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Occult HCV infection is correlated to unfavorable genotypes in hemophilia patients
The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.
This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.
The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.
“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.
The authors reported that they had no disclosures.
SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.
The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.
This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.
The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.
“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.
The authors reported that they had no disclosures.
SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.
The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.
This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.
The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.
“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.
The authors reported that they had no disclosures.
SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.
FROM INFECTION, GENETICS AND EVOLUTION
FDA approves first treatment for advanced epithelioid sarcoma
The Food and Drug Administration has granted accelerated approval to tazemetostat (Tazverik) for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
Approval was based on overall response rate in a trial enrolling 62 patients with metastatic or locally advanced epithelioid sarcoma. The overall response rate was 15%, with 1.6% of patients having a complete response and 13% having a partial response. Of the nine patients that had a response, six (67%) had a response lasting 6 months or longer, the FDA said in a press statement.
The most common side effects for patients taking tazemetostat were pain, fatigue, nausea, decreased appetite, vomiting, and constipation. Patients treated with tazemetostat are at increased risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia.
“Epithelioid sarcoma accounts for less than 1% of all soft-tissue sarcomas,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the Center for Drug Evaluation and Research. “Until today, there were no treatment options specifically for patients with epithelioid sarcoma. The approval of Tazverik provides a treatment option that specifically targets this disease.”
Tazemetostat must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks, the FDA said.
The Food and Drug Administration has granted accelerated approval to tazemetostat (Tazverik) for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
Approval was based on overall response rate in a trial enrolling 62 patients with metastatic or locally advanced epithelioid sarcoma. The overall response rate was 15%, with 1.6% of patients having a complete response and 13% having a partial response. Of the nine patients that had a response, six (67%) had a response lasting 6 months or longer, the FDA said in a press statement.
The most common side effects for patients taking tazemetostat were pain, fatigue, nausea, decreased appetite, vomiting, and constipation. Patients treated with tazemetostat are at increased risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia.
“Epithelioid sarcoma accounts for less than 1% of all soft-tissue sarcomas,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the Center for Drug Evaluation and Research. “Until today, there were no treatment options specifically for patients with epithelioid sarcoma. The approval of Tazverik provides a treatment option that specifically targets this disease.”
Tazemetostat must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks, the FDA said.
The Food and Drug Administration has granted accelerated approval to tazemetostat (Tazverik) for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
Approval was based on overall response rate in a trial enrolling 62 patients with metastatic or locally advanced epithelioid sarcoma. The overall response rate was 15%, with 1.6% of patients having a complete response and 13% having a partial response. Of the nine patients that had a response, six (67%) had a response lasting 6 months or longer, the FDA said in a press statement.
The most common side effects for patients taking tazemetostat were pain, fatigue, nausea, decreased appetite, vomiting, and constipation. Patients treated with tazemetostat are at increased risk of developing secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia.
“Epithelioid sarcoma accounts for less than 1% of all soft-tissue sarcomas,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the Center for Drug Evaluation and Research. “Until today, there were no treatment options specifically for patients with epithelioid sarcoma. The approval of Tazverik provides a treatment option that specifically targets this disease.”
Tazemetostat must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks, the FDA said.
DOACs for treatment of cancer-associated venous thromboembolism
Bleeding risk may determine best option
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Bleeding risk may determine best option
Bleeding risk may determine best option
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Case
A 52-year-old female with past medical history of diabetes, hypertension, and stage 4 lung cancer on palliative chemotherapy presents with acute-onset dyspnea, pleuritic chest pain, and cough. Her exam is notable for tachycardia, hypoxemia, and diminished breath sounds. A CT pulmonary embolism study shows new left segmental thrombus. What is her preferred method of anticoagulation?
Brief overview of the issue
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern in the context of malignancy and is associated with higher rates of mortality at 1 year.
The standard of care in the recent past has relied on low-molecular-weight heparin (LMWH) after several trials showed decreased VTE recurrence in cancer patients, compared with vitamin K antagonist (VKA) treatment.1,2 LMWH has been recommended as a first-line treatment by clinical guidelines for cancer-related VTE given lower drug-drug interactions between LMWH and chemotherapy regimens, as compared with traditional VKAs, and it does not rely on intestinal absorption.3
In more recent years, the focus has shifted to direct oral anticoagulants (DOACs) as potential treatment options for cancer-related VTE given their ease of administration, low side-effect profile, and decreased cost. Until recently, studies have mainly been small and largely retrospective, however, several larger randomized control studies have recently been published.
Overview of the data
Several retrospective trials have investigated the use of DOACs in cancer-associated VTE. One study looking at VTE recurrence rates showed a trend towards lower rates with rivaroxaban, compared with LMWH at 6 months (13% vs. 17%) that was significantly lower at 12 months (16.5 % vs. 22%). Similar results were found when comparing rivaroxaban to warfarin. Major bleeding rates were similar among cohorts.4
Several other retrospective cohort studies looking at treatment of cancer-associated VTE treated with LMWH vs. DOACs found that overall patients treated with DOACs had cancers with lower risk for VTE and had lower burden of metastatic disease. When this was adjusted for, there was no significant difference in the rate of recurrent cancer-associated thrombosis or major bleeding.5,6
Recently several prospective studies have corroborated the noninferiority or slight superiority of DOACs when compared with LMWH in treatment of cancer-associated VTE, while showing similar rates of bleeding. These are summarized as follows: a prospective, open-label, randomized controlled (RCT), noninferiority trial of 1,046 patients with malignancy-related VTE assigned to either LMWH for at least 5 days, followed by oral edoxaban vs. subcutaneous dalteparin for at least 6 months and up to 12 months. Investigators found no significant difference in the rate of recurrent VTE in the edoxaban group (12.8%), as compared to the dalteparin group (13.5%, P = .006 for noninferiority). Risk of major bleeding was not significantly different between the groups.7
A small RCT of 203 patients comparing recurrent VTE rates with rivaroxaban vs. dalteparin found significantly fewer recurrent clots in the rivaroxaban group compared to the dalteparin group (11% vs 4%) with no significant difference in the 6-month cumulative rate of major bleeding, 4% in the dalteparin group and 6% for the rivaroxaban group.8 Preliminary results from the ADAM VTE trial comparing apixaban to dalteparin found significantly fewer recurrent VTE in the apixaban group (3.4% vs. 14.1%) with no significant difference in major bleeding events (0% vs 2.1%).9 The Caravaggio study is a large multinational randomized, controlled, open-label, noninferiority trial looking at apixaban vs. dalteparin with endpoints being 6-month recurrent VTE and bleeding risk that will likely report results soon.
