model,” Dr Barrett said.

The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.

“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.

In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.

“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”

The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.

They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.

“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.

MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.

The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.

What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.

“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.

Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).

“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”

Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).

In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.

“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”

Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.

Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.

CRS with CTL019

Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.

“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”

The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.

“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”

Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.

The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.

“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.

Studying CRS

IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.

He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.

With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.

“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.

To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.

The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.

The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.

“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”

The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.

“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.

The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.

“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.

To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.

The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.

On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.

Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.

The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.

Nanostring profiling

The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.

They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.

“There was a clear separation in cytokine production in this model,” Dr Barrett said.

The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.

“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.

In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.

“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”

The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.

They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.

“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Investigators have found that life-threatening cytokine release syndrome (CRS) and its symptoms are due to the release of macrophage activation syndrome (MAS) cytokines, such as IL-6, IL-8, and IL2RA.

MAS cytokines, at least in vitro, are not made by chimeric antigen receptor (CAR) T cells and are not necessary for CAR T-cell efficacy, the team says.

The cytokines are produced by antigen-presenting cells (APCs) in response to CAR-mediated killing of leukemia.

What’s more, they say, is that this is likely to be different for each CAR structure and possibly even tumor type.

“Understanding these mechanisms, as it relates to our treatment, will be critical to understanding how best to take care of patients and maintain efficacy without toxicity,” said David Barrett, MD, PhD, of the University of Pennsylvania in Philadelphia.

Dr Barrett discussed the relationship between IL-6, CRS, and CAR T-cell therapy at the 2016 ASH Annual Meeting (abstract 654).

“Every CAR system is slightly different,” he explained, “and it’s very important to understand that when we’re talking about efficacy and toxicity.”

Dr Barrett focused on CTL019 (also known as CART19), the CD19-directed 4-1BB CD3ζ CAR used at the Children’s Hospital of Philadelphia (CHOP).

In pediatric acute lymphoblastic leukemia (ALL), CTL019 produced a 93% response rate at 1 month and an overall survival rate of 79% at 12 months in 59 patients.

“Some relapses take place,” Dr Barrett noted. “This is not a perfect therapy, although it has been transformative in the care of patients.”

Eighty-eight percent of the patients experienced CRS of any grade, and 2 died from it. CRS causes high fever and myalgias, and severe CRS causes unstable hypotension that can require mechanical ventilation.

Tocilizumab, the IL-6R blocking antibody, was used in 27% of the patients, generally for grade 4 CRS.

CRS with CTL019

Dr Barrett described CRS in the first patient treated with CTL019 at CHOP in April 2012. The CRS was quite severe, with high fevers and unstable hypotension requiring multiple vasopressors and the need for mechanical ventilation.

“[W]e had no idea what was happening,” he said. “We didn’t understand what the source of the illness was.”

The patient did not respond to steroids or to etanercept, which Dr Barrett indicated is known to help in acute respiratory distress in transplant patients.

“And it was only through some incredible clinical acumen of the treating physicians as well as incredible critical care that was delivered by our ICU that kept this patient alive long enough for us to try tocilizumab,” Dr Barrett continued, “which, thankfully, worked by blocking the most severe side effects in this patient and allowed her to survive.”

Dr Barrett described the course of another patient who developed grade 4 CRS that continued to get worse even after he received tocilizumab, siltuximab, and steroids.

The patient required vasoactive drugs, had seizures, required milrinone, and was placed on a ventilator. One year after receiving CAR T-cell therapy, he recovered.

“This is an incredibly terrifying syndrome to take care of when we don’t understand what’s triggering it or how to stop it,” Dr Barrett emphasized.

Studying CRS

IL-6 is clearly a critical cytokine in the toxicity of CAR T-cell therapy, Dr Barrett said, but IFNγ and other cytokines are also important.

He and his colleagues performed a comprehensive cytokine analysis of pediatric patients treated with CTL019—specifically, engineered T cells composed of an anti-CD19 single-chain variable fragment, CD3ζ activation domain, a 4-1BB costimulatory domain, and transduced with a lentivirus grown on CD3/CD28 beads with a little bit of IL-2.

With that specific CAR, Dr Barrett said they observed a MAS pattern—IFNγ, IL-10, IL-6, and IL-8, which are most elevated in grades 4 and 5 CRS.

“[S]o this pattern, and this clinical syndrome [CRS] was what we believe was driving toxicity in this model,” he said.

To figure out why this was happening, the investigators created 4-1BB CAR-mediated CRS in a mouse model.

The team took leukemia cells from the first patient treated and clinical T cells from her CAR product and put them in an NSG mouse model that they had used for preclinical development.

The investigators then measured cytokine production in the serum of animals 3 and 7 days post-treatment with CTL019.

“And nothing happened,” Dr Barrett said. “The mice didn’t get sick, they cleared their leukemia, and when you looked for cytokines, you found IFNγ, IL-2, and GM-CSF, but you did not find IL-6.”

