Hematology

New guidelines issued jointly by four major international hematology groups focus on the management of patients with von Willebrand disease (VWD), the most common bleeding disorder in the world.

The evidence-based guidelines, published in Blood Advances, were developed in collaboration by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. They outline key recommendations spanning the care of patients with a broad range of therapeutic needs.

“We addressed some of the questions that were most important to the community, but certainly there are a lot of areas that we couldn’t cover” said coauthor Veronica H. Flood, MD, of the Medical College of Wisconsin in Milwaukee.

The guidelines process began with a survey sent to the von Willebrand disease community, including patients, caregivers, nurses, physicians, and scientists. The respondents were asked to prioritize issues that they felt should be addressed in the guidelines.

“Interestingly, some of the issues were the same between patients and caregivers and physicians, and some were different, but there were obviously some areas that we just couldn’t cover,” she said in an interview.

One of the areas of greatest concern for respondents was bleeding in women, and many of the recommendations include specific considerations for management of gynecologic and obstetric patients, Dr. Flood said.

“We also tried to make the questions applicable to as many patients with von Willebrand disease as possible,” she added.

Some of the questions, such as recommendation 1, regarding prophylaxis, are geared toward management of patients with severe disease, while others, such as recommendations for treatment of menstrual bleeding, are more suited for patients with milder VWD.

All of the recommendations in the guidelines are “conditional” (suggested), due to very low certainty in the evidence of effects, the authors noted.
 

Prophylaxis

The guidelines suggest long-term prophylaxis for patients with a history of severe and frequent bleeds, with periodic assessment of the need for prophylaxis.

Desmopressin

For those patients who may benefit from the use of desmopressin, primarily those with type 1 VWD, and who have a baseline von Willebrand factor (VWF) level below 0.30 IU/mL, the panel issued a conditional recommendation for a desmopressin trial with treatment based on the patient’s results compared with not performing a trial and treating with tranexamic acid or factor concentrate. The guidelines also advise against treating with desmopressin in the absence of a trial. In a section of “good practice statements,” the guidelines indicate that using desmopressin in patients with type 2B VWD is generally contraindicated, because of the risk of thrombocytopenia as a result of increased platelet binding. In addition, desmopressin is generally contraindicated in patients with active cardiovascular disease, patients with seizure disorders, patients less than 2 years old, and patients with type 1C VWD in the setting of surgery.

Antithrombotic therapy

The guideline panelists conditionally recommend antithrombotic therapy with either antiplatelet agents or anticoagulants, with an emphasis on reassessing bleeding risk throughout the course of treatment.

An accompanying good practice statement calls for individualized assessments of risks and benefits of specific antithrombotic therapies by a multidisciplinary team including hematologists, cardiovascular specialists, and the patient.
 

Major surgery

This section includes a recommendation for targeting both factor VIII and VWF activity levels to a minimum of 50 IU/mL for at least 3 days after surgery, and a suggestion against using factor VIII target levels alone.

Minor surgery/invasive procedures

The panelists suggest increasing VWF activity levels to a minimum of 0.50 IU/mL with desmopressin or factor concentrate with the addition of tranexamic acid over raising VWF levels to at least 0.50 IU/mL with desmopressin or factor concentrate alone.

In addition, the panelists suggest “giving tranexamic acid alone over increasing VWF activity levels to a minimum threshold of 0.50 IU/mL with any intervention in patients with type 1 VWD with baseline VWF activity levels of 0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures.”
 

Heavy menstrual bleeding

In women with heavy menstrual bleeding who do not plan to conceive, the panel suggests either combined hormonal therapy or levonorgestrel-releasing intrauterine system, or tranexamic acid over desmopressin.

In women who wish to conceive, the panel suggests using tranexamic acid over desmopressin.
 

Neuraxial anesthesia during labor

For women in labor for whom neuraxial anesthesia is considered, the guidelines suggest targeting a VWF activity level from 0.50 to 1.50 IU/mL over targeting a level above 1.50 IU/mL.

Postpartum management

“The guideline panel suggests the use of tranexamic acid over not using it in women with type 1 VWD or low VWF levels (and this may also apply to types 2 and 3 VWD) during the postpartum period,” the guidelines say.

An accompanying good practice statement says that tranexamic acid can be provided orally or intravenously. The oral dose is 25 mg/kg three times daily for 10-14 days, or longer if blood loss remains heavy.

Dr. Flood said that the guidelines were developed under the assumption that they would apply to care of patients in regions with a high or moderately high degree of clinical resources.

“We recognize that this eliminates a great deal of the globe, and our hope is that ASH and the other sponsoring organizations are going to let us revise this and do a version for lower-resourced settings,” she said.

New guidelines issued jointly by four major international hematology groups focus on the management of patients with von Willebrand disease (VWD), the most common bleeding disorder in the world.

The evidence-based guidelines, published in Blood Advances, were developed in collaboration by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. They outline key recommendations spanning the care of patients with a broad range of therapeutic needs.

“We addressed some of the questions that were most important to the community, but certainly there are a lot of areas that we couldn’t cover” said coauthor Veronica H. Flood, MD, of the Medical College of Wisconsin in Milwaukee.

The guidelines process began with a survey sent to the von Willebrand disease community, including patients, caregivers, nurses, physicians, and scientists. The respondents were asked to prioritize issues that they felt should be addressed in the guidelines.

“Interestingly, some of the issues were the same between patients and caregivers and physicians, and some were different, but there were obviously some areas that we just couldn’t cover,” she said in an interview.

One of the areas of greatest concern for respondents was bleeding in women, and many of the recommendations include specific considerations for management of gynecologic and obstetric patients, Dr. Flood said.

“We also tried to make the questions applicable to as many patients with von Willebrand disease as possible,” she added.

Some of the questions, such as recommendation 1, regarding prophylaxis, are geared toward management of patients with severe disease, while others, such as recommendations for treatment of menstrual bleeding, are more suited for patients with milder VWD.

All of the recommendations in the guidelines are “conditional” (suggested), due to very low certainty in the evidence of effects, the authors noted.
 

Prophylaxis

The guidelines suggest long-term prophylaxis for patients with a history of severe and frequent bleeds, with periodic assessment of the need for prophylaxis.

Desmopressin

For those patients who may benefit from the use of desmopressin, primarily those with type 1 VWD, and who have a baseline von Willebrand factor (VWF) level below 0.30 IU/mL, the panel issued a conditional recommendation for a desmopressin trial with treatment based on the patient’s results compared with not performing a trial and treating with tranexamic acid or factor concentrate. The guidelines also advise against treating with desmopressin in the absence of a trial. In a section of “good practice statements,” the guidelines indicate that using desmopressin in patients with type 2B VWD is generally contraindicated, because of the risk of thrombocytopenia as a result of increased platelet binding. In addition, desmopressin is generally contraindicated in patients with active cardiovascular disease, patients with seizure disorders, patients less than 2 years old, and patients with type 1C VWD in the setting of surgery.

Antithrombotic therapy

The guideline panelists conditionally recommend antithrombotic therapy with either antiplatelet agents or anticoagulants, with an emphasis on reassessing bleeding risk throughout the course of treatment.

An accompanying good practice statement calls for individualized assessments of risks and benefits of specific antithrombotic therapies by a multidisciplinary team including hematologists, cardiovascular specialists, and the patient.
 

Major surgery

This section includes a recommendation for targeting both factor VIII and VWF activity levels to a minimum of 50 IU/mL for at least 3 days after surgery, and a suggestion against using factor VIII target levels alone.

Minor surgery/invasive procedures

The panelists suggest increasing VWF activity levels to a minimum of 0.50 IU/mL with desmopressin or factor concentrate with the addition of tranexamic acid over raising VWF levels to at least 0.50 IU/mL with desmopressin or factor concentrate alone.

In addition, the panelists suggest “giving tranexamic acid alone over increasing VWF activity levels to a minimum threshold of 0.50 IU/mL with any intervention in patients with type 1 VWD with baseline VWF activity levels of 0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures.”
 

Heavy menstrual bleeding

In women with heavy menstrual bleeding who do not plan to conceive, the panel suggests either combined hormonal therapy or levonorgestrel-releasing intrauterine system, or tranexamic acid over desmopressin.

In women who wish to conceive, the panel suggests using tranexamic acid over desmopressin.
 

Neuraxial anesthesia during labor

For women in labor for whom neuraxial anesthesia is considered, the guidelines suggest targeting a VWF activity level from 0.50 to 1.50 IU/mL over targeting a level above 1.50 IU/mL.

Postpartum management

“The guideline panel suggests the use of tranexamic acid over not using it in women with type 1 VWD or low VWF levels (and this may also apply to types 2 and 3 VWD) during the postpartum period,” the guidelines say.

An accompanying good practice statement says that tranexamic acid can be provided orally or intravenously. The oral dose is 25 mg/kg three times daily for 10-14 days, or longer if blood loss remains heavy.

Dr. Flood said that the guidelines were developed under the assumption that they would apply to care of patients in regions with a high or moderately high degree of clinical resources.

“We recognize that this eliminates a great deal of the globe, and our hope is that ASH and the other sponsoring organizations are going to let us revise this and do a version for lower-resourced settings,” she said.

New guidelines issued jointly by four major international hematology groups focus on the management of patients with von Willebrand disease (VWD), the most common bleeding disorder in the world.

The evidence-based guidelines, published in Blood Advances, were developed in collaboration by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. They outline key recommendations spanning the care of patients with a broad range of therapeutic needs.

“We addressed some of the questions that were most important to the community, but certainly there are a lot of areas that we couldn’t cover” said coauthor Veronica H. Flood, MD, of the Medical College of Wisconsin in Milwaukee.

The guidelines process began with a survey sent to the von Willebrand disease community, including patients, caregivers, nurses, physicians, and scientists. The respondents were asked to prioritize issues that they felt should be addressed in the guidelines.