Risk of bleeding is also a major consideration in VTE treatment as studies suggest that patients with metastatic cancer are at sixfold higher risk for anticoagulant-associated bleeding.3 Subgroup analysis of Hokusai VTE cancer study found that major bleeding occurred in 32 of 522 patients given edoxaban and 16 of 524 patients treated with dalteparin. Excess of major bleeding with edoxaban was confined to patients with GI cancer. However, rates of severe major bleeding at presentation were similar.10
Overall, the existing data suggests that DOACs may be a viable option in the treatment of malignancy-associated VTE given its similar efficacy in preventing recurrent VTE without significant increased risk of major bleeding. The 2018 International Society on Thrombosis and Haemostasis VTE in cancer guidelines have been updated to include rivaroxaban and edoxaban for use in patients at low risk of bleeding, but recommend an informed discussion between patients and clinicians in deciding between DOAC and LMWH.11 The Chest VTE guidelines have not been updated since 2016, prior to when the above mentioned DOAC studies were published.
Application of data to our patient
Compared with patients without cancer, anticoagulation in cancer patients with acute VTE is challenging because of higher rates of VTE recurrence and bleeding, as well as the potential for drug interactions with anticancer agents. Our patient is not at increased risk for gastrointestinal bleeding and no drug interactions exist between her current chemotherapy regimen and the available DOACs, therefore she is a candidate for treatment with a DOAC.
After an informed discussion, she chose to start rivaroxaban for treatment of her pulmonary embolism. While more studies are needed to definitively determine the best treatment for cancer-associated VTE, DOACs appear to be an attractive alternative to LMWH. Patient preferences of taking oral medications over injections as well as the significant cost savings of DOACs over LMWH will likely play into many patients’ and providers’ anticoagulant choices.
Bottom line
Direct oral anticoagulants are a treatment option for cancer-associated VTE in patients at low risk of bleeding complications. Patients at increased risk of bleeding (especially patients with GI malignancies) should continue to be treated with LMWH.
Dr. Spence is a hospitalist and palliative care physician at Denver Health, and an assistant professor of medicine at the University of Colorado at Denver, Aurora. Dr. Miller and Dr. Liu are hospitalists at Denver Health, and assistant professors of medicine at the University of Colorado at Denver.
References
1. Hull RD et al. Long term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patient with cancer. Am J Med. 2006;19(12):1062-72.
2. Lee AY et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53.
3. Ay C et al. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants. Ann Oncol. 2019 Mar 27 [epub].
4. Streiff MB et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018 May;93(5):664-71.
5. Phelps MK et al. A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer – A real-world experience. J Oncol Pharm Pract. 2019 Jun;25(4):793-800.
6. Simmons B et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol. 2018 Apr 4. (Epub).
7. Raskob GE et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-24.
8. Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-23.
9. McBane, RD et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2018 Nov 29;132(suppl 1):421.
10. Kraaijpoel N et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE cancer study. Thromb Haemost. 2018 Aug;118(8):1439-49.
11. Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Key points
- DOACs are a reasonable treatment option for malignancy-associated VTE in patients without GI tract malignancies and at low risk for bleeding complications.
- In patients with gastrointestinal malignancies or increased risk of bleeding, DOACs may have an increased bleeding risk and therefore LMWH is recommended.
- An informed discussion should occur between providers and patients to determine the best treatment option for cancer patients with VTE.
Additional reading
Dong Y et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019 May 6.
Khorana AA et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891-94.
Tritschler T et al. Venous thromboembolism advances in diagnosis and treatment. JAMA. 2018 Oct;320(15):1583-94.
Quiz
Which of the following is the recommended treatment of VTE in a patient with brain metastases?
A. Unfractionated heparin
B. Low molecular weight heparin
C. Direct oral anticoagulant
D. Vitamin K antagonist
The answer is B. Although there are very few data, LMWH is the recommended agent in patients with VTE and brain metastases.
A. LMWH has been shown to decrease mortality in patients with VTE and cancer, compared with unfractionated heparin (risk ratio, 0.66).
C. The safety of DOACs is not yet well established in patients with brain tumors. Antidotes and/or specific reversal agents for some DOACs are not available.
D. Vitamin K antagonists such as warfarin are not recommended in cancer patients because LMWH has a reduced risk of recurrent VTE without increased risk of bleeding.
Experts break down latest CAR T-cell advances in lymphoma
ORLANDO – There’s now mature data surrounding the use of chimeric antigen receptor (CAR) T-cell therapy in lymphoma, and the annual meeting of the American Society of Hematology brought forth additional information from real-world studies, insights about what is driving relapse, and promising data on mantle cell lymphoma.