The team had also included etanercept and tocilizumab in this model, but since the mice didn’t make the toxic cytokines, the antibodies didn’t do anything.

“So why did she get so sick but yet her cancer and her CAR T cells did not make these mice sick and not generate these cytokines?” Dr Barrett asked.

The investigators hypothesized that APCs—not the CAR T cells—were responsible for the toxic cytokines secreted.

“[I]t would be the CAR T-cell-mediated killing of leukemia which would induce this cytokine release from the antigen-presenting cell lineages,” Dr Barrett explained.

To test this theory, the investigators co-cultured CTL019 and Nalm-6 leukemia, with or without cells derived from peripheral blood monocytes.

The team found that IL-6 levels were elevated several logs when CAR T cells killed leukemia in the presence of the APCs.

On the other hand, co-culture of only CTL019 and Nalm-6 produced high levels of GM-CSF, IFNγ, IL-2, and IL-10 but no detectable IL-6 or IL-8.

Transwell in vitro experiments separating CTL019 and Nalm-6 from the APCs showed the same pattern.

The investigators thus confirmed that IL-6 is made by APCs in response to CAR-mediated killing of leukemia.

Nanostring profiling

The team then performed nanostring RNA analysis of separated cell populations recovered from that experiment.

They found that IL-6 and IL-8 are produced by APCs but not by CTL019. IL-2 and IFNγ are produced by CTL019 and not by APCs, and GM-CSF was produced from CTL019.

“There was a clear separation in cytokine production in this model,” Dr Barrett said.

The investigators also observed that the CTL019 nanostring profile was unaffected by proximity to the APCs and all the IL-6 they make.

“CART19 T cells did not seem to care, on a transcriptional level, that all this IL-6 was floating around,” Dr Barrett said.

In contrast, the APCs do change, he said, when CAR T cells are killing leukemia nearby.

“There are dozens and dozens of changes,” he said, “including many in chemokines and IL-6 and IL-8.”

The investigators performed multiple in vitro killing assays and found no difference in CAR T-cell killing potential in the presence or absence of the MAS cytokines.

They also performed peripheral blood analysis of patients experiencing CRS of grades 2 to 5. The team observed that clinical CRS may be divided into MAS and not-MAS patterns. In addition, they detected no IL-6 transcript in any of the CAR T cells isolated from these patients.

“I think we’re going to discover that cytokine release syndrome is a clinical entity that has multiple mechanisms,” Dr Barrett said. “And so it’s very important, when we are talking about our models and talking about our results, to be sure that we’re all speaking the same language.”

Ofatumumab

Photo courtesy of GSK

Salvage treatment with an ofatumumab-based regimen is no better than a rituximab-based regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 3 study.

The study, ORCHARRD, was a comparison of ofatumumab plus cisplatin, cytarabine, and dexamethasone (O-DHAP) and rituximab plus DHAP (R-DHAP), both followed by autologous stem cell transplant (auto-SCT), in patients with relapsed/refractory DLBCL.

The data showed no significant difference between the 2 treatment arms with regard to progression-free survival (PFS), event-free survival (EFS), or overall survival (OS).

And the incidence of serious adverse events (AEs) was similar between the arms.

Gustaaf W. van Imhoff, MD, PhD, of University Medical Center Groningen in Groningen, Netherlands, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was proposed by HOVON, sponsored by GlaxoSmithKline (GSK), and funded by GSK, Genmab A/S, and Novartis AG. Ofatumumab became an asset of Novartis AG in March 2015.

Patients and treatment

The study included 447 adults with CD20+ DLBCL who had experienced their first relapse or who were refractory to first-line treatment with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or a similar regimen.

The patients’ median age was 57 (range, 18 to 83), 63% had stage III/IV disease, and 71% of patients either did not achieve a complete response (CR) to first-line treatment or had a CR lasting less than 1 year.

The patients were randomized to receive O-DHAP (n=222) or R-DHAP (n=225). They received ofatumumab at 1000 mg or rituximab at 375 mg/m² on days 1 and 8 of cycle 1 and day 1 of cycles 2 and 3 of DHAP (4 infusions of either drug).

The patients who had responded after 2 cycles of treatment received the third cycle, followed by high-dose therapy and auto-SCT. Failure to achieve a response after cycle 2 was included as an event.

Response and survival

The response rate was 38% with O-DHAP and 42% with R-DHAP. The CR rate was 15% and 22%, respectively.

Thirty-three percent of patients in the O-DHAP arm and 37% in the R-DHAP arm underwent auto-SCT on protocol.

At 2 years, PFS was 24% with O-DHAP and 26% with R-DHAP (hazard ratio [HR]=1.12, P=0.33).

Two-year EFS was 16% with O-DHAP and 18% with R-DHAP. (HR=1.10, P=0.35). And 2-year OS was 41% with O-DHAP and 38% with R-DHAP (HR=0.90, P=0.38).