“Interestingly, some of the issues were the same between patients and caregivers and physicians, and some were different, but there were obviously some areas that we just couldn’t cover,” she said in an interview.

One of the areas of greatest concern for respondents was bleeding in women, and many of the recommendations include specific considerations for management of gynecologic and obstetric patients, Dr. Flood said.

“We also tried to make the questions applicable to as many patients with von Willebrand disease as possible,” she added.

Some of the questions, such as recommendation 1, regarding prophylaxis, are geared toward management of patients with severe disease, while others, such as recommendations for treatment of menstrual bleeding, are more suited for patients with milder VWD.

All of the recommendations in the guidelines are “conditional” (suggested), due to very low certainty in the evidence of effects, the authors noted.
 

Prophylaxis

The guidelines suggest long-term prophylaxis for patients with a history of severe and frequent bleeds, with periodic assessment of the need for prophylaxis.

Desmopressin

For those patients who may benefit from the use of desmopressin, primarily those with type 1 VWD, and who have a baseline von Willebrand factor (VWF) level below 0.30 IU/mL, the panel issued a conditional recommendation for a desmopressin trial with treatment based on the patient’s results compared with not performing a trial and treating with tranexamic acid or factor concentrate. The guidelines also advise against treating with desmopressin in the absence of a trial. In a section of “good practice statements,” the guidelines indicate that using desmopressin in patients with type 2B VWD is generally contraindicated, because of the risk of thrombocytopenia as a result of increased platelet binding. In addition, desmopressin is generally contraindicated in patients with active cardiovascular disease, patients with seizure disorders, patients less than 2 years old, and patients with type 1C VWD in the setting of surgery.

Antithrombotic therapy

The guideline panelists conditionally recommend antithrombotic therapy with either antiplatelet agents or anticoagulants, with an emphasis on reassessing bleeding risk throughout the course of treatment.

An accompanying good practice statement calls for individualized assessments of risks and benefits of specific antithrombotic therapies by a multidisciplinary team including hematologists, cardiovascular specialists, and the patient.
 

Major surgery

This section includes a recommendation for targeting both factor VIII and VWF activity levels to a minimum of 50 IU/mL for at least 3 days after surgery, and a suggestion against using factor VIII target levels alone.

Minor surgery/invasive procedures

The panelists suggest increasing VWF activity levels to a minimum of 0.50 IU/mL with desmopressin or factor concentrate with the addition of tranexamic acid over raising VWF levels to at least 0.50 IU/mL with desmopressin or factor concentrate alone.

In addition, the panelists suggest “giving tranexamic acid alone over increasing VWF activity levels to a minimum threshold of 0.50 IU/mL with any intervention in patients with type 1 VWD with baseline VWF activity levels of 0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures.”
 

Heavy menstrual bleeding

In women with heavy menstrual bleeding who do not plan to conceive, the panel suggests either combined hormonal therapy or levonorgestrel-releasing intrauterine system, or tranexamic acid over desmopressin.

In women who wish to conceive, the panel suggests using tranexamic acid over desmopressin.
 

Neuraxial anesthesia during labor

For women in labor for whom neuraxial anesthesia is considered, the guidelines suggest targeting a VWF activity level from 0.50 to 1.50 IU/mL over targeting a level above 1.50 IU/mL.

Postpartum management

“The guideline panel suggests the use of tranexamic acid over not using it in women with type 1 VWD or low VWF levels (and this may also apply to types 2 and 3 VWD) during the postpartum period,” the guidelines say.

An accompanying good practice statement says that tranexamic acid can be provided orally or intravenously. The oral dose is 25 mg/kg three times daily for 10-14 days, or longer if blood loss remains heavy.

Dr. Flood said that the guidelines were developed under the assumption that they would apply to care of patients in regions with a high or moderately high degree of clinical resources.

“We recognize that this eliminates a great deal of the globe, and our hope is that ASH and the other sponsoring organizations are going to let us revise this and do a version for lower-resourced settings,” she said.

Background: Chronic kidney disease (CKD) is both a prothrombotic state and a condition with an elevated bleeding risk that increases in a linear fashion as estimated glomerular filtration rate (eGFR) decreases. These features of the disease along with the exclusion of patients with CKD from most anticoagulation trials have resulted in uncertainty about overall risks and benefits of anticoagulant use in this population.

The most compelling data were seen in the management of atrial fibrillation in early-stage CKD (five studies representing 11,332 patients) in which high-dose DOACs were associated with a lower risk for stroke or systemic embolism (risk ratio, 0.79; 95% confidence interval, 0.66-0.92), hemorrhagic stroke (RR, 0.48; 95% CI, 0.30-0.76), and all-cause death (RR, 0.88; 95% CI, 0.78-0.99). Overall stroke reduction was primarily hemorrhagic, and DOACs were equivalent to vitamin K antagonists (VKAs) for ischemic stroke risk.

The analysis also suggests that, in CKD, DOACs may reduce major bleeding when compared with VKAs across a variety of indications, though that finding was not statistically significant.

Efficacy of DOACs, compared with VKAs, in treatment of venous thromboembolism was uncertain, and patients with end-stage kidney disease and advanced CKD (creatinine clearance, less than 25 mL/min) were excluded from all trials comparing DOACs with VKAs, with limited overall data in these populations.

Bottom line: For patients with atrial fibrillation and early-stage CKD, direct oral anticoagulants show a promising risk-benefit profile when compared with vitamin K antagonists. Very few data are available on the safety and efficacy of anticoagulants in patients with advanced CKD and end-stage kidney disease.

Citation: Ha JT et al. Benefits and harms of oral anticoagulant therapy in chronic kidney disease. Ann Intern Med. 2019 Aug 6;171(3):181-9.

Dr. Herrle is a hospitalist at Maine Medical Center in Portland and at Stephens Memorial Hospital in Norway, Maine.

Background: Chronic kidney disease (CKD) is both a prothrombotic state and a condition with an elevated bleeding risk that increases in a linear fashion as estimated glomerular filtration rate (eGFR) decreases. These features of the disease along with the exclusion of patients with CKD from most anticoagulation trials have resulted in uncertainty about overall risks and benefits of anticoagulant use in this population.

The most compelling data were seen in the management of atrial fibrillation in early-stage CKD (five studies representing 11,332 patients) in which high-dose DOACs were associated with a lower risk for stroke or systemic embolism (risk ratio, 0.79; 95% confidence interval, 0.66-0.92), hemorrhagic stroke (RR, 0.48; 95% CI, 0.30-0.76), and all-cause death (RR, 0.88; 95% CI, 0.78-0.99). Overall stroke reduction was primarily hemorrhagic, and DOACs were equivalent to vitamin K antagonists (VKAs) for ischemic stroke risk.

The analysis also suggests that, in CKD, DOACs may reduce major bleeding when compared with VKAs across a variety of indications, though that finding was not statistically significant.

Efficacy of DOACs, compared with VKAs, in treatment of venous thromboembolism was uncertain, and patients with end-stage kidney disease and advanced CKD (creatinine clearance, less than 25 mL/min) were excluded from all trials comparing DOACs with VKAs, with limited overall data in these populations.

Bottom line: For patients with atrial fibrillation and early-stage CKD, direct oral anticoagulants show a promising risk-benefit profile when compared with vitamin K antagonists. Very few data are available on the safety and efficacy of anticoagulants in patients with advanced CKD and end-stage kidney disease.

Citation: Ha JT et al. Benefits and harms of oral anticoagulant therapy in chronic kidney disease. Ann Intern Med. 2019 Aug 6;171(3):181-9.

Dr. Herrle is a hospitalist at Maine Medical Center in Portland and at Stephens Memorial Hospital in Norway, Maine.

Background: Chronic kidney disease (CKD) is both a prothrombotic state and a condition with an elevated bleeding risk that increases in a linear fashion as estimated glomerular filtration rate (eGFR) decreases. These features of the disease along with the exclusion of patients with CKD from most anticoagulation trials have resulted in uncertainty about overall risks and benefits of anticoagulant use in this population.

The most compelling data were seen in the management of atrial fibrillation in early-stage CKD (five studies representing 11,332 patients) in which high-dose DOACs were associated with a lower risk for stroke or systemic embolism (risk ratio, 0.79; 95% confidence interval, 0.66-0.92), hemorrhagic stroke (RR, 0.48; 95% CI, 0.30-0.76), and all-cause death (RR, 0.88; 95% CI, 0.78-0.99). Overall stroke reduction was primarily hemorrhagic, and DOACs were equivalent to vitamin K antagonists (VKAs) for ischemic stroke risk.

The analysis also suggests that, in CKD, DOACs may reduce major bleeding when compared with VKAs across a variety of indications, though that finding was not statistically significant.

Efficacy of DOACs, compared with VKAs, in treatment of venous thromboembolism was uncertain, and patients with end-stage kidney disease and advanced CKD (creatinine clearance, less than 25 mL/min) were excluded from all trials comparing DOACs with VKAs, with limited overall data in these populations.

Bottom line: For patients with atrial fibrillation and early-stage CKD, direct oral anticoagulants show a promising risk-benefit profile when compared with vitamin K antagonists. Very few data are available on the safety and efficacy of anticoagulants in patients with advanced CKD and end-stage kidney disease.

Citation: Ha JT et al. Benefits and harms of oral anticoagulant therapy in chronic kidney disease. Ann Intern Med. 2019 Aug 6;171(3):181-9.

Dr. Herrle is a hospitalist at Maine Medical Center in Portland and at Stephens Memorial Hospital in Norway, Maine.

Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.

The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.

The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.

“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.

“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.

Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.

“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.

“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
 

Study details

This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.

Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.

The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.

The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.

The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.

Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.

The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.

Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.

Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.

Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.

The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.

Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.

In contrast, there were few differences between infected and noninfected hematologic cancer patients.

Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.

However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.

The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.

This was particularly the case for patients with cancers that affect B cells.

The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.

“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.

The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.

The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.

“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.

“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.

Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.

“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.

“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
 

Study details

This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.

Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.

The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.

The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.

The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.

Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.

The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.

Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.

Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.

Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.

The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.

Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.

In contrast, there were few differences between infected and noninfected hematologic cancer patients.

Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.

However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.

The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.

This was particularly the case for patients with cancers that affect B cells.

The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.

“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with cancer, particularly those with solid tumors, mounted an immune response to COVID-19 similar to that seen in people without cancer, but among patients with hematologic cancers, immune responses were less pronounced and were highly variable, typically taking longer to clear the virus.

The findings come from a small U.K. study published online Jan. 4 in Cancer Cell as a fast-track preprint article.

The findings may have implications for vaccinating against COVID-19, said the researchers, led by Sheeba Irshad, MD, PhD, a Cancer Research UK clinician scientist based at King’s College London.

“Our study provides some confidence and reassurance to care providers that many of our patients with solid cancers will mount a good immune response against the virus, develop antibodies that last, and hopefully resume their cancer treatment as soon as possible,” Dr. Irshad said in a statement.

“These conclusions imply that many patients, despite being on immunosuppressive therapies, will respond satisfactorily to COVID-19 vaccines,” she added.

Although “the data would suggest that solid cancer patients are likely to mount an efficient immune response to the vaccine ... the same cannot be said for hematological cancers, especially those with B-cell malignancies,” Dr. Irshad said in an interview.

“They may be susceptible to persistent infection despite developing antibodies, so the next stage of our study will focus on monitoring their response to the vaccines.

“At present, the best way to protect them alongside vaccinating them may be to vaccinate all their health care providers and carers to achieve herd immunity and continue to respect the public health measures put in place,” such as wearing a mask, practicing social distancing, and testing asymptomatic persons, she commented.
 

Study details

This study, known as the SARS-CoV-2 for Cancer Patients study, involved 76 patients with cancer; 41 of these patients had COVID-19, and 35 served as non-COVID cancer control patients.

Peripheral blood was collected from all patients; multiple samples were taken every 2-4 days where possible.

The COVID-19 and control groups were matched for age, body mass index, and tumor type, and both groups included patients with solid and hematologic cancers.

The groups were also comparable in terms of the proportion of patients with stage IV disease, those who received palliative as opposed to radical treatment, and patients who were treated within 4 weeks of recruitment to the study.

The results showed that 24.4% of cancer patients who were exposed to COVID-19 remained asymptomatic, 21.9% had mild disease, 31.7% had moderate disease, and 21.9% had severe disease.

Patients with hematologic cancers were more likely to experience dyspnea than those with solid tumors, and 39% received corticosteroid/antiviral therapies that specifically targeted COVID-19 infection.

The median duration of virus shedding was 39 days across the whole cohort. It was notably longer among patients with hematologic cancers, at a median of 55 days versus 29 days for patients with solid tumors.

Of 46 patients who survived beyond 30 days and for whom complete data were available, the team found that those with moderate or severe COVID-19 were more likely to be diagnosed with progressive cancer at their next assessment in comparison with those who were asymptomatic with COVID-19 or with control patients.

Solid-cancer patients with moderate to severe COVID-19 had sustained lymphopenia and increased neutrophil-to-lymphocyte ratios up to days 40-49 of the infection, whereas among those with mild infection, clinical blood parameters were typically in the normal range.

Although overall blood profiles of patients with hematologic cancers were similar to those of patients with solid cancers, the trajectories between mild and moderate/severe COVID-19 overlapped, and there was a large degree of heterogeneity between patients.

The team also reports that among patients with solid tumors, all parameters returned to values that were close to baseline 4-6 weeks after the patients tested negative for COVID-19 on nasopharyngeal swabbing; by contrast, many of the patients with hematologic cancers experienced ongoing immune dysregulation.

Further analysis revealed differences in immune signatures between patients with solid cancers who had active SARS-CoV-2 infection and noninfected control patients. The former showed, for example, interleukin-8, IL-6, and IL-10, IP-10 enrichment.

In contrast, there were few differences between infected and noninfected hematologic cancer patients.

Across both cohorts, approximately 75% of patients had detectable antibodies against COVID-19. Antibodies were sustained for up to 78 days after exposure to the virus.

However, patients with solid tumors showed earlier seroconversion than those with hematologic cancers. The latter had more varied responses to infection, displaying three distinct phenotypes: failure to mount an antibody response, with prolonged viral shedding, even beyond day 50 after the first positive swab; an antibody response but failure to clear the virus; and an antibody response and successful clearing of the virus.

The team noted that overall patients with hematologic cancers showed a mild response to COVID-19 in the active/early phases of the disease and that the response grew stronger over time, similar to the immune changes typically seen with chronic infections.

This was particularly the case for patients with cancers that affect B cells.

The team acknowledged that there are several limitations to the study, including its small sample size and lack of statistical power to detect differences between, for example, different treatment modalities.

“An important question which remains unanswered is if a ‘reinforced’ immune system following immunotherapy results in an under-/overactivation of the immune response” to COVID-19, the investigators commented. They note that one such patient had a good response.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas’ Foundation NHS Trust. It is funded from grants from the KCL Charity funds, MRC, Cancer Research UK, program grants from Breast Cancer Now at King’s College London and by grants to the Breast Cancer Now Toby Robin’s Research Center at the Institute of Cancer Research, London, and the Wellcome Trust Investigator Award, and is supported by the Cancer Research UK Cancer Immunotherapy Accelerator and the UK COVID-Immunology-Consortium. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

There is no question that COVID-19 infection increases the risks of serious thromboembolic events, including pulmonary embolism (PE), but it also increases the risk of bleeding, complicating the benefit-to-risk calculations for anticoagulation, according to a review of data at the virtual Going Back to the Heart of Cardiology meeting.

“Bleeding is a significant cause of morbidity in patients with COVID-19, and this is an important concept to appreciate,” reported Rachel P. Rosovsky, MD, director of thrombosis research, Massachusetts General Hospital, Boston.

At least five guidelines, including those issued by the American College of Cardiology, International Society on Thrombosis and Haemostasis (ISTH), and the American College of Chest Physicians, have recently addressed anticoagulation in patients infected with COVID-19, but there are “substantive differences” between them, according to Dr. Rosovsky. The reason is that they are essentially no high quality trials to guide practice. Rather, the recommendations are based primarily on retrospective studies and expert opinion.

The single most common theme from the guidelines is that anticoagulation must be individualized to balance patient-specific risks of venous thromboembolism (VTE) and bleeding, said Dr. Rosovsky, whose group published a recent comparison of these guidelines (Flaczyk A et al. Crit Care 2020;24:559).

Although there is general consensus that all hospitalized patients with COVID-19 should receive anticoagulation unless there are contraindications, there are differences in the recommended intensity of the anticoagulation for different risk groups and there is even less is less consensus on the need to anticoagulate outpatients or patients after discharge, according to Dr. Rosovsky

In her own center, the standard is a prophylactic dose of low molecular weight heparin (LMWH) in an algorithm that calls for dose adjustments for some groups such as those with renal impairment or obesity. Alternative forms of anticoagulation are recommended for patients with a history of thrombocytopenia or are at high risk for hemorrhage. Full dose LMWH is recommended in patients already on an oral anticoagulant at time of hospitalization.

“The biggest question right now is when to consider increasing from a prophylactic dose to intermediate or full dose anticoagulation in high risk patients, especially those in the ICU patients,” Dr. Rosovsky said.

Current practices are diverse, according to a recently published survey led by Dr. Rosovsky (Rosovsky RP et al. Res Pract Thromb Haemost. 2020;4:969-83). According to the survey, which had responses from more than 500 physicians in 41 countries, 30% of centers escalate from a prophylactic dose of anticoagulation to an intermediate dose when patients move to the ICU. Although not all answered this question, 25% reported that they do not escalate at ICU transfer. For 15% of respondents, dose escalation is being offered to patients with a D-dimer exceeding six-times the upper limit of normal.

These practices have developed in the absence of prospective clinical trials, which are urgently needed, according to Dr. Rosovsky. The reason that trials specific to COVID-19 are particularly important is that this infection also engenders a high risk of major bleeding.

For example, in a multicenter retrospective study of 400 hospital-admitted COVID-19 patients the rates of major bleeding was 4.8% or exactly the same as the rate of radiographically confirmed VTE. At 7.6%, the rates of VTE and major bleeding were also exactly the same for ICU patients (Al-Samkari H et al. Blood 2020;136:489-500).

“An elevated D-dimer was a marker for both VTE and major bleeding,” reported Dr. Rosovsky, who was the senior author of this study. On the basis of odds ratio (OR), the risk of VTE was increased more than six-fold (OR, 6.79) and the risk of major bleeding by more than three-fold (OR, 3.56) when the D-dimer exceeded 2,500 ng/mL.

The risk of VTE from COVID-19 infection is well documented. For example, autopsy studies have shown widespread thrombosis, including PE, in patients who have died from COVID-19 infection, according to Dr. Rosovsky.

There is also evidence of benefit from anticoagulation. In an retrospective study from China undertaken early in the pandemic, there was no overall mortality benefit at 28 days among those who did receive LMWH when compared to those who did not, but there was a 20% absolute mortality benefit (52.4% vs. 32.8%; P = .017) in those with a D-dimer six-fold ULN (Tang N et al. J Thromb Haemost 2020;18:1094-9).

These types of data support the use of anticoagulation to manage VTE risk in at least some patients, but the reported rates of VTE across institutions and across inpatient and outpatient settings have varied “dramatically,” according to Dr. Rosovsky. The balance of VTE and major bleeding is delicate. In one retrospective study, the mortality advantage for therapeutic versus prophylactic dose of LMWH did not reach statistical significance, but the rate of major bleeding was nearly doubled (3.0% vs. 1.7%) (Nadkarni GN et al J Am Coll Cardiol 2020;76:1815-26).