The roundtable participants included Brian Hill, MD, of the Cleveland Clinic Taussig Cancer Center; Frederick L. Locke, MD, of the Moffit Cancer Center in Tampa, Fla.; and Peter Riedell, MD, of the University of Chicago.
Among the studies highlighted by the panel was the Transcend NHL 001 study (Abstract 241), which looked at third-line use of lisocabtagene maraleucel (liso-cel) in patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and other indolent non-Hodgkin lymphoma subtypes. More than 300 patients were enrolled, and liso-cel met all primary and secondary efficacy endpoints, with an overall response rate of more than 70%. The notable take-home point from the study was the safety profile, Dr. Riedell noted. Liso-cel was associated with a lower rate of cytokine release syndrome and neurologic toxicity, compared with the currently approved products.
Since patients in the study had a lower incidence and later onset of cytokine release syndrome, liso-cel could be a candidate for outpatient administration, Dr. Locke said. However, doing that would require “significant infrastructure” in hospitals and clinics to properly support patients, especially given that the treatment-related mortality on the study was similar to approved CAR T-cell products at about 3%. “You have to be ready to admit the patient to the hospital very rapidly, and you have to have the providers and the nurses who are vigilant when the patient is not in the hospital,” he said.
Another notable study presented at ASH examined the characteristics and outcomes of patients receiving bridging therapy while awaiting treatment with axicabtagene ciloleucel (Abstract 245). This real-world study adds interesting information to the field because, in some of the studies that were pivotal to the approval of CAR T-cell therapy, bridging therapy was not allowed, Dr. Locke said.
In this analysis, researchers found that the overall survival was worse among patients who received bridging. This finding suggests that patients who received bridging therapy had a different biology or that the therapy itself may have had an effect on the host or tumor microenvironment that affected the efficacy of the CAR T-cell therapy, the researchers reported.
The panel also highlighted the Zuma-2 study, which looked at KTE-X19, an anti-CD19 CAR T-cell therapy, among more than 70 patients with relapsed/refractory mantle cell lymphoma who had failed treatment with a Bruton’s tyrosine kinase inhibitor (Abstract 754). “This was, I thought, kind of a sleeper study at ASH,” said Dr. Hill, who was one of the authors of the study.
The overall response rate was 93% with about two-thirds of patients achieving a complete response. Researchers found that the response was consistent across subgroups, including Ki-67 and patients with prior use of steroids or bridging therapy. Dr. Locke, who was also a study author, said the results are a “game changer.”
“I’m very excited about it,” Dr. Riedell said, noting that these are patients without a lot of treatment options.
The panel also discussed other studies from ASH, including an analysis of tumor tissue samples from patients in the ZUMA-1 trial who had responded and subsequently relapsed (Abstract 203); a multicenter prospective analysis of circulating tumor DNA in diffuse large B-cell lymphoma patients who had relapsed after treatment with axicabtagene ciloleucel (Abstract 884); and the early use of corticosteroids to prevent toxicities in patients in cohort 4 of the ZUMA-1 trial (Abstract 243).
Dr. Hill reported consulting with Juno/Celgene/BMS and Novartis and research and consulting for Kite/Gilead. Dr. Locke reported consulting for Cellular Biomedicine Group and being a scientific adviser to Kite/Gilead, Novartis, Celgene/BMS, GammaDelta Therapeutics, Calibr, and Allogene. Dr. Riedell reported consulting for Bayer and Verastem, consulting for and research funding from Novartis and BMS/Celgene, and consulting for, research funding from, and speaking for Kite.
ORLANDO – There’s now mature data surrounding the use of chimeric antigen receptor (CAR) T-cell therapy in lymphoma, and the annual meeting of the American Society of Hematology brought forth additional information from real-world studies, insights about what is driving relapse, and promising data on mantle cell lymphoma.
The roundtable participants included Brian Hill, MD, of the Cleveland Clinic Taussig Cancer Center; Frederick L. Locke, MD, of the Moffit Cancer Center in Tampa, Fla.; and Peter Riedell, MD, of the University of Chicago.
Among the studies highlighted by the panel was the Transcend NHL 001 study (Abstract 241), which looked at third-line use of lisocabtagene maraleucel (liso-cel) in patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and other indolent non-Hodgkin lymphoma subtypes. More than 300 patients were enrolled, and liso-cel met all primary and secondary efficacy endpoints, with an overall response rate of more than 70%. The notable take-home point from the study was the safety profile, Dr. Riedell noted. Liso-cel was associated with a lower rate of cytokine release syndrome and neurologic toxicity, compared with the currently approved products.
Since patients in the study had a lower incidence and later onset of cytokine release syndrome, liso-cel could be a candidate for outpatient administration, Dr. Locke said. However, doing that would require “significant infrastructure” in hospitals and clinics to properly support patients, especially given that the treatment-related mortality on the study was similar to approved CAR T-cell products at about 3%. “You have to be ready to admit the patient to the hospital very rapidly, and you have to have the providers and the nurses who are vigilant when the patient is not in the hospital,” he said.
Another notable study presented at ASH examined the characteristics and outcomes of patients receiving bridging therapy while awaiting treatment with axicabtagene ciloleucel (Abstract 245). This real-world study adds interesting information to the field because, in some of the studies that were pivotal to the approval of CAR T-cell therapy, bridging therapy was not allowed, Dr. Locke said.
In this analysis, researchers found that the overall survival was worse among patients who received bridging. This finding suggests that patients who received bridging therapy had a different biology or that the therapy itself may have had an effect on the host or tumor microenvironment that affected the efficacy of the CAR T-cell therapy, the researchers reported.