The researchers found that having a negative PET scan after cycle 3 was associated with better PFS and OS.

Two-year PFS was 32% for patients with a positive PET scan after cycle 3 and 70% for those with a negative PET scan (P=0.001). Two-year OS was 43% for patients with positive PET scan and 78% for those with a negative PET scan (P=0.0018).

Safety

Fifty-two percent of all patients had 1 or more serious AE, and the incidence of serious AEs was similar between the treatment arms. The most common serious AEs were febrile neutropenia (13%), acute renal failure (5%), thrombocytopenia (5%), and vomiting (5%).

Fatal serious AEs occurred in 6% of patients. These were mainly related to infectious complications and occurred in a similar proportion of patients in both treatment arms.

The incidence of rash was higher in the O-DHAP arm (22% vs 9%), as was the incidence of raised serum creatinine (23% vs 16%).

Dose interruptions/delays (of either anti-CD20 therapy or chemotherapy) as a result of AEs occurred in 49% of patients in the O-DHAP arm and 30% in the R-DHAP arm.

AEs causing dose delays/interruptions included (in the O-DHAP and R-DHAP arms, respectively) neutropenia (6% and 7%), rash (9% and <1%), thrombocytopenia (5% and 4%), urticaria (6% and <1%), pyrexia (4% and 2%), febrile neutropenia (4% and 1%), hypersensitivity (4% and 1%), infusion-related reactions (5% and <1%), decrease in platelet count (2% and 3%), and pruritus (4% and 0%).

Sixteen percent of all patients had AEs that led to permanent discontinuation of study treatment. The rate of such AEs was similar between the treatment arms. The most frequent event leading to discontinuation was renal toxicity (8%).

Ofatumumab

Photo courtesy of GSK

Salvage treatment with an ofatumumab-based regimen is no better than a rituximab-based regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 3 study.

The study, ORCHARRD, was a comparison of ofatumumab plus cisplatin, cytarabine, and dexamethasone (O-DHAP) and rituximab plus DHAP (R-DHAP), both followed by autologous stem cell transplant (auto-SCT), in patients with relapsed/refractory DLBCL.

The data showed no significant difference between the 2 treatment arms with regard to progression-free survival (PFS), event-free survival (EFS), or overall survival (OS).

And the incidence of serious adverse events (AEs) was similar between the arms.

Gustaaf W. van Imhoff, MD, PhD, of University Medical Center Groningen in Groningen, Netherlands, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was proposed by HOVON, sponsored by GlaxoSmithKline (GSK), and funded by GSK, Genmab A/S, and Novartis AG. Ofatumumab became an asset of Novartis AG in March 2015.

Patients and treatment

The study included 447 adults with CD20+ DLBCL who had experienced their first relapse or who were refractory to first-line treatment with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or a similar regimen.

The patients’ median age was 57 (range, 18 to 83), 63% had stage III/IV disease, and 71% of patients either did not achieve a complete response (CR) to first-line treatment or had a CR lasting less than 1 year.

The patients were randomized to receive O-DHAP (n=222) or R-DHAP (n=225). They received ofatumumab at 1000 mg or rituximab at 375 mg/m² on days 1 and 8 of cycle 1 and day 1 of cycles 2 and 3 of DHAP (4 infusions of either drug).

The patients who had responded after 2 cycles of treatment received the third cycle, followed by high-dose therapy and auto-SCT. Failure to achieve a response after cycle 2 was included as an event.

Response and survival

The response rate was 38% with O-DHAP and 42% with R-DHAP. The CR rate was 15% and 22%, respectively.

Thirty-three percent of patients in the O-DHAP arm and 37% in the R-DHAP arm underwent auto-SCT on protocol.

At 2 years, PFS was 24% with O-DHAP and 26% with R-DHAP (hazard ratio [HR]=1.12, P=0.33).

Two-year EFS was 16% with O-DHAP and 18% with R-DHAP. (HR=1.10, P=0.35). And 2-year OS was 41% with O-DHAP and 38% with R-DHAP (HR=0.90, P=0.38).

The researchers found that having a negative PET scan after cycle 3 was associated with better PFS and OS.

Two-year PFS was 32% for patients with a positive PET scan after cycle 3 and 70% for those with a negative PET scan (P=0.001). Two-year OS was 43% for patients with positive PET scan and 78% for those with a negative PET scan (P=0.0018).

Safety

Fifty-two percent of all patients had 1 or more serious AE, and the incidence of serious AEs was similar between the treatment arms. The most common serious AEs were febrile neutropenia (13%), acute renal failure (5%), thrombocytopenia (5%), and vomiting (5%).

Fatal serious AEs occurred in 6% of patients. These were mainly related to infectious complications and occurred in a similar proportion of patients in both treatment arms.