Because of the many variables that might affect risk of VTE and risk of major bleeding in any individual patient, the benefit-to-risk calculation of anticoagulation is “complex,” according to Dr. Rosovsky. It is for this reason she urged clinicians to consider entering patients into clinical trials designed to generate evidence-based answers.

There is large and growing body of retrospective data that have helped characterize the risk of VTE and bleeding in patients with COVID-19, but “there is no substitute for a well-controlled clinical trial,” agreed Robert A. Harrington, MD, chairman of the department of medicine, Stanford (Calif.) University.

He and the comoderator of the session in which these data were presented agreed that anticoagulation must be administered within a narrow therapeutic window that will be best defined through controlled trial designs.

“There is a significant risk of doing harm,” said Fatima Rodriguez, MD, assistant professor of cardiology at Stanford University. She seconded the critical role of trial participation when possible and the need for clinical trials to better guide treatment decisions.

The meeting was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

There is no question that COVID-19 infection increases the risks of serious thromboembolic events, including pulmonary embolism (PE), but it also increases the risk of bleeding, complicating the benefit-to-risk calculations for anticoagulation, according to a review of data at the virtual Going Back to the Heart of Cardiology meeting.

“Bleeding is a significant cause of morbidity in patients with COVID-19, and this is an important concept to appreciate,” reported Rachel P. Rosovsky, MD, director of thrombosis research, Massachusetts General Hospital, Boston.

At least five guidelines, including those issued by the American College of Cardiology, International Society on Thrombosis and Haemostasis (ISTH), and the American College of Chest Physicians, have recently addressed anticoagulation in patients infected with COVID-19, but there are “substantive differences” between them, according to Dr. Rosovsky. The reason is that they are essentially no high quality trials to guide practice. Rather, the recommendations are based primarily on retrospective studies and expert opinion.

The single most common theme from the guidelines is that anticoagulation must be individualized to balance patient-specific risks of venous thromboembolism (VTE) and bleeding, said Dr. Rosovsky, whose group published a recent comparison of these guidelines (Flaczyk A et al. Crit Care 2020;24:559).

Although there is general consensus that all hospitalized patients with COVID-19 should receive anticoagulation unless there are contraindications, there are differences in the recommended intensity of the anticoagulation for different risk groups and there is even less is less consensus on the need to anticoagulate outpatients or patients after discharge, according to Dr. Rosovsky

In her own center, the standard is a prophylactic dose of low molecular weight heparin (LMWH) in an algorithm that calls for dose adjustments for some groups such as those with renal impairment or obesity. Alternative forms of anticoagulation are recommended for patients with a history of thrombocytopenia or are at high risk for hemorrhage. Full dose LMWH is recommended in patients already on an oral anticoagulant at time of hospitalization.

“The biggest question right now is when to consider increasing from a prophylactic dose to intermediate or full dose anticoagulation in high risk patients, especially those in the ICU patients,” Dr. Rosovsky said.

Current practices are diverse, according to a recently published survey led by Dr. Rosovsky (Rosovsky RP et al. Res Pract Thromb Haemost. 2020;4:969-83). According to the survey, which had responses from more than 500 physicians in 41 countries, 30% of centers escalate from a prophylactic dose of anticoagulation to an intermediate dose when patients move to the ICU. Although not all answered this question, 25% reported that they do not escalate at ICU transfer. For 15% of respondents, dose escalation is being offered to patients with a D-dimer exceeding six-times the upper limit of normal.

These practices have developed in the absence of prospective clinical trials, which are urgently needed, according to Dr. Rosovsky. The reason that trials specific to COVID-19 are particularly important is that this infection also engenders a high risk of major bleeding.

For example, in a multicenter retrospective study of 400 hospital-admitted COVID-19 patients the rates of major bleeding was 4.8% or exactly the same as the rate of radiographically confirmed VTE. At 7.6%, the rates of VTE and major bleeding were also exactly the same for ICU patients (Al-Samkari H et al. Blood 2020;136:489-500).

“An elevated D-dimer was a marker for both VTE and major bleeding,” reported Dr. Rosovsky, who was the senior author of this study. On the basis of odds ratio (OR), the risk of VTE was increased more than six-fold (OR, 6.79) and the risk of major bleeding by more than three-fold (OR, 3.56) when the D-dimer exceeded 2,500 ng/mL.

The risk of VTE from COVID-19 infection is well documented. For example, autopsy studies have shown widespread thrombosis, including PE, in patients who have died from COVID-19 infection, according to Dr. Rosovsky.

There is also evidence of benefit from anticoagulation. In an retrospective study from China undertaken early in the pandemic, there was no overall mortality benefit at 28 days among those who did receive LMWH when compared to those who did not, but there was a 20% absolute mortality benefit (52.4% vs. 32.8%; P = .017) in those with a D-dimer six-fold ULN (Tang N et al. J Thromb Haemost 2020;18:1094-9).

These types of data support the use of anticoagulation to manage VTE risk in at least some patients, but the reported rates of VTE across institutions and across inpatient and outpatient settings have varied “dramatically,” according to Dr. Rosovsky. The balance of VTE and major bleeding is delicate. In one retrospective study, the mortality advantage for therapeutic versus prophylactic dose of LMWH did not reach statistical significance, but the rate of major bleeding was nearly doubled (3.0% vs. 1.7%) (Nadkarni GN et al J Am Coll Cardiol 2020;76:1815-26).

Because of the many variables that might affect risk of VTE and risk of major bleeding in any individual patient, the benefit-to-risk calculation of anticoagulation is “complex,” according to Dr. Rosovsky. It is for this reason she urged clinicians to consider entering patients into clinical trials designed to generate evidence-based answers.

There is large and growing body of retrospective data that have helped characterize the risk of VTE and bleeding in patients with COVID-19, but “there is no substitute for a well-controlled clinical trial,” agreed Robert A. Harrington, MD, chairman of the department of medicine, Stanford (Calif.) University.

He and the comoderator of the session in which these data were presented agreed that anticoagulation must be administered within a narrow therapeutic window that will be best defined through controlled trial designs.

“There is a significant risk of doing harm,” said Fatima Rodriguez, MD, assistant professor of cardiology at Stanford University. She seconded the critical role of trial participation when possible and the need for clinical trials to better guide treatment decisions.

The meeting was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

There is no question that COVID-19 infection increases the risks of serious thromboembolic events, including pulmonary embolism (PE), but it also increases the risk of bleeding, complicating the benefit-to-risk calculations for anticoagulation, according to a review of data at the virtual Going Back to the Heart of Cardiology meeting.

“Bleeding is a significant cause of morbidity in patients with COVID-19, and this is an important concept to appreciate,” reported Rachel P. Rosovsky, MD, director of thrombosis research, Massachusetts General Hospital, Boston.

At least five guidelines, including those issued by the American College of Cardiology, International Society on Thrombosis and Haemostasis (ISTH), and the American College of Chest Physicians, have recently addressed anticoagulation in patients infected with COVID-19, but there are “substantive differences” between them, according to Dr. Rosovsky. The reason is that they are essentially no high quality trials to guide practice. Rather, the recommendations are based primarily on retrospective studies and expert opinion.

The single most common theme from the guidelines is that anticoagulation must be individualized to balance patient-specific risks of venous thromboembolism (VTE) and bleeding, said Dr. Rosovsky, whose group published a recent comparison of these guidelines (Flaczyk A et al. Crit Care 2020;24:559).

Although there is general consensus that all hospitalized patients with COVID-19 should receive anticoagulation unless there are contraindications, there are differences in the recommended intensity of the anticoagulation for different risk groups and there is even less is less consensus on the need to anticoagulate outpatients or patients after discharge, according to Dr. Rosovsky

In her own center, the standard is a prophylactic dose of low molecular weight heparin (LMWH) in an algorithm that calls for dose adjustments for some groups such as those with renal impairment or obesity. Alternative forms of anticoagulation are recommended for patients with a history of thrombocytopenia or are at high risk for hemorrhage. Full dose LMWH is recommended in patients already on an oral anticoagulant at time of hospitalization.

“The biggest question right now is when to consider increasing from a prophylactic dose to intermediate or full dose anticoagulation in high risk patients, especially those in the ICU patients,” Dr. Rosovsky said.

Current practices are diverse, according to a recently published survey led by Dr. Rosovsky (Rosovsky RP et al. Res Pract Thromb Haemost. 2020;4:969-83). According to the survey, which had responses from more than 500 physicians in 41 countries, 30% of centers escalate from a prophylactic dose of anticoagulation to an intermediate dose when patients move to the ICU. Although not all answered this question, 25% reported that they do not escalate at ICU transfer. For 15% of respondents, dose escalation is being offered to patients with a D-dimer exceeding six-times the upper limit of normal.

These practices have developed in the absence of prospective clinical trials, which are urgently needed, according to Dr. Rosovsky. The reason that trials specific to COVID-19 are particularly important is that this infection also engenders a high risk of major bleeding.

For example, in a multicenter retrospective study of 400 hospital-admitted COVID-19 patients the rates of major bleeding was 4.8% or exactly the same as the rate of radiographically confirmed VTE. At 7.6%, the rates of VTE and major bleeding were also exactly the same for ICU patients (Al-Samkari H et al. Blood 2020;136:489-500).

“An elevated D-dimer was a marker for both VTE and major bleeding,” reported Dr. Rosovsky, who was the senior author of this study. On the basis of odds ratio (OR), the risk of VTE was increased more than six-fold (OR, 6.79) and the risk of major bleeding by more than three-fold (OR, 3.56) when the D-dimer exceeded 2,500 ng/mL.

The risk of VTE from COVID-19 infection is well documented. For example, autopsy studies have shown widespread thrombosis, including PE, in patients who have died from COVID-19 infection, according to Dr. Rosovsky.