The panel also highlighted the Zuma-2 study, which looked at KTE-X19, an anti-CD19 CAR T-cell therapy, among more than 70 patients with relapsed/refractory mantle cell lymphoma who had failed treatment with a Bruton’s tyrosine kinase inhibitor (Abstract 754). “This was, I thought, kind of a sleeper study at ASH,” said Dr. Hill, who was one of the authors of the study.
The overall response rate was 93% with about two-thirds of patients achieving a complete response. Researchers found that the response was consistent across subgroups, including Ki-67 and patients with prior use of steroids or bridging therapy. Dr. Locke, who was also a study author, said the results are a “game changer.”
“I’m very excited about it,” Dr. Riedell said, noting that these are patients without a lot of treatment options.
The panel also discussed other studies from ASH, including an analysis of tumor tissue samples from patients in the ZUMA-1 trial who had responded and subsequently relapsed (Abstract 203); a multicenter prospective analysis of circulating tumor DNA in diffuse large B-cell lymphoma patients who had relapsed after treatment with axicabtagene ciloleucel (Abstract 884); and the early use of corticosteroids to prevent toxicities in patients in cohort 4 of the ZUMA-1 trial (Abstract 243).
Dr. Hill reported consulting with Juno/Celgene/BMS and Novartis and research and consulting for Kite/Gilead. Dr. Locke reported consulting for Cellular Biomedicine Group and being a scientific adviser to Kite/Gilead, Novartis, Celgene/BMS, GammaDelta Therapeutics, Calibr, and Allogene. Dr. Riedell reported consulting for Bayer and Verastem, consulting for and research funding from Novartis and BMS/Celgene, and consulting for, research funding from, and speaking for Kite.
ORLANDO – There’s now mature data surrounding the use of chimeric antigen receptor (CAR) T-cell therapy in lymphoma, and the annual meeting of the American Society of Hematology brought forth additional information from real-world studies, insights about what is driving relapse, and promising data on mantle cell lymphoma.
The roundtable participants included Brian Hill, MD, of the Cleveland Clinic Taussig Cancer Center; Frederick L. Locke, MD, of the Moffit Cancer Center in Tampa, Fla.; and Peter Riedell, MD, of the University of Chicago.
Among the studies highlighted by the panel was the Transcend NHL 001 study (Abstract 241), which looked at third-line use of lisocabtagene maraleucel (liso-cel) in patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and other indolent non-Hodgkin lymphoma subtypes. More than 300 patients were enrolled, and liso-cel met all primary and secondary efficacy endpoints, with an overall response rate of more than 70%. The notable take-home point from the study was the safety profile, Dr. Riedell noted. Liso-cel was associated with a lower rate of cytokine release syndrome and neurologic toxicity, compared with the currently approved products.
Since patients in the study had a lower incidence and later onset of cytokine release syndrome, liso-cel could be a candidate for outpatient administration, Dr. Locke said. However, doing that would require “significant infrastructure” in hospitals and clinics to properly support patients, especially given that the treatment-related mortality on the study was similar to approved CAR T-cell products at about 3%. “You have to be ready to admit the patient to the hospital very rapidly, and you have to have the providers and the nurses who are vigilant when the patient is not in the hospital,” he said.
Another notable study presented at ASH examined the characteristics and outcomes of patients receiving bridging therapy while awaiting treatment with axicabtagene ciloleucel (Abstract 245). This real-world study adds interesting information to the field because, in some of the studies that were pivotal to the approval of CAR T-cell therapy, bridging therapy was not allowed, Dr. Locke said.
In this analysis, researchers found that the overall survival was worse among patients who received bridging. This finding suggests that patients who received bridging therapy had a different biology or that the therapy itself may have had an effect on the host or tumor microenvironment that affected the efficacy of the CAR T-cell therapy, the researchers reported.
The panel also highlighted the Zuma-2 study, which looked at KTE-X19, an anti-CD19 CAR T-cell therapy, among more than 70 patients with relapsed/refractory mantle cell lymphoma who had failed treatment with a Bruton’s tyrosine kinase inhibitor (Abstract 754). “This was, I thought, kind of a sleeper study at ASH,” said Dr. Hill, who was one of the authors of the study.
The overall response rate was 93% with about two-thirds of patients achieving a complete response. Researchers found that the response was consistent across subgroups, including Ki-67 and patients with prior use of steroids or bridging therapy. Dr. Locke, who was also a study author, said the results are a “game changer.”
“I’m very excited about it,” Dr. Riedell said, noting that these are patients without a lot of treatment options.
The panel also discussed other studies from ASH, including an analysis of tumor tissue samples from patients in the ZUMA-1 trial who had responded and subsequently relapsed (Abstract 203); a multicenter prospective analysis of circulating tumor DNA in diffuse large B-cell lymphoma patients who had relapsed after treatment with axicabtagene ciloleucel (Abstract 884); and the early use of corticosteroids to prevent toxicities in patients in cohort 4 of the ZUMA-1 trial (Abstract 243).
Dr. Hill reported consulting with Juno/Celgene/BMS and Novartis and research and consulting for Kite/Gilead. Dr. Locke reported consulting for Cellular Biomedicine Group and being a scientific adviser to Kite/Gilead, Novartis, Celgene/BMS, GammaDelta Therapeutics, Calibr, and Allogene. Dr. Riedell reported consulting for Bayer and Verastem, consulting for and research funding from Novartis and BMS/Celgene, and consulting for, research funding from, and speaking for Kite.
EXPERT ANALYSIS FROM ASH 2019
Start of myeloma therapy may be delayed for women, minorities
Women and racial minorities with multiple myeloma may be at increased risk of delayed treatment, a situation that should be addressed urgently, according to authors of a recent analysis of a clinical oncology database.