The incidence of rash was higher in the O-DHAP arm (22% vs 9%), as was the incidence of raised serum creatinine (23% vs 16%).

Dose interruptions/delays (of either anti-CD20 therapy or chemotherapy) as a result of AEs occurred in 49% of patients in the O-DHAP arm and 30% in the R-DHAP arm.

AEs causing dose delays/interruptions included (in the O-DHAP and R-DHAP arms, respectively) neutropenia (6% and 7%), rash (9% and <1%), thrombocytopenia (5% and 4%), urticaria (6% and <1%), pyrexia (4% and 2%), febrile neutropenia (4% and 1%), hypersensitivity (4% and 1%), infusion-related reactions (5% and <1%), decrease in platelet count (2% and 3%), and pruritus (4% and 0%).

Sixteen percent of all patients had AEs that led to permanent discontinuation of study treatment. The rate of such AEs was similar between the treatment arms. The most frequent event leading to discontinuation was renal toxicity (8%).

Ofatumumab

Photo courtesy of GSK

Salvage treatment with an ofatumumab-based regimen is no better than a rituximab-based regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 3 study.

The study, ORCHARRD, was a comparison of ofatumumab plus cisplatin, cytarabine, and dexamethasone (O-DHAP) and rituximab plus DHAP (R-DHAP), both followed by autologous stem cell transplant (auto-SCT), in patients with relapsed/refractory DLBCL.

The data showed no significant difference between the 2 treatment arms with regard to progression-free survival (PFS), event-free survival (EFS), or overall survival (OS).

And the incidence of serious adverse events (AEs) was similar between the arms.

Gustaaf W. van Imhoff, MD, PhD, of University Medical Center Groningen in Groningen, Netherlands, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was proposed by HOVON, sponsored by GlaxoSmithKline (GSK), and funded by GSK, Genmab A/S, and Novartis AG. Ofatumumab became an asset of Novartis AG in March 2015.

Patients and treatment

The study included 447 adults with CD20+ DLBCL who had experienced their first relapse or who were refractory to first-line treatment with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or a similar regimen.

The patients’ median age was 57 (range, 18 to 83), 63% had stage III/IV disease, and 71% of patients either did not achieve a complete response (CR) to first-line treatment or had a CR lasting less than 1 year.

The patients were randomized to receive O-DHAP (n=222) or R-DHAP (n=225). They received ofatumumab at 1000 mg or rituximab at 375 mg/m² on days 1 and 8 of cycle 1 and day 1 of cycles 2 and 3 of DHAP (4 infusions of either drug).

The patients who had responded after 2 cycles of treatment received the third cycle, followed by high-dose therapy and auto-SCT. Failure to achieve a response after cycle 2 was included as an event.

Response and survival

The response rate was 38% with O-DHAP and 42% with R-DHAP. The CR rate was 15% and 22%, respectively.

Thirty-three percent of patients in the O-DHAP arm and 37% in the R-DHAP arm underwent auto-SCT on protocol.

At 2 years, PFS was 24% with O-DHAP and 26% with R-DHAP (hazard ratio [HR]=1.12, P=0.33).

Two-year EFS was 16% with O-DHAP and 18% with R-DHAP. (HR=1.10, P=0.35). And 2-year OS was 41% with O-DHAP and 38% with R-DHAP (HR=0.90, P=0.38).

The researchers found that having a negative PET scan after cycle 3 was associated with better PFS and OS.

Two-year PFS was 32% for patients with a positive PET scan after cycle 3 and 70% for those with a negative PET scan (P=0.001). Two-year OS was 43% for patients with positive PET scan and 78% for those with a negative PET scan (P=0.0018).

Safety

Fifty-two percent of all patients had 1 or more serious AE, and the incidence of serious AEs was similar between the treatment arms. The most common serious AEs were febrile neutropenia (13%), acute renal failure (5%), thrombocytopenia (5%), and vomiting (5%).

Fatal serious AEs occurred in 6% of patients. These were mainly related to infectious complications and occurred in a similar proportion of patients in both treatment arms.

The incidence of rash was higher in the O-DHAP arm (22% vs 9%), as was the incidence of raised serum creatinine (23% vs 16%).

Dose interruptions/delays (of either anti-CD20 therapy or chemotherapy) as a result of AEs occurred in 49% of patients in the O-DHAP arm and 30% in the R-DHAP arm.

AEs causing dose delays/interruptions included (in the O-DHAP and R-DHAP arms, respectively) neutropenia (6% and 7%), rash (9% and <1%), thrombocytopenia (5% and 4%), urticaria (6% and <1%), pyrexia (4% and 2%), febrile neutropenia (4% and 1%), hypersensitivity (4% and 1%), infusion-related reactions (5% and <1%), decrease in platelet count (2% and 3%), and pruritus (4% and 0%).

Sixteen percent of all patients had AEs that led to permanent discontinuation of study treatment. The rate of such AEs was similar between the treatment arms. The most frequent event leading to discontinuation was renal toxicity (8%).