There is also evidence of benefit from anticoagulation. In an retrospective study from China undertaken early in the pandemic, there was no overall mortality benefit at 28 days among those who did receive LMWH when compared to those who did not, but there was a 20% absolute mortality benefit (52.4% vs. 32.8%; P = .017) in those with a D-dimer six-fold ULN (Tang N et al. J Thromb Haemost 2020;18:1094-9).

These types of data support the use of anticoagulation to manage VTE risk in at least some patients, but the reported rates of VTE across institutions and across inpatient and outpatient settings have varied “dramatically,” according to Dr. Rosovsky. The balance of VTE and major bleeding is delicate. In one retrospective study, the mortality advantage for therapeutic versus prophylactic dose of LMWH did not reach statistical significance, but the rate of major bleeding was nearly doubled (3.0% vs. 1.7%) (Nadkarni GN et al J Am Coll Cardiol 2020;76:1815-26).

Because of the many variables that might affect risk of VTE and risk of major bleeding in any individual patient, the benefit-to-risk calculation of anticoagulation is “complex,” according to Dr. Rosovsky. It is for this reason she urged clinicians to consider entering patients into clinical trials designed to generate evidence-based answers.

There is large and growing body of retrospective data that have helped characterize the risk of VTE and bleeding in patients with COVID-19, but “there is no substitute for a well-controlled clinical trial,” agreed Robert A. Harrington, MD, chairman of the department of medicine, Stanford (Calif.) University.

He and the comoderator of the session in which these data were presented agreed that anticoagulation must be administered within a narrow therapeutic window that will be best defined through controlled trial designs.

“There is a significant risk of doing harm,” said Fatima Rodriguez, MD, assistant professor of cardiology at Stanford University. She seconded the critical role of trial participation when possible and the need for clinical trials to better guide treatment decisions.

The meeting was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

The real strength of the 4T score for heparin-induced thrombocytopenia (HIT) is its negative predictive value, according to hematologist Adam Cuker, MD, of the department of medicine at the University of Pennsylvania, Philadelphia.

The score assigns patients points based on degree of thrombocytopenia, timing of platelet count fall in relation to heparin exposure, presence of thrombosis and other sequelae, and the likelihood of other causes of thrombocytopenia.

A low score – 3 points or less – has a negative predictive value of 99.8%, “so HIT is basically ruled out; you do not need to order lab testing for HIT or manage the patient empirically for HIT,” and should look for other causes of thrombocytopenia, said Dr. Cuker, lead author of the American Society of Hematology’s most recent HIT guidelines.

Intermediate scores of 4 or 5 points, and high scores of 6-8 points, are a different story. The positive predictive value of an intermediate score is only 14%, and of a high score, 64%, so although they don’t confirm the diagnosis, “you have to take the possibility of HIT seriously.” Discontinue heparin, start a nonheparin anticoagulant, and order a HIT immunoassay. If it’s positive, order a functional assay to confirm the diagnosis, he said.

Suspicion of HIT “is perhaps the most common consult that we get on the hematology service. These are tough consults because it is a high-stakes decision.” There is about a 6% risk of thromboembolism, amputation, and death for every day treatment is delayed. “On the other hand, the nonheparin anticoagulants are expensive, and they carry about a 1% daily risk of major bleeding,” Dr. Cuker explained during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

ELISA immunoassay detects antiplatelet factor 4 heparin antibodies but doesn’t tell whether or not they are able to activate platelets and cause HIT. Functional tests such as the serotonin-release assay detect only those antibodies able to do so, but the assays are difficult to perform, and often require samples to be sent out to a reference lab.

ASH did not specify a particular nonheparin anticoagulant in its 2018 guidelines because “the best choice for your patient” depends on which drugs you have available, your familiarity with them, and patient factors, Dr. Cuker said at the conference sponsored by MedscapeLive.

It makes sense, for instance, to use a short-acting agent such as argatroban or bivalirudin in patients who are critically ill, at high risk of bleeding, or likely to need an urgent unplanned procedure. Fondaparinux or direct oral anticoagulants (DOACs) make sense if patients are clinically stable with good organ function and no more than average bleeding risk, because they are easier to administer and facilitate transition to the outpatient setting.

DOACs are newcomers to ASH’s guidelines. Just 81 patients had been reported in the literature when they were being drafted, but only 2 patients had recurrence or progression of thromboembolic events, and there were no major bleeds. The results compared favorably with other options.

The studies were subject to selection and reporting biases, “but, nonetheless, the panel felt the results were positive enough that DOACs ought to be listed as an option,” Dr. Cuker said.

The guidelines note that parenteral options may be the best choice for life- or limb-threatening thrombosis “because few such patients have been treated with a DOAC.” Anticoagulation must continue until platelet counts recover.

Dr. Cuker is a consultant for Synergy and has institutional research support from Alexion, Bayer, Sanofi, and other companies. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

The real strength of the 4T score for heparin-induced thrombocytopenia (HIT) is its negative predictive value, according to hematologist Adam Cuker, MD, of the department of medicine at the University of Pennsylvania, Philadelphia.

The score assigns patients points based on degree of thrombocytopenia, timing of platelet count fall in relation to heparin exposure, presence of thrombosis and other sequelae, and the likelihood of other causes of thrombocytopenia.

A low score – 3 points or less – has a negative predictive value of 99.8%, “so HIT is basically ruled out; you do not need to order lab testing for HIT or manage the patient empirically for HIT,” and should look for other causes of thrombocytopenia, said Dr. Cuker, lead author of the American Society of Hematology’s most recent HIT guidelines.

Intermediate scores of 4 or 5 points, and high scores of 6-8 points, are a different story. The positive predictive value of an intermediate score is only 14%, and of a high score, 64%, so although they don’t confirm the diagnosis, “you have to take the possibility of HIT seriously.” Discontinue heparin, start a nonheparin anticoagulant, and order a HIT immunoassay. If it’s positive, order a functional assay to confirm the diagnosis, he said.

Suspicion of HIT “is perhaps the most common consult that we get on the hematology service. These are tough consults because it is a high-stakes decision.” There is about a 6% risk of thromboembolism, amputation, and death for every day treatment is delayed. “On the other hand, the nonheparin anticoagulants are expensive, and they carry about a 1% daily risk of major bleeding,” Dr. Cuker explained during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

ELISA immunoassay detects antiplatelet factor 4 heparin antibodies but doesn’t tell whether or not they are able to activate platelets and cause HIT. Functional tests such as the serotonin-release assay detect only those antibodies able to do so, but the assays are difficult to perform, and often require samples to be sent out to a reference lab.

ASH did not specify a particular nonheparin anticoagulant in its 2018 guidelines because “the best choice for your patient” depends on which drugs you have available, your familiarity with them, and patient factors, Dr. Cuker said at the conference sponsored by MedscapeLive.

It makes sense, for instance, to use a short-acting agent such as argatroban or bivalirudin in patients who are critically ill, at high risk of bleeding, or likely to need an urgent unplanned procedure. Fondaparinux or direct oral anticoagulants (DOACs) make sense if patients are clinically stable with good organ function and no more than average bleeding risk, because they are easier to administer and facilitate transition to the outpatient setting.

DOACs are newcomers to ASH’s guidelines. Just 81 patients had been reported in the literature when they were being drafted, but only 2 patients had recurrence or progression of thromboembolic events, and there were no major bleeds. The results compared favorably with other options.

The studies were subject to selection and reporting biases, “but, nonetheless, the panel felt the results were positive enough that DOACs ought to be listed as an option,” Dr. Cuker said.

The guidelines note that parenteral options may be the best choice for life- or limb-threatening thrombosis “because few such patients have been treated with a DOAC.” Anticoagulation must continue until platelet counts recover.

Dr. Cuker is a consultant for Synergy and has institutional research support from Alexion, Bayer, Sanofi, and other companies. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

The real strength of the 4T score for heparin-induced thrombocytopenia (HIT) is its negative predictive value, according to hematologist Adam Cuker, MD, of the department of medicine at the University of Pennsylvania, Philadelphia.

The score assigns patients points based on degree of thrombocytopenia, timing of platelet count fall in relation to heparin exposure, presence of thrombosis and other sequelae, and the likelihood of other causes of thrombocytopenia.

A low score – 3 points or less – has a negative predictive value of 99.8%, “so HIT is basically ruled out; you do not need to order lab testing for HIT or manage the patient empirically for HIT,” and should look for other causes of thrombocytopenia, said Dr. Cuker, lead author of the American Society of Hematology’s most recent HIT guidelines.

Intermediate scores of 4 or 5 points, and high scores of 6-8 points, are a different story. The positive predictive value of an intermediate score is only 14%, and of a high score, 64%, so although they don’t confirm the diagnosis, “you have to take the possibility of HIT seriously.” Discontinue heparin, start a nonheparin anticoagulant, and order a HIT immunoassay. If it’s positive, order a functional assay to confirm the diagnosis, he said.

Suspicion of HIT “is perhaps the most common consult that we get on the hematology service. These are tough consults because it is a high-stakes decision.” There is about a 6% risk of thromboembolism, amputation, and death for every day treatment is delayed. “On the other hand, the nonheparin anticoagulants are expensive, and they carry about a 1% daily risk of major bleeding,” Dr. Cuker explained during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.

ELISA immunoassay detects antiplatelet factor 4 heparin antibodies but doesn’t tell whether or not they are able to activate platelets and cause HIT. Functional tests such as the serotonin-release assay detect only those antibodies able to do so, but the assays are difficult to perform, and often require samples to be sent out to a reference lab.

ASH did not specify a particular nonheparin anticoagulant in its 2018 guidelines because “the best choice for your patient” depends on which drugs you have available, your familiarity with them, and patient factors, Dr. Cuker said at the conference sponsored by MedscapeLive.

It makes sense, for instance, to use a short-acting agent such as argatroban or bivalirudin in patients who are critically ill, at high risk of bleeding, or likely to need an urgent unplanned procedure. Fondaparinux or direct oral anticoagulants (DOACs) make sense if patients are clinically stable with good organ function and no more than average bleeding risk, because they are easier to administer and facilitate transition to the outpatient setting.