By contrast, patients receiving myeloma treatment sooner after diagnosis included patients who were over 80 years of age, had multiple comorbidities, were treated at specialized cancer programs or in areas other than the Northeast, and had Medicaid or did not have private insurance, the authors reported.
Contrary to what was expected, levels of education and income did not significantly affect the timeliness of treatment in this analysis by Vivek Kumar, MD, of Dana-Farber Cancer Institute in Boston and coinvestigators.
While results of studies to date are “conflicting” as to whether timeliness of myeloma therapy will affect patient outcomes, recent studies in breast cancer and other tumor types suggest earlier treatment intervention may reduce morbidity, improve quality of life, and possibly prolong survival, according to Dr. Kumar and colleagues.
Moreover, the focus of myeloma treatment has shifted toward earlier treatment in light of the superiority of today’s treatment options, which was demonstrated in the 2014 update of the International Myeloma Working Group (IMWG) diagnostic criteria, according to the investigators.
“The definition of active MM [multiple myeloma] has been updated so that patients who may have been considered to have smoldering MM previously are now treated sooner to prevent end-organ damage whenever possible,” said Dr. Kumar and coauthors in their report in JCO Oncology Practice.
The analysis of timely myeloma treatment was based on for 74,722 patients in the National Cancer Database who received a diagnosis of multiple myeloma between 2004 and 2015 and went on to receive systemic treatment within the first year of diagnosis.
Delay in treatment, defined as receiving antimyeloma therapy 40 or more days after diagnosis, occurred in 18,375 of those patients, or about one-quarter of the study cohort. The mean time from diagnosis to start of treatment in that group was 63 days.
Compared with patients who received treatment within 7 days of diagnosis, patients with delays in treatment were more likely to be women (odds ratio, 1.15; 95% confidence interval, 1.1-1.2) and more likely to be non-Hispanic black (OR, 1.21; 95% CI, 1.14-1.28), the investigators reported.
A previous analysis of the SEER-Medicare database suggested that certain antimyeloma agents are used later in racial and ethnic minorities, including Hispanic patients, who had the highest median time to first dose of bortezomib, Dr. Kumar and colleagues noted.
However, no report before the present one had looked at the time to overall initial treatment in racial and ethnic minorities, they added.
Patients diagnosed in more recent years had higher odds of treatment delay, though this could have been caused by an increase in the number of patients diagnosed early; prior to the 2014 IMWG diagnostic criteria revision, many would have been offered therapy only when signs of end-organ damage were present, while patients without end-organ damage would have been said to have smoldering disease, authors said.
Patients 80 years of age and older and those with a higher Charlson comorbidity score had a lower likelihood of treatment delay in this analysis, possibly reflecting the frailty of those patients and an urgent need for treatment, according to investigators.
Uninsured patients and those with Medicaid were less likely than insured patients to experience treatment delay, according to the report.
“This may be associated with the fact that, for these insurances, prior authorization is typically not required before initiating treatment,” said Dr. Kumar and colleagues. “However, this could also depend on several other possible factors, including availability of caregiver support and seeking medical care later.”
Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
SOURCE: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
Women and racial minorities with multiple myeloma may be at increased risk of delayed treatment, a situation that should be addressed urgently, according to authors of a recent analysis of a clinical oncology database.
By contrast, patients receiving myeloma treatment sooner after diagnosis included patients who were over 80 years of age, had multiple comorbidities, were treated at specialized cancer programs or in areas other than the Northeast, and had Medicaid or did not have private insurance, the authors reported.
Contrary to what was expected, levels of education and income did not significantly affect the timeliness of treatment in this analysis by Vivek Kumar, MD, of Dana-Farber Cancer Institute in Boston and coinvestigators.
While results of studies to date are “conflicting” as to whether timeliness of myeloma therapy will affect patient outcomes, recent studies in breast cancer and other tumor types suggest earlier treatment intervention may reduce morbidity, improve quality of life, and possibly prolong survival, according to Dr. Kumar and colleagues.
Moreover, the focus of myeloma treatment has shifted toward earlier treatment in light of the superiority of today’s treatment options, which was demonstrated in the 2014 update of the International Myeloma Working Group (IMWG) diagnostic criteria, according to the investigators.
“The definition of active MM [multiple myeloma] has been updated so that patients who may have been considered to have smoldering MM previously are now treated sooner to prevent end-organ damage whenever possible,” said Dr. Kumar and coauthors in their report in JCO Oncology Practice.
The analysis of timely myeloma treatment was based on for 74,722 patients in the National Cancer Database who received a diagnosis of multiple myeloma between 2004 and 2015 and went on to receive systemic treatment within the first year of diagnosis.
Delay in treatment, defined as receiving antimyeloma therapy 40 or more days after diagnosis, occurred in 18,375 of those patients, or about one-quarter of the study cohort. The mean time from diagnosis to start of treatment in that group was 63 days.
Compared with patients who received treatment within 7 days of diagnosis, patients with delays in treatment were more likely to be women (odds ratio, 1.15; 95% confidence interval, 1.1-1.2) and more likely to be non-Hispanic black (OR, 1.21; 95% CI, 1.14-1.28), the investigators reported.
A previous analysis of the SEER-Medicare database suggested that certain antimyeloma agents are used later in racial and ethnic minorities, including Hispanic patients, who had the highest median time to first dose of bortezomib, Dr. Kumar and colleagues noted.
However, no report before the present one had looked at the time to overall initial treatment in racial and ethnic minorities, they added.