CT scan showing PE

Image from Medical

College of Georgia

Suffering from obstructive sleep apnea (OSA) increases a person’s risk of pulmonary embolism (PE) recurrence, according to a study published in CHEST.

It has been hypothesized that OSA may promote the formation of blood clots.

Because venous thromboembolism is a chronic condition, researchers wanted to examine how OSA affected the rate of repeat PE occurrence.

They found that, after the first PE, OSA increases the risk for recurrence.

“There is growing evidence from cross-sectional and longitudinal studies that obstructive sleep apnea is a risk factor for pulmonary embolism,” explained study author Alberto Alonso-Fernández, MD, PhD, of Hospital Universitario Son Espases, Palma de Mallorca, Spain.

“This association represents a major public health burden, given the high prevalence of both disorders and the mortality rates of PE. However, to our knowledge, no longitudinal studies to date have explored the role of OSA as a risk factor for recurrent thromboembolic events.”

Therefore, Dr Alonso-Fernández and his colleagues followed 120 patients for 5 to 8 years after their first occurrence of PE. The patients were not taking oral anticoagulants at the start of the study.

The patients’ sleep was monitored for signs of OSA. A patient was classified as having OSA when the obstructive component was dominant and the apnea hypopnea index (AHI) was ≥ 10 per hour (10 h^–1).

Nineteen of the patients had recurrent PE during the follow-up period, and 16 of them suffered from OSA.

Multivariate analysis revealed several independent risk factors for recurrent PE, including:

• AHI ≥ 10 h^–1—hazard ratio (HR)=20.7
• Mean nocturnal oxygen saturation (nSaO2)—HR=0.39
• Time with SaO2 < 90% (CT90%)—HR=0.90
• D-dimer level—HR=1.001.

“The main finding in this study is that, after a first episode of PE, patients with OSA had a higher risk of recurrent PE than those without OSA,” Dr Alonso-Fernández said.

“Moreover, AHI and nocturnal hypoxemia, assessed by the mean nocturnal oxygen saturation and percentage of total time the patient spent with their oxygen saturation below 90%, are independent risk factors for PE recurrence and for resuming anticoagulation because of a new thromboembolic event.”

Twenty-four patients resumed oral anticoagulation. Independent risk factors for resuming anticoagulation included:

• AHI ≥ 10 h^–1—HR=20.66
• Mean nSaO2—HR=0.54
• Epworth Sleepiness Scale—HR=0.73.

Explaining the findings

Addressing why OSA may make people more susceptible to subsequent PE events, Dr Alonso-Fernández said, “PE is the result of Virchow’s classic risk triad—namely, vascular endothelial impairment, stasis of blood flow, and/or increased coagulability. OSA could hypothetically affect all 3 mechanistic pathways.”

“Intermittent hypoxia increases oxidative stress and inflammatory response that impairs endothelial function. OSA-related hemodynamic alterations and sedentarism may slow intravenous flow, and lastly, increased coagulability, platelet activity, and decreased fibrinolytic capacity in OSA may be improved after CPAP [continuous positive airway pressure].”

Several factors have been identified as playing a role in recurrent PE, including cancer, continued estrogen use, vena cava filters, high post-anticoagulation D-dimer, male gender, and obesity.

The current study suggested that OSA is an independent risk factor for recurrent PE, even after adjusting for several factors, including body mass index. OSA is a common problem among obese people, and the researchers assert that the risk of recurrent PE that is attributed to obesity might be partially related to OSA.

“Obesity is associated with sedentarism and venous stasis, and it has also been related to impaired fibrinolysis and high concentrations of clotting factors that might lead to a prothrombotic state that can further increase because obesity is associated with high estrogen levels and chronic low-grade inflammation,” Dr Alonso-Fernández said.

“It is tempting to speculate that OSA and obesity may additively or synergistically lead to upregulation of procoagulant activity that may intensify the risk of PE recurrence.”

Dr Alonso-Fernández and his colleagues believe that knowing OSA is an independent risk factor for recurrent PE can help physicians better understand treatment options. CPAP use is a proven intervention for OSA, and patients with OSA may need to stay on anticoagulation therapy longer to reduce their risk for another PE.

“Given the high prevalence of OSA in patients with PE, the procoagulable state induced by the intermittent hypoxia, and the risk for PE recurrence, the potential of CPAP and/or extend oral anticoagulation to reduce PE recurrence and mortality in patients with PE and OSA clearly warrants further study,” Dr Alonso-Fernández concluded.

CT scan showing PE

Image from Medical

College of Georgia

Suffering from obstructive sleep apnea (OSA) increases a person’s risk of pulmonary embolism (PE) recurrence, according to a study published in CHEST.

It has been hypothesized that OSA may promote the formation of blood clots.