DOACs are newcomers to ASH’s guidelines. Just 81 patients had been reported in the literature when they were being drafted, but only 2 patients had recurrence or progression of thromboembolic events, and there were no major bleeds. The results compared favorably with other options.

The studies were subject to selection and reporting biases, “but, nonetheless, the panel felt the results were positive enough that DOACs ought to be listed as an option,” Dr. Cuker said.

The guidelines note that parenteral options may be the best choice for life- or limb-threatening thrombosis “because few such patients have been treated with a DOAC.” Anticoagulation must continue until platelet counts recover.

Dr. Cuker is a consultant for Synergy and has institutional research support from Alexion, Bayer, Sanofi, and other companies. MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Individuals with nonsevere hemophilia A (NSHA) in the United States showed increased mortality based upon increasing age, male sex, and infections, according to the results of a large database analysis.

However, even though inhibitors, which can develop from factor VIII (FVIII) hemophilia therapy, were detected at an earlier age than previously reported, their presence was not associated with an increased risk of mortality according to the report published in Blood Advances (2020;4[19]:4739-47).

The researchers assessed 6,624 individuals born between 1920 and 2018 (5,694 [86.0%] men and 930 women) with NSHA from the ATHNdataset, according to Ming Y. Lim, MBBCH, MS, of the division of hematology and hematologic malignancies, University of Utah, Salt Lake City, and colleagues.

Demographically, the proportion of Black participants in the ATHNdataset was lower at 8.2%, than the 11.6% found in U.S. hemophilia population as a whole. A total of 77.3% (n = 5,122) had documented exposure to FVIII concentrates, 8.4% (n = 555) had no documented exposure, and information was unknown for the remaining 14.3%.
 

Causes of mortality

The researchers found that inhibitors occurred at an early age of 13 years with a prevalence of 2.6%, compared with the commonly reported median age of about 30 years for inhibitor development, but their presence was not associated with an increased risk of mortality, according to the authors. Instead, they found that mortality rates in the NSHA cohort were influenced by age, male sex, and hepatitis C and HIV infections.

The researchers speculated that the earlier age of inhibitor development may be due to the fact of the increased availability of FVIII concentrates over time, and that they may have been used more often from 2010 to 2018, compared with previously reported INSIGHT study (1980-2011).

In a multivariable analysis, men with NSHA were found to have 2.6 times the risk of death. Mortality risk increased twofold with each additional decade of age. Persons with hepatitis C had twice the risk of death and persons with HIV had almost four times the risk, compared with persons without these conditions.

The most common primary cause of death was malignancy (20.0%). The observed number of deaths from liver disease in the NSHA cohort was almost five times the expected death rate at 14%. Hemophilia-related deaths were 5.9%.

“Continued monitoring of persons with NSHA by comprehensive care visits at HTC should occur annually to address hemophilia-related issues and other age-related comorbidities, in collaboration with the primary care physician and other subspecialists. Importantly, we found that in the NSHA cohort, the development of inhibitors occurred at an earlier age than previously reported. This highlights the importance of routine monitoring for inhibitors in the NSHA population, regardless of age, especially if they have recently received intense factor replacement therapy,” the researchers concluded.

Ms. Lim reported no conflicts. Other authors reported research and consulting funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

SOURCE: Lim MY et al. Blood Adv. 2020;4(19):4739-47.

Individuals with nonsevere hemophilia A (NSHA) in the United States showed increased mortality based upon increasing age, male sex, and infections, according to the results of a large database analysis.

However, even though inhibitors, which can develop from factor VIII (FVIII) hemophilia therapy, were detected at an earlier age than previously reported, their presence was not associated with an increased risk of mortality according to the report published in Blood Advances (2020;4[19]:4739-47).

The researchers assessed 6,624 individuals born between 1920 and 2018 (5,694 [86.0%] men and 930 women) with NSHA from the ATHNdataset, according to Ming Y. Lim, MBBCH, MS, of the division of hematology and hematologic malignancies, University of Utah, Salt Lake City, and colleagues.

Demographically, the proportion of Black participants in the ATHNdataset was lower at 8.2%, than the 11.6% found in U.S. hemophilia population as a whole. A total of 77.3% (n = 5,122) had documented exposure to FVIII concentrates, 8.4% (n = 555) had no documented exposure, and information was unknown for the remaining 14.3%.
 

Causes of mortality

The researchers found that inhibitors occurred at an early age of 13 years with a prevalence of 2.6%, compared with the commonly reported median age of about 30 years for inhibitor development, but their presence was not associated with an increased risk of mortality, according to the authors. Instead, they found that mortality rates in the NSHA cohort were influenced by age, male sex, and hepatitis C and HIV infections.

The researchers speculated that the earlier age of inhibitor development may be due to the fact of the increased availability of FVIII concentrates over time, and that they may have been used more often from 2010 to 2018, compared with previously reported INSIGHT study (1980-2011).

In a multivariable analysis, men with NSHA were found to have 2.6 times the risk of death. Mortality risk increased twofold with each additional decade of age. Persons with hepatitis C had twice the risk of death and persons with HIV had almost four times the risk, compared with persons without these conditions.

The most common primary cause of death was malignancy (20.0%). The observed number of deaths from liver disease in the NSHA cohort was almost five times the expected death rate at 14%. Hemophilia-related deaths were 5.9%.

“Continued monitoring of persons with NSHA by comprehensive care visits at HTC should occur annually to address hemophilia-related issues and other age-related comorbidities, in collaboration with the primary care physician and other subspecialists. Importantly, we found that in the NSHA cohort, the development of inhibitors occurred at an earlier age than previously reported. This highlights the importance of routine monitoring for inhibitors in the NSHA population, regardless of age, especially if they have recently received intense factor replacement therapy,” the researchers concluded.

Ms. Lim reported no conflicts. Other authors reported research and consulting funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

SOURCE: Lim MY et al. Blood Adv. 2020;4(19):4739-47.

Individuals with nonsevere hemophilia A (NSHA) in the United States showed increased mortality based upon increasing age, male sex, and infections, according to the results of a large database analysis.

However, even though inhibitors, which can develop from factor VIII (FVIII) hemophilia therapy, were detected at an earlier age than previously reported, their presence was not associated with an increased risk of mortality according to the report published in Blood Advances (2020;4[19]:4739-47).

The researchers assessed 6,624 individuals born between 1920 and 2018 (5,694 [86.0%] men and 930 women) with NSHA from the ATHNdataset, according to Ming Y. Lim, MBBCH, MS, of the division of hematology and hematologic malignancies, University of Utah, Salt Lake City, and colleagues.

Demographically, the proportion of Black participants in the ATHNdataset was lower at 8.2%, than the 11.6% found in U.S. hemophilia population as a whole. A total of 77.3% (n = 5,122) had documented exposure to FVIII concentrates, 8.4% (n = 555) had no documented exposure, and information was unknown for the remaining 14.3%.
 

Causes of mortality

The researchers found that inhibitors occurred at an early age of 13 years with a prevalence of 2.6%, compared with the commonly reported median age of about 30 years for inhibitor development, but their presence was not associated with an increased risk of mortality, according to the authors. Instead, they found that mortality rates in the NSHA cohort were influenced by age, male sex, and hepatitis C and HIV infections.

The researchers speculated that the earlier age of inhibitor development may be due to the fact of the increased availability of FVIII concentrates over time, and that they may have been used more often from 2010 to 2018, compared with previously reported INSIGHT study (1980-2011).

In a multivariable analysis, men with NSHA were found to have 2.6 times the risk of death. Mortality risk increased twofold with each additional decade of age. Persons with hepatitis C had twice the risk of death and persons with HIV had almost four times the risk, compared with persons without these conditions.

The most common primary cause of death was malignancy (20.0%). The observed number of deaths from liver disease in the NSHA cohort was almost five times the expected death rate at 14%. Hemophilia-related deaths were 5.9%.

“Continued monitoring of persons with NSHA by comprehensive care visits at HTC should occur annually to address hemophilia-related issues and other age-related comorbidities, in collaboration with the primary care physician and other subspecialists. Importantly, we found that in the NSHA cohort, the development of inhibitors occurred at an earlier age than previously reported. This highlights the importance of routine monitoring for inhibitors in the NSHA population, regardless of age, especially if they have recently received intense factor replacement therapy,” the researchers concluded.

Ms. Lim reported no conflicts. Other authors reported research and consulting funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

SOURCE: Lim MY et al. Blood Adv. 2020;4(19):4739-47.

Among patients taking direct oral anticoagulants (DOACs), elective endoscopy procedures carry a risk of bleeding and thromboembolic events similar to that seen in those receiving vitamin K antagonists (VKAs), according to a multicenter, prospective observational study conducted at 12 Spanish academic and community centers.

DOACs have several advantages over VKAs, including more predictable pharmacokinetic profiles and fewer food and drug interactions, but they have not been well studied in the elective endoscopy setting. Some previous studies suggested a lower risk with DOACs than with VKAs, but they were retrospective or based on administrative databases.

It also remains unclear when anticoagulant therapy should be resumed following high-risk procedures. The new study, which was led by Enrique Rodríguez de Santiago of Universidad de Alcalá (Spain) and published in Clinical Gastroenterology and Hepatology, suggested that early resumption may be safe. “It certainly showed there was an acceptable rate of clinically significant rate of bleeding for patients on anticoagulants, and the thing I appreciated the most was that there was no statistically significant difference in terms of bleeding depending on when you resumed the anticoagulant,” said Robert Jay Sealock, MD, assistant professor of medicine at Baylor College of Medicine in Houston. Dr. Sealock was not involved in the study.

The researchers examined data from 1,623 patients who underwent 1,874 endoscopic procedures. Among these patients, 62.7% were taking VKAs, and 37.3% were taking DOACs; 58.9% were men, and the mean age was 74.2 years. Overall, 75.5% were on anticoagulant therapy for atrial fibrillation.