Patients diagnosed in more recent years had higher odds of treatment delay, though this could have been caused by an increase in the number of patients diagnosed early; prior to the 2014 IMWG diagnostic criteria revision, many would have been offered therapy only when signs of end-organ damage were present, while patients without end-organ damage would have been said to have smoldering disease, authors said.
Patients 80 years of age and older and those with a higher Charlson comorbidity score had a lower likelihood of treatment delay in this analysis, possibly reflecting the frailty of those patients and an urgent need for treatment, according to investigators.
Uninsured patients and those with Medicaid were less likely than insured patients to experience treatment delay, according to the report.
“This may be associated with the fact that, for these insurances, prior authorization is typically not required before initiating treatment,” said Dr. Kumar and colleagues. “However, this could also depend on several other possible factors, including availability of caregiver support and seeking medical care later.”
Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
SOURCE: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
Women and racial minorities with multiple myeloma may be at increased risk of delayed treatment, a situation that should be addressed urgently, according to authors of a recent analysis of a clinical oncology database.
By contrast, patients receiving myeloma treatment sooner after diagnosis included patients who were over 80 years of age, had multiple comorbidities, were treated at specialized cancer programs or in areas other than the Northeast, and had Medicaid or did not have private insurance, the authors reported.
Contrary to what was expected, levels of education and income did not significantly affect the timeliness of treatment in this analysis by Vivek Kumar, MD, of Dana-Farber Cancer Institute in Boston and coinvestigators.
While results of studies to date are “conflicting” as to whether timeliness of myeloma therapy will affect patient outcomes, recent studies in breast cancer and other tumor types suggest earlier treatment intervention may reduce morbidity, improve quality of life, and possibly prolong survival, according to Dr. Kumar and colleagues.
Moreover, the focus of myeloma treatment has shifted toward earlier treatment in light of the superiority of today’s treatment options, which was demonstrated in the 2014 update of the International Myeloma Working Group (IMWG) diagnostic criteria, according to the investigators.
“The definition of active MM [multiple myeloma] has been updated so that patients who may have been considered to have smoldering MM previously are now treated sooner to prevent end-organ damage whenever possible,” said Dr. Kumar and coauthors in their report in JCO Oncology Practice.
The analysis of timely myeloma treatment was based on for 74,722 patients in the National Cancer Database who received a diagnosis of multiple myeloma between 2004 and 2015 and went on to receive systemic treatment within the first year of diagnosis.
Delay in treatment, defined as receiving antimyeloma therapy 40 or more days after diagnosis, occurred in 18,375 of those patients, or about one-quarter of the study cohort. The mean time from diagnosis to start of treatment in that group was 63 days.
Compared with patients who received treatment within 7 days of diagnosis, patients with delays in treatment were more likely to be women (odds ratio, 1.15; 95% confidence interval, 1.1-1.2) and more likely to be non-Hispanic black (OR, 1.21; 95% CI, 1.14-1.28), the investigators reported.
A previous analysis of the SEER-Medicare database suggested that certain antimyeloma agents are used later in racial and ethnic minorities, including Hispanic patients, who had the highest median time to first dose of bortezomib, Dr. Kumar and colleagues noted.
However, no report before the present one had looked at the time to overall initial treatment in racial and ethnic minorities, they added.
Patients diagnosed in more recent years had higher odds of treatment delay, though this could have been caused by an increase in the number of patients diagnosed early; prior to the 2014 IMWG diagnostic criteria revision, many would have been offered therapy only when signs of end-organ damage were present, while patients without end-organ damage would have been said to have smoldering disease, authors said.
Patients 80 years of age and older and those with a higher Charlson comorbidity score had a lower likelihood of treatment delay in this analysis, possibly reflecting the frailty of those patients and an urgent need for treatment, according to investigators.
Uninsured patients and those with Medicaid were less likely than insured patients to experience treatment delay, according to the report.
“This may be associated with the fact that, for these insurances, prior authorization is typically not required before initiating treatment,” said Dr. Kumar and colleagues. “However, this could also depend on several other possible factors, including availability of caregiver support and seeking medical care later.”
Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
SOURCE: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
FROM JCO ONCOLOGY PRACTICE
Key clinical point:
Major finding: Patients with delays in treatment were more likely to be women (odds ratio, 1.15) and more likely to be non-Hispanic blacks (OR, 1.21).
Study details: Retrospective analysis of 74,722 patients in the National Cancer Database diagnosed with multiple myeloma between 2004 and 2015.
Disclosures: Dr. Kumar reported no conflicts of interest related to the analysis. Coauthors reported disclosures with Takeda, Guardant Health, and other pharmaceutical companies.
Source: Kumar V et al. JCO Oncology Practice. 2020 Jan 21. doi: 10.1200/JOP.19.00309.
Adult survivors of childhood cancer are experiencing fewer major cardiac events
Adult survivors of pediatric cancers appear to be experiencing fewer major cardiac events in adulthood partly because of reduced radiotherapy exposure, especially among survivors of Hodgkin lymphoma, recent research published in BMJ has shown.
“Contemporary cancer treatment has focused on advancing cure rates while attempting to minimize long term adverse effects,” Daniel A. Mulrooney, MD, of the Division of Cancer Survivorship, Department of Oncology, at St. Jude Children’s Research Hospital, Arlington, Va., and colleagues wrote. “Patterns of exposure to cardiotoxic treatment have changed over time, with fewer children receiving chest directed radiation, with lower doses and smaller volumes for those who do, and an increased use of anthracyclines, albeit with reduced cumulative doses as the risk for late-onset heart failure became apparent.”