Because venous thromboembolism is a chronic condition, researchers wanted to examine how OSA affected the rate of repeat PE occurrence.

They found that, after the first PE, OSA increases the risk for recurrence.

“There is growing evidence from cross-sectional and longitudinal studies that obstructive sleep apnea is a risk factor for pulmonary embolism,” explained study author Alberto Alonso-Fernández, MD, PhD, of Hospital Universitario Son Espases, Palma de Mallorca, Spain.

“This association represents a major public health burden, given the high prevalence of both disorders and the mortality rates of PE. However, to our knowledge, no longitudinal studies to date have explored the role of OSA as a risk factor for recurrent thromboembolic events.”

Therefore, Dr Alonso-Fernández and his colleagues followed 120 patients for 5 to 8 years after their first occurrence of PE. The patients were not taking oral anticoagulants at the start of the study.

The patients’ sleep was monitored for signs of OSA. A patient was classified as having OSA when the obstructive component was dominant and the apnea hypopnea index (AHI) was ≥ 10 per hour (10 h^–1).

Nineteen of the patients had recurrent PE during the follow-up period, and 16 of them suffered from OSA.

Multivariate analysis revealed several independent risk factors for recurrent PE, including:

• AHI ≥ 10 h^–1—hazard ratio (HR)=20.7
• Mean nocturnal oxygen saturation (nSaO2)—HR=0.39
• Time with SaO2 < 90% (CT90%)—HR=0.90
• D-dimer level—HR=1.001.

“The main finding in this study is that, after a first episode of PE, patients with OSA had a higher risk of recurrent PE than those without OSA,” Dr Alonso-Fernández said.

“Moreover, AHI and nocturnal hypoxemia, assessed by the mean nocturnal oxygen saturation and percentage of total time the patient spent with their oxygen saturation below 90%, are independent risk factors for PE recurrence and for resuming anticoagulation because of a new thromboembolic event.”

Twenty-four patients resumed oral anticoagulation. Independent risk factors for resuming anticoagulation included:

• AHI ≥ 10 h^–1—HR=20.66
• Mean nSaO2—HR=0.54
• Epworth Sleepiness Scale—HR=0.73.

Explaining the findings

Addressing why OSA may make people more susceptible to subsequent PE events, Dr Alonso-Fernández said, “PE is the result of Virchow’s classic risk triad—namely, vascular endothelial impairment, stasis of blood flow, and/or increased coagulability. OSA could hypothetically affect all 3 mechanistic pathways.”

“Intermittent hypoxia increases oxidative stress and inflammatory response that impairs endothelial function. OSA-related hemodynamic alterations and sedentarism may slow intravenous flow, and lastly, increased coagulability, platelet activity, and decreased fibrinolytic capacity in OSA may be improved after CPAP [continuous positive airway pressure].”

Several factors have been identified as playing a role in recurrent PE, including cancer, continued estrogen use, vena cava filters, high post-anticoagulation D-dimer, male gender, and obesity.

The current study suggested that OSA is an independent risk factor for recurrent PE, even after adjusting for several factors, including body mass index. OSA is a common problem among obese people, and the researchers assert that the risk of recurrent PE that is attributed to obesity might be partially related to OSA.

“Obesity is associated with sedentarism and venous stasis, and it has also been related to impaired fibrinolysis and high concentrations of clotting factors that might lead to a prothrombotic state that can further increase because obesity is associated with high estrogen levels and chronic low-grade inflammation,” Dr Alonso-Fernández said.

“It is tempting to speculate that OSA and obesity may additively or synergistically lead to upregulation of procoagulant activity that may intensify the risk of PE recurrence.”

Dr Alonso-Fernández and his colleagues believe that knowing OSA is an independent risk factor for recurrent PE can help physicians better understand treatment options. CPAP use is a proven intervention for OSA, and patients with OSA may need to stay on anticoagulation therapy longer to reduce their risk for another PE.

“Given the high prevalence of OSA in patients with PE, the procoagulable state induced by the intermittent hypoxia, and the risk for PE recurrence, the potential of CPAP and/or extend oral anticoagulation to reduce PE recurrence and mortality in patients with PE and OSA clearly warrants further study,” Dr Alonso-Fernández concluded.

CT scan showing PE

Image from Medical

College of Georgia

Suffering from obstructive sleep apnea (OSA) increases a person’s risk of pulmonary embolism (PE) recurrence, according to a study published in CHEST.

It has been hypothesized that OSA may promote the formation of blood clots.

Because venous thromboembolism is a chronic condition, researchers wanted to examine how OSA affected the rate of repeat PE occurrence.

They found that, after the first PE, OSA increases the risk for recurrence.

“There is growing evidence from cross-sectional and longitudinal studies that obstructive sleep apnea is a risk factor for pulmonary embolism,” explained study author Alberto Alonso-Fernández, MD, PhD, of Hospital Universitario Son Espases, Palma de Mallorca, Spain.