The most common procedures were colonoscopy (68.3%) and esophagogastroduodenoscopy (27.3%).

Within 30 days, The risk of bleeding was similar between patients taking VKAs (6.2%; 95% confidence interval, 4.8-7.8%) and DOACs (6.7%; 95% CI, 4.9-9%). This was true regardless of intervention and site. Overall, 1.4% of subjects experienced a thromboembolic event (95% CI, 0.9-2.1%), and there was no significant difference between the VKA group (1.3%; 95% CI, 0.8-2.2%) and the DOAC group (1.5%; 95% CI, 0.8-2.8%).

Clinically significant gastrointestinal bleeding occurred in 6.4% of subjects (95% CI, 5.3-7.7%); 2.7% of clinically significant gastrointestinal bleeding events were intraprocedural and 4.1% were delayed. The lowest risk of bleeding occurred with diagnostic endoscopy (1.1%) and biopsy (2.2%). The risk of bleeding for high-risk procedures was 11.5% (95% CI, 9.4-14%).

The overall mortality was 1.4%, with two deaths related to thromboembolic events, both in the DOAC group. The other deaths were considered to be unrelated to the procedure or periprocedural interruption of anticoagulants.

The researchers also examined the timing of anticoagulant resumption. Overall, 59.2% of subjects received bridging therapy, including 85% of the VKA group and 16% of the DOAC group (P < .001). This was not associated with increased endoscopy-related bleeding in either the VKA (3.3% with bridging therapy vs. 6.4% without; P = .14) or the DOAC group (8.3% vs. 6.4%; P = .48).

A total of 747 patients underwent a high-risk procedure, 46.3% of patients resumed anticoagulant therapy within 24 hours of the procedure, and 46.2% between 24 and 48 hours. After inverse probability of treatment weighting adjustment, a delay in anticoagulant resumption was not associated with a reduction in the frequency of postprocedural clinically significant gastrointestinal bleeding.

Still, the research left some questions unanswered. Most of the high-risk procedures were hot (41.8%) or cold snare polypectomies (39.8%). There weren’t enough data in the study to evaluate risk in patients undergoing other high-risk procedures such as balloon dilation for strictures, endoscopic ultrasound with fine-needle aspiration, and sphincterotomy. “That’s one group that we still don’t really have enough data about, particularly those patients who are on DOACs,” said Dr. Sealock.

The study also found a high number of patients on bridging therapy. “It highlighted the fact that we probably use bridging therapy too much in patients undergoing endoscopy,” said Dr. Sealock. He recommended using tools that generate recommendations for bridging therapy and timing for withholding and resuming anticoagulants based on procedure and patient characteristics.

SOURCE: de Santiago ER et al. Clin Gastroenterol Hepatol. 2020 Dec 03. doi: 10.1016/j.cgh.2020.11.037.

Among patients taking direct oral anticoagulants (DOACs), elective endoscopy procedures carry a risk of bleeding and thromboembolic events similar to that seen in those receiving vitamin K antagonists (VKAs), according to a multicenter, prospective observational study conducted at 12 Spanish academic and community centers.

DOACs have several advantages over VKAs, including more predictable pharmacokinetic profiles and fewer food and drug interactions, but they have not been well studied in the elective endoscopy setting. Some previous studies suggested a lower risk with DOACs than with VKAs, but they were retrospective or based on administrative databases.

It also remains unclear when anticoagulant therapy should be resumed following high-risk procedures. The new study, which was led by Enrique Rodríguez de Santiago of Universidad de Alcalá (Spain) and published in Clinical Gastroenterology and Hepatology, suggested that early resumption may be safe. “It certainly showed there was an acceptable rate of clinically significant rate of bleeding for patients on anticoagulants, and the thing I appreciated the most was that there was no statistically significant difference in terms of bleeding depending on when you resumed the anticoagulant,” said Robert Jay Sealock, MD, assistant professor of medicine at Baylor College of Medicine in Houston. Dr. Sealock was not involved in the study.

The researchers examined data from 1,623 patients who underwent 1,874 endoscopic procedures. Among these patients, 62.7% were taking VKAs, and 37.3% were taking DOACs; 58.9% were men, and the mean age was 74.2 years. Overall, 75.5% were on anticoagulant therapy for atrial fibrillation.

The most common procedures were colonoscopy (68.3%) and esophagogastroduodenoscopy (27.3%).

Within 30 days, The risk of bleeding was similar between patients taking VKAs (6.2%; 95% confidence interval, 4.8-7.8%) and DOACs (6.7%; 95% CI, 4.9-9%). This was true regardless of intervention and site. Overall, 1.4% of subjects experienced a thromboembolic event (95% CI, 0.9-2.1%), and there was no significant difference between the VKA group (1.3%; 95% CI, 0.8-2.2%) and the DOAC group (1.5%; 95% CI, 0.8-2.8%).

Clinically significant gastrointestinal bleeding occurred in 6.4% of subjects (95% CI, 5.3-7.7%); 2.7% of clinically significant gastrointestinal bleeding events were intraprocedural and 4.1% were delayed. The lowest risk of bleeding occurred with diagnostic endoscopy (1.1%) and biopsy (2.2%). The risk of bleeding for high-risk procedures was 11.5% (95% CI, 9.4-14%).

The overall mortality was 1.4%, with two deaths related to thromboembolic events, both in the DOAC group. The other deaths were considered to be unrelated to the procedure or periprocedural interruption of anticoagulants.

The researchers also examined the timing of anticoagulant resumption. Overall, 59.2% of subjects received bridging therapy, including 85% of the VKA group and 16% of the DOAC group (P < .001). This was not associated with increased endoscopy-related bleeding in either the VKA (3.3% with bridging therapy vs. 6.4% without; P = .14) or the DOAC group (8.3% vs. 6.4%; P = .48).

A total of 747 patients underwent a high-risk procedure, 46.3% of patients resumed anticoagulant therapy within 24 hours of the procedure, and 46.2% between 24 and 48 hours. After inverse probability of treatment weighting adjustment, a delay in anticoagulant resumption was not associated with a reduction in the frequency of postprocedural clinically significant gastrointestinal bleeding.

Still, the research left some questions unanswered. Most of the high-risk procedures were hot (41.8%) or cold snare polypectomies (39.8%). There weren’t enough data in the study to evaluate risk in patients undergoing other high-risk procedures such as balloon dilation for strictures, endoscopic ultrasound with fine-needle aspiration, and sphincterotomy. “That’s one group that we still don’t really have enough data about, particularly those patients who are on DOACs,” said Dr. Sealock.

The study also found a high number of patients on bridging therapy. “It highlighted the fact that we probably use bridging therapy too much in patients undergoing endoscopy,” said Dr. Sealock. He recommended using tools that generate recommendations for bridging therapy and timing for withholding and resuming anticoagulants based on procedure and patient characteristics.

SOURCE: de Santiago ER et al. Clin Gastroenterol Hepatol. 2020 Dec 03. doi: 10.1016/j.cgh.2020.11.037.

Among patients taking direct oral anticoagulants (DOACs), elective endoscopy procedures carry a risk of bleeding and thromboembolic events similar to that seen in those receiving vitamin K antagonists (VKAs), according to a multicenter, prospective observational study conducted at 12 Spanish academic and community centers.

DOACs have several advantages over VKAs, including more predictable pharmacokinetic profiles and fewer food and drug interactions, but they have not been well studied in the elective endoscopy setting. Some previous studies suggested a lower risk with DOACs than with VKAs, but they were retrospective or based on administrative databases.

It also remains unclear when anticoagulant therapy should be resumed following high-risk procedures. The new study, which was led by Enrique Rodríguez de Santiago of Universidad de Alcalá (Spain) and published in Clinical Gastroenterology and Hepatology, suggested that early resumption may be safe. “It certainly showed there was an acceptable rate of clinically significant rate of bleeding for patients on anticoagulants, and the thing I appreciated the most was that there was no statistically significant difference in terms of bleeding depending on when you resumed the anticoagulant,” said Robert Jay Sealock, MD, assistant professor of medicine at Baylor College of Medicine in Houston. Dr. Sealock was not involved in the study.

The researchers examined data from 1,623 patients who underwent 1,874 endoscopic procedures. Among these patients, 62.7% were taking VKAs, and 37.3% were taking DOACs; 58.9% were men, and the mean age was 74.2 years. Overall, 75.5% were on anticoagulant therapy for atrial fibrillation.

The most common procedures were colonoscopy (68.3%) and esophagogastroduodenoscopy (27.3%).

Within 30 days, The risk of bleeding was similar between patients taking VKAs (6.2%; 95% confidence interval, 4.8-7.8%) and DOACs (6.7%; 95% CI, 4.9-9%). This was true regardless of intervention and site. Overall, 1.4% of subjects experienced a thromboembolic event (95% CI, 0.9-2.1%), and there was no significant difference between the VKA group (1.3%; 95% CI, 0.8-2.2%) and the DOAC group (1.5%; 95% CI, 0.8-2.8%).

Clinically significant gastrointestinal bleeding occurred in 6.4% of subjects (95% CI, 5.3-7.7%); 2.7% of clinically significant gastrointestinal bleeding events were intraprocedural and 4.1% were delayed. The lowest risk of bleeding occurred with diagnostic endoscopy (1.1%) and biopsy (2.2%). The risk of bleeding for high-risk procedures was 11.5% (95% CI, 9.4-14%).

The overall mortality was 1.4%, with two deaths related to thromboembolic events, both in the DOAC group. The other deaths were considered to be unrelated to the procedure or periprocedural interruption of anticoagulants.

The researchers also examined the timing of anticoagulant resumption. Overall, 59.2% of subjects received bridging therapy, including 85% of the VKA group and 16% of the DOAC group (P < .001). This was not associated with increased endoscopy-related bleeding in either the VKA (3.3% with bridging therapy vs. 6.4% without; P = .14) or the DOAC group (8.3% vs. 6.4%; P = .48).