Although research has been published on improved survival rates of children who underwent cancer treatment in the 1990s, compared with those who received treatment in the 1980s and 1970s, Dr. Mulrooney and colleagues set out to determine whether cardiac outcomes were reduced as well. They conducted a retrospective study of 23,462 5-year survivors of pediatric cancer, which consisted of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft-tissue sarcomas, and bone sarcomas diagnosed between January 1970 and December 1999. Researchers compared the cardiac outcomes of the survivors, including heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias, with a comparison group of their siblings (n = 5,057) separated by decade. The adult survivors tended to be women (46% vs. 40%) with a median age of 6.1 years at diagnosis and 27.7 years at final follow-up.
Of the 6,193 participants treated for cancer in the 1970s, the 20-year cumulative incidence of heart failure was 0.69%, while the 9,363 participants treated in the 1980s had an incidence of 0.74%, and 7,906 participants in the 1990s had a cumulative incidence of 0.54% over 20 years. The 20-year cumulative incidence for coronary artery disease (CAD) was 0.38% for participants in the 1970s, 0.24% for participants in the 1980s, and 0.19% for participants in the 1990s (P less than .01). Researchers noted the 20-year cumulative incidence of valvular disease, pericardial disease, and arrhythmias did not decrease between the 1970s and the 1990s.
When comparing the rate of major cardiac events of participants in the 1980s and 1990s with those of the 1970s, CAD diagnoses significantly decreased in the 1980s (hazard ratio, 0.65; 95% confidence interval, 0.45-0.92) and 1990s (HR, 0.53; 95% CI, 0.36-0.77), while there was no significant decrease in heart failure or valvular heart disease risk over time. After adjusting for cardiac radiation, overall risk for CAD was attenuated (HR, 0.90; 0.78-1.05), and Hodgkin lymphoma survivors saw the greatest change between unadjusted (HR, 0.77; 95% CI, 0.66-0.89) and adjusted risk (HR, 0.87; 95% CI, 0.69-1.10) when accounting for cardiac radiation.
“While additional longitudinal follow-up is needed to establish whether similar reductions in the cumulative incidence of heart failure can be confirmed in multivariable analysis, these results suggest that efforts to modify cancer therapies in children and promote health surveillance for survivors are beginning to show benefits not only in overall survival but also in late adverse cardiac effects,” the researchers concluded.
In a related editorial, Mike Hawkins, DPhil, of the Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research at the University of Birmingham (England), and colleagues said that, while measuring cardiotoxicity is important for this patient population, traditional risk factors with independent associations to cardiac outcomes should also be studied. Guidelines on follow-up for these patients are also needed to inform clinical practice, such as those produced by the International Late Effects of Childhood Cancer Guideline Harmonization Group, they added.
“Survivorship issues are extremely important to patients, their families, and their doctors,” they said. “In two research priority setting initiatives in the United Kingdom, detailed consultation with patients with cancer, survivors, families, friends, and healthcare professionals identified further research into the consequences of cancer as a top priority.”
This study was funded by grants from the National Cancer Institute, Cancer Center Support (CORE) to St. Jude Children’s Research Hospital and American Lebanese Syrian Associated Charities. The authors of the study and the editorial reported no relevant conflicts of interest.
SOURCE: Mulrooney A et al. BMJ. 2020. doi: 10.1136/bmj.l6794.
Adult survivors of pediatric cancers appear to be experiencing fewer major cardiac events in adulthood partly because of reduced radiotherapy exposure, especially among survivors of Hodgkin lymphoma, recent research published in BMJ has shown.
“Contemporary cancer treatment has focused on advancing cure rates while attempting to minimize long term adverse effects,” Daniel A. Mulrooney, MD, of the Division of Cancer Survivorship, Department of Oncology, at St. Jude Children’s Research Hospital, Arlington, Va., and colleagues wrote. “Patterns of exposure to cardiotoxic treatment have changed over time, with fewer children receiving chest directed radiation, with lower doses and smaller volumes for those who do, and an increased use of anthracyclines, albeit with reduced cumulative doses as the risk for late-onset heart failure became apparent.”
Although research has been published on improved survival rates of children who underwent cancer treatment in the 1990s, compared with those who received treatment in the 1980s and 1970s, Dr. Mulrooney and colleagues set out to determine whether cardiac outcomes were reduced as well. They conducted a retrospective study of 23,462 5-year survivors of pediatric cancer, which consisted of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft-tissue sarcomas, and bone sarcomas diagnosed between January 1970 and December 1999. Researchers compared the cardiac outcomes of the survivors, including heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias, with a comparison group of their siblings (n = 5,057) separated by decade. The adult survivors tended to be women (46% vs. 40%) with a median age of 6.1 years at diagnosis and 27.7 years at final follow-up.
Of the 6,193 participants treated for cancer in the 1970s, the 20-year cumulative incidence of heart failure was 0.69%, while the 9,363 participants treated in the 1980s had an incidence of 0.74%, and 7,906 participants in the 1990s had a cumulative incidence of 0.54% over 20 years. The 20-year cumulative incidence for coronary artery disease (CAD) was 0.38% for participants in the 1970s, 0.24% for participants in the 1980s, and 0.19% for participants in the 1990s (P less than .01). Researchers noted the 20-year cumulative incidence of valvular disease, pericardial disease, and arrhythmias did not decrease between the 1970s and the 1990s.
When comparing the rate of major cardiac events of participants in the 1980s and 1990s with those of the 1970s, CAD diagnoses significantly decreased in the 1980s (hazard ratio, 0.65; 95% confidence interval, 0.45-0.92) and 1990s (HR, 0.53; 95% CI, 0.36-0.77), while there was no significant decrease in heart failure or valvular heart disease risk over time. After adjusting for cardiac radiation, overall risk for CAD was attenuated (HR, 0.90; 0.78-1.05), and Hodgkin lymphoma survivors saw the greatest change between unadjusted (HR, 0.77; 95% CI, 0.66-0.89) and adjusted risk (HR, 0.87; 95% CI, 0.69-1.10) when accounting for cardiac radiation.