“This association represents a major public health burden, given the high prevalence of both disorders and the mortality rates of PE. However, to our knowledge, no longitudinal studies to date have explored the role of OSA as a risk factor for recurrent thromboembolic events.”

Therefore, Dr Alonso-Fernández and his colleagues followed 120 patients for 5 to 8 years after their first occurrence of PE. The patients were not taking oral anticoagulants at the start of the study.

The patients’ sleep was monitored for signs of OSA. A patient was classified as having OSA when the obstructive component was dominant and the apnea hypopnea index (AHI) was ≥ 10 per hour (10 h^–1).

Nineteen of the patients had recurrent PE during the follow-up period, and 16 of them suffered from OSA.

Multivariate analysis revealed several independent risk factors for recurrent PE, including:

• AHI ≥ 10 h^–1—hazard ratio (HR)=20.7
• Mean nocturnal oxygen saturation (nSaO2)—HR=0.39
• Time with SaO2 < 90% (CT90%)—HR=0.90
• D-dimer level—HR=1.001.

“The main finding in this study is that, after a first episode of PE, patients with OSA had a higher risk of recurrent PE than those without OSA,” Dr Alonso-Fernández said.

“Moreover, AHI and nocturnal hypoxemia, assessed by the mean nocturnal oxygen saturation and percentage of total time the patient spent with their oxygen saturation below 90%, are independent risk factors for PE recurrence and for resuming anticoagulation because of a new thromboembolic event.”

Twenty-four patients resumed oral anticoagulation. Independent risk factors for resuming anticoagulation included:

• AHI ≥ 10 h^–1—HR=20.66
• Mean nSaO2—HR=0.54
• Epworth Sleepiness Scale—HR=0.73.

Explaining the findings

Addressing why OSA may make people more susceptible to subsequent PE events, Dr Alonso-Fernández said, “PE is the result of Virchow’s classic risk triad—namely, vascular endothelial impairment, stasis of blood flow, and/or increased coagulability. OSA could hypothetically affect all 3 mechanistic pathways.”

“Intermittent hypoxia increases oxidative stress and inflammatory response that impairs endothelial function. OSA-related hemodynamic alterations and sedentarism may slow intravenous flow, and lastly, increased coagulability, platelet activity, and decreased fibrinolytic capacity in OSA may be improved after CPAP [continuous positive airway pressure].”

Several factors have been identified as playing a role in recurrent PE, including cancer, continued estrogen use, vena cava filters, high post-anticoagulation D-dimer, male gender, and obesity.

The current study suggested that OSA is an independent risk factor for recurrent PE, even after adjusting for several factors, including body mass index. OSA is a common problem among obese people, and the researchers assert that the risk of recurrent PE that is attributed to obesity might be partially related to OSA.

“Obesity is associated with sedentarism and venous stasis, and it has also been related to impaired fibrinolysis and high concentrations of clotting factors that might lead to a prothrombotic state that can further increase because obesity is associated with high estrogen levels and chronic low-grade inflammation,” Dr Alonso-Fernández said.

“It is tempting to speculate that OSA and obesity may additively or synergistically lead to upregulation of procoagulant activity that may intensify the risk of PE recurrence.”

Dr Alonso-Fernández and his colleagues believe that knowing OSA is an independent risk factor for recurrent PE can help physicians better understand treatment options. CPAP use is a proven intervention for OSA, and patients with OSA may need to stay on anticoagulation therapy longer to reduce their risk for another PE.

“Given the high prevalence of OSA in patients with PE, the procoagulable state induced by the intermittent hypoxia, and the risk for PE recurrence, the potential of CPAP and/or extend oral anticoagulation to reduce PE recurrence and mortality in patients with PE and OSA clearly warrants further study,” Dr Alonso-Fernández concluded.

Red blood cells

Having iron deficiency anemia (IDA) may increase a person’s risk of hearing loss, according to a study published in JAMA Otolaryngology-Head & Neck Surgery.

The study indicated that adults with IDA had nearly twice the risk of sensorineural hearing loss and more than twice the risk of combined hearing loss as adults without IDA.

Researchers said the goals of future studies will be to better understand the association between IDA and hearing loss and determine whether promptly diagnosing and treating IDA may have a positive effect on the overall health of adults with hearing loss.

For this study, Kathleen M. Schieffer, of the Pennsylvania State University College of Medicine in Hershey, Pennsylvania, and her colleagues examined data from deidentified electronic medical records.

The data encompassed 305,339 adults. They had a mean age of 50.1 (range, 21 to 90), and 43% were male.

The prevalence of IDA in this population was 0.7%.

There was a 1.6% prevalence of combined hearing loss, which was defined as any combination of conductive hearing loss (due to problems with the bones of the middle ear), sensorineural hearing loss (when there is damage to the cochlea or to the nerve pathways from the inner ear to the brain), deafness, and unspecified hearing loss.