A total of 747 patients underwent a high-risk procedure, 46.3% of patients resumed anticoagulant therapy within 24 hours of the procedure, and 46.2% between 24 and 48 hours. After inverse probability of treatment weighting adjustment, a delay in anticoagulant resumption was not associated with a reduction in the frequency of postprocedural clinically significant gastrointestinal bleeding.

Still, the research left some questions unanswered. Most of the high-risk procedures were hot (41.8%) or cold snare polypectomies (39.8%). There weren’t enough data in the study to evaluate risk in patients undergoing other high-risk procedures such as balloon dilation for strictures, endoscopic ultrasound with fine-needle aspiration, and sphincterotomy. “That’s one group that we still don’t really have enough data about, particularly those patients who are on DOACs,” said Dr. Sealock.

The study also found a high number of patients on bridging therapy. “It highlighted the fact that we probably use bridging therapy too much in patients undergoing endoscopy,” said Dr. Sealock. He recommended using tools that generate recommendations for bridging therapy and timing for withholding and resuming anticoagulants based on procedure and patient characteristics.

SOURCE: de Santiago ER et al. Clin Gastroenterol Hepatol. 2020 Dec 03. doi: 10.1016/j.cgh.2020.11.037.

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Tending to patients who opt for outpatient autologous stem cell transplants is well tolerated by caregivers, so long as they have the resources and support necessary, according to a recent Italian report.

Investigators surveyed the primary caregivers – most often the spouse – of 25 multiple myeloma patients who, in consultation with their caregiver, opted for an outpatient procedure and 71 others who chose standard inpatient treatment, and compared the results. Outpatients were discharged a day after transplant with twice-weekly clinic visits until sustained hematologic recovery as reported in Clinical Lymphoma, Myeloma and Leukemia.

The teams used portions of the Caregiver Reaction Assessment survey that focused on self-reported sense of family support plus affect on daily activities and general health. Surveys were taken a week before transplant and 3 months afterwards.

Results did not differ significantly between outpatient and inpatient caregivers at either point, and there was no meaningful change in responses over time.

“The outpatient model neither improves nor impairs global caregivers’ burden, compared with” inpatient transplant. Outpatient caregivers “do not show that they suffer from a greater burden of responsibility as compared to those belonging to the inpatient’s arm,” said investigators led by Massimo Martino, MD, director of stem cell transplants at the Great Metropolitan Hospital in Reggio Calabria, Italy, where the patients were treated.

The relatively short-lasting neutropenia and the limited nonhematologic toxicity of high-dose melphalan make multiple myeloma good candidates for outpatient programs. Indeed, the incidence rate of mucositis, fever, chemotherapy-induced nausea and vomiting, and other adverse events did not differ between in and outpatients, which is in keeping with previous reports supporting the feasibility and safety of outpatient programs.

However, the burden on loved ones is considerable. At least during the aplastic phase, outpatient caregivers are on call around the clock and spend most of their time with the patient. Homes have to be kept meticulously clean, vital signs checked, medications administered, and ins and outs monitored, among other duties normally handled by inpatient staff.

The main limit of the study was that outpatients were a self-selected group. They and their caregivers may simply have had the resources and support needed for successful outpatient transplants, while other patients did not. As the investigators put it, “we cannot exclude the problem of residual confounding due to unmeasured variables” such as “factors underlying patients’ preference, which could potentially impact the study results.”

Administering the follow-up survey 3 months after transplant might also have missed the acute impact on outpatient caregivers. It’s been “reported that the quality of life of patients undergoing an” outpatient procedure decreases immediately post treatment but bounces back by 6 months. “The same result can probably be observed in caregivers,” the team said.

The outpatient and inpatient groups were comparable, with a majority of men and a mean age of about 60 years in both. The number of infused stem cells, engraftment kinetics, and hematopoietic cell transplantation–comorbidity index scores did not differ significantly between the two groups.

There was no funding for the work, and the investigators reported that they didn’t have any conflicts of interest.

[email protected]

SOURCE: Martino M et al. Clin Lymphoma Myeloma Leuk. 2020 Nov 19. doi: 10.1016/j.clml.2020.11.011.

Tending to patients who opt for outpatient autologous stem cell transplants is well tolerated by caregivers, so long as they have the resources and support necessary, according to a recent Italian report.

Investigators surveyed the primary caregivers – most often the spouse – of 25 multiple myeloma patients who, in consultation with their caregiver, opted for an outpatient procedure and 71 others who chose standard inpatient treatment, and compared the results. Outpatients were discharged a day after transplant with twice-weekly clinic visits until sustained hematologic recovery as reported in Clinical Lymphoma, Myeloma and Leukemia.

The teams used portions of the Caregiver Reaction Assessment survey that focused on self-reported sense of family support plus affect on daily activities and general health. Surveys were taken a week before transplant and 3 months afterwards.

Results did not differ significantly between outpatient and inpatient caregivers at either point, and there was no meaningful change in responses over time.

“The outpatient model neither improves nor impairs global caregivers’ burden, compared with” inpatient transplant. Outpatient caregivers “do not show that they suffer from a greater burden of responsibility as compared to those belonging to the inpatient’s arm,” said investigators led by Massimo Martino, MD, director of stem cell transplants at the Great Metropolitan Hospital in Reggio Calabria, Italy, where the patients were treated.

The relatively short-lasting neutropenia and the limited nonhematologic toxicity of high-dose melphalan make multiple myeloma good candidates for outpatient programs. Indeed, the incidence rate of mucositis, fever, chemotherapy-induced nausea and vomiting, and other adverse events did not differ between in and outpatients, which is in keeping with previous reports supporting the feasibility and safety of outpatient programs.

However, the burden on loved ones is considerable. At least during the aplastic phase, outpatient caregivers are on call around the clock and spend most of their time with the patient. Homes have to be kept meticulously clean, vital signs checked, medications administered, and ins and outs monitored, among other duties normally handled by inpatient staff.

The main limit of the study was that outpatients were a self-selected group. They and their caregivers may simply have had the resources and support needed for successful outpatient transplants, while other patients did not. As the investigators put it, “we cannot exclude the problem of residual confounding due to unmeasured variables” such as “factors underlying patients’ preference, which could potentially impact the study results.”

Administering the follow-up survey 3 months after transplant might also have missed the acute impact on outpatient caregivers. It’s been “reported that the quality of life of patients undergoing an” outpatient procedure decreases immediately post treatment but bounces back by 6 months. “The same result can probably be observed in caregivers,” the team said.

The outpatient and inpatient groups were comparable, with a majority of men and a mean age of about 60 years in both. The number of infused stem cells, engraftment kinetics, and hematopoietic cell transplantation–comorbidity index scores did not differ significantly between the two groups.

There was no funding for the work, and the investigators reported that they didn’t have any conflicts of interest.

[email protected]

SOURCE: Martino M et al. Clin Lymphoma Myeloma Leuk. 2020 Nov 19. doi: 10.1016/j.clml.2020.11.011.

Tending to patients who opt for outpatient autologous stem cell transplants is well tolerated by caregivers, so long as they have the resources and support necessary, according to a recent Italian report.

Investigators surveyed the primary caregivers – most often the spouse – of 25 multiple myeloma patients who, in consultation with their caregiver, opted for an outpatient procedure and 71 others who chose standard inpatient treatment, and compared the results. Outpatients were discharged a day after transplant with twice-weekly clinic visits until sustained hematologic recovery as reported in Clinical Lymphoma, Myeloma and Leukemia.

The teams used portions of the Caregiver Reaction Assessment survey that focused on self-reported sense of family support plus affect on daily activities and general health. Surveys were taken a week before transplant and 3 months afterwards.

Results did not differ significantly between outpatient and inpatient caregivers at either point, and there was no meaningful change in responses over time.

“The outpatient model neither improves nor impairs global caregivers’ burden, compared with” inpatient transplant. Outpatient caregivers “do not show that they suffer from a greater burden of responsibility as compared to those belonging to the inpatient’s arm,” said investigators led by Massimo Martino, MD, director of stem cell transplants at the Great Metropolitan Hospital in Reggio Calabria, Italy, where the patients were treated.

The relatively short-lasting neutropenia and the limited nonhematologic toxicity of high-dose melphalan make multiple myeloma good candidates for outpatient programs. Indeed, the incidence rate of mucositis, fever, chemotherapy-induced nausea and vomiting, and other adverse events did not differ between in and outpatients, which is in keeping with previous reports supporting the feasibility and safety of outpatient programs.

However, the burden on loved ones is considerable. At least during the aplastic phase, outpatient caregivers are on call around the clock and spend most of their time with the patient. Homes have to be kept meticulously clean, vital signs checked, medications administered, and ins and outs monitored, among other duties normally handled by inpatient staff.

The main limit of the study was that outpatients were a self-selected group. They and their caregivers may simply have had the resources and support needed for successful outpatient transplants, while other patients did not. As the investigators put it, “we cannot exclude the problem of residual confounding due to unmeasured variables” such as “factors underlying patients’ preference, which could potentially impact the study results.”

Administering the follow-up survey 3 months after transplant might also have missed the acute impact on outpatient caregivers. It’s been “reported that the quality of life of patients undergoing an” outpatient procedure decreases immediately post treatment but bounces back by 6 months. “The same result can probably be observed in caregivers,” the team said.

The outpatient and inpatient groups were comparable, with a majority of men and a mean age of about 60 years in both. The number of infused stem cells, engraftment kinetics, and hematopoietic cell transplantation–comorbidity index scores did not differ significantly between the two groups.

There was no funding for the work, and the investigators reported that they didn’t have any conflicts of interest.

[email protected]

SOURCE: Martino M et al. Clin Lymphoma Myeloma Leuk. 2020 Nov 19. doi: 10.1016/j.clml.2020.11.011.