“While additional longitudinal follow-up is needed to establish whether similar reductions in the cumulative incidence of heart failure can be confirmed in multivariable analysis, these results suggest that efforts to modify cancer therapies in children and promote health surveillance for survivors are beginning to show benefits not only in overall survival but also in late adverse cardiac effects,” the researchers concluded.
In a related editorial, Mike Hawkins, DPhil, of the Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research at the University of Birmingham (England), and colleagues said that, while measuring cardiotoxicity is important for this patient population, traditional risk factors with independent associations to cardiac outcomes should also be studied. Guidelines on follow-up for these patients are also needed to inform clinical practice, such as those produced by the International Late Effects of Childhood Cancer Guideline Harmonization Group, they added.
“Survivorship issues are extremely important to patients, their families, and their doctors,” they said. “In two research priority setting initiatives in the United Kingdom, detailed consultation with patients with cancer, survivors, families, friends, and healthcare professionals identified further research into the consequences of cancer as a top priority.”
This study was funded by grants from the National Cancer Institute, Cancer Center Support (CORE) to St. Jude Children’s Research Hospital and American Lebanese Syrian Associated Charities. The authors of the study and the editorial reported no relevant conflicts of interest.
SOURCE: Mulrooney A et al. BMJ. 2020. doi: 10.1136/bmj.l6794.
Adult survivors of pediatric cancers appear to be experiencing fewer major cardiac events in adulthood partly because of reduced radiotherapy exposure, especially among survivors of Hodgkin lymphoma, recent research published in BMJ has shown.
“Contemporary cancer treatment has focused on advancing cure rates while attempting to minimize long term adverse effects,” Daniel A. Mulrooney, MD, of the Division of Cancer Survivorship, Department of Oncology, at St. Jude Children’s Research Hospital, Arlington, Va., and colleagues wrote. “Patterns of exposure to cardiotoxic treatment have changed over time, with fewer children receiving chest directed radiation, with lower doses and smaller volumes for those who do, and an increased use of anthracyclines, albeit with reduced cumulative doses as the risk for late-onset heart failure became apparent.”
Although research has been published on improved survival rates of children who underwent cancer treatment in the 1990s, compared with those who received treatment in the 1980s and 1970s, Dr. Mulrooney and colleagues set out to determine whether cardiac outcomes were reduced as well. They conducted a retrospective study of 23,462 5-year survivors of pediatric cancer, which consisted of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft-tissue sarcomas, and bone sarcomas diagnosed between January 1970 and December 1999. Researchers compared the cardiac outcomes of the survivors, including heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias, with a comparison group of their siblings (n = 5,057) separated by decade. The adult survivors tended to be women (46% vs. 40%) with a median age of 6.1 years at diagnosis and 27.7 years at final follow-up.
Of the 6,193 participants treated for cancer in the 1970s, the 20-year cumulative incidence of heart failure was 0.69%, while the 9,363 participants treated in the 1980s had an incidence of 0.74%, and 7,906 participants in the 1990s had a cumulative incidence of 0.54% over 20 years. The 20-year cumulative incidence for coronary artery disease (CAD) was 0.38% for participants in the 1970s, 0.24% for participants in the 1980s, and 0.19% for participants in the 1990s (P less than .01). Researchers noted the 20-year cumulative incidence of valvular disease, pericardial disease, and arrhythmias did not decrease between the 1970s and the 1990s.
When comparing the rate of major cardiac events of participants in the 1980s and 1990s with those of the 1970s, CAD diagnoses significantly decreased in the 1980s (hazard ratio, 0.65; 95% confidence interval, 0.45-0.92) and 1990s (HR, 0.53; 95% CI, 0.36-0.77), while there was no significant decrease in heart failure or valvular heart disease risk over time. After adjusting for cardiac radiation, overall risk for CAD was attenuated (HR, 0.90; 0.78-1.05), and Hodgkin lymphoma survivors saw the greatest change between unadjusted (HR, 0.77; 95% CI, 0.66-0.89) and adjusted risk (HR, 0.87; 95% CI, 0.69-1.10) when accounting for cardiac radiation.
“While additional longitudinal follow-up is needed to establish whether similar reductions in the cumulative incidence of heart failure can be confirmed in multivariable analysis, these results suggest that efforts to modify cancer therapies in children and promote health surveillance for survivors are beginning to show benefits not only in overall survival but also in late adverse cardiac effects,” the researchers concluded.
In a related editorial, Mike Hawkins, DPhil, of the Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research at the University of Birmingham (England), and colleagues said that, while measuring cardiotoxicity is important for this patient population, traditional risk factors with independent associations to cardiac outcomes should also be studied. Guidelines on follow-up for these patients are also needed to inform clinical practice, such as those produced by the International Late Effects of Childhood Cancer Guideline Harmonization Group, they added.
“Survivorship issues are extremely important to patients, their families, and their doctors,” they said. “In two research priority setting initiatives in the United Kingdom, detailed consultation with patients with cancer, survivors, families, friends, and healthcare professionals identified further research into the consequences of cancer as a top priority.”
This study was funded by grants from the National Cancer Institute, Cancer Center Support (CORE) to St. Jude Children’s Research Hospital and American Lebanese Syrian Associated Charities. The authors of the study and the editorial reported no relevant conflicts of interest.
SOURCE: Mulrooney A et al. BMJ. 