Both sensorineural hearing loss and combined hearing loss were significantly associated with IDA.

Sensorineural hearing loss was present in 1.1% of individuals with IDA (P=0.005), and combined hearing loss was present in 3.4% of individuals with IDA (P<0.001).

Logistic regression analysis showed increased odds of sensorineural hearing loss and combined hearing loss among adults with IDA.

The odds ratio (adjusted for sex) was 1.82 for sensorineural hearing loss and 2.41 for combined hearing loss.

Red blood cells

Having iron deficiency anemia (IDA) may increase a person’s risk of hearing loss, according to a study published in JAMA Otolaryngology-Head & Neck Surgery.

The study indicated that adults with IDA had nearly twice the risk of sensorineural hearing loss and more than twice the risk of combined hearing loss as adults without IDA.

Researchers said the goals of future studies will be to better understand the association between IDA and hearing loss and determine whether promptly diagnosing and treating IDA may have a positive effect on the overall health of adults with hearing loss.

For this study, Kathleen M. Schieffer, of the Pennsylvania State University College of Medicine in Hershey, Pennsylvania, and her colleagues examined data from deidentified electronic medical records.

The data encompassed 305,339 adults. They had a mean age of 50.1 (range, 21 to 90), and 43% were male.

The prevalence of IDA in this population was 0.7%.

There was a 1.6% prevalence of combined hearing loss, which was defined as any combination of conductive hearing loss (due to problems with the bones of the middle ear), sensorineural hearing loss (when there is damage to the cochlea or to the nerve pathways from the inner ear to the brain), deafness, and unspecified hearing loss.

Both sensorineural hearing loss and combined hearing loss were significantly associated with IDA.

Sensorineural hearing loss was present in 1.1% of individuals with IDA (P=0.005), and combined hearing loss was present in 3.4% of individuals with IDA (P<0.001).

Logistic regression analysis showed increased odds of sensorineural hearing loss and combined hearing loss among adults with IDA.

The odds ratio (adjusted for sex) was 1.82 for sensorineural hearing loss and 2.41 for combined hearing loss.

Red blood cells

Having iron deficiency anemia (IDA) may increase a person’s risk of hearing loss, according to a study published in JAMA Otolaryngology-Head & Neck Surgery.

The study indicated that adults with IDA had nearly twice the risk of sensorineural hearing loss and more than twice the risk of combined hearing loss as adults without IDA.

Researchers said the goals of future studies will be to better understand the association between IDA and hearing loss and determine whether promptly diagnosing and treating IDA may have a positive effect on the overall health of adults with hearing loss.

For this study, Kathleen M. Schieffer, of the Pennsylvania State University College of Medicine in Hershey, Pennsylvania, and her colleagues examined data from deidentified electronic medical records.

The data encompassed 305,339 adults. They had a mean age of 50.1 (range, 21 to 90), and 43% were male.

The prevalence of IDA in this population was 0.7%.

There was a 1.6% prevalence of combined hearing loss, which was defined as any combination of conductive hearing loss (due to problems with the bones of the middle ear), sensorineural hearing loss (when there is damage to the cochlea or to the nerve pathways from the inner ear to the brain), deafness, and unspecified hearing loss.

Both sensorineural hearing loss and combined hearing loss were significantly associated with IDA.

Sensorineural hearing loss was present in 1.1% of individuals with IDA (P=0.005), and combined hearing loss was present in 3.4% of individuals with IDA (P<0.001).

Logistic regression analysis showed increased odds of sensorineural hearing loss and combined hearing loss among adults with IDA.

The odds ratio (adjusted for sex) was 1.82 for sensorineural hearing loss and 2.41 for combined hearing loss.

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

Since 2011, HIV incidence appears unchanged in the European Union/European Economic Area with between 29,000 and 33,000 new cases reported annually up to 2015, according to the European Centre for Disease Prevention and Control.

A study in the journal AIDS found that smoking is a highly prevalent exposure with important consequences for pregnancy in HIV-positive pregnant women in the United States, even in the presence of potent highly active antiretroviral therapy.

copyright alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

Since 2011, HIV incidence appears unchanged in the European Union/European Economic Area with between 29,000 and 33,000 new cases reported annually up to 2015, according to the European Centre for Disease Prevention and Control.

A study in the journal AIDS found that smoking is a highly prevalent exposure with important consequences for pregnancy in HIV-positive pregnant women in the United States, even in the presence of potent highly active antiretroviral therapy.

copyright alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

Since 2011, HIV incidence appears unchanged in the European Union/European Economic Area with between 29,000 and 33,000 new cases reported annually up to 2015, according to the European Centre for Disease Prevention and Control.

A study in the journal AIDS found that smoking is a highly prevalent exposure with important consequences for pregnancy in HIV-positive pregnant women in the United States, even in the presence of potent highly active antiretroviral therapy.

copyright alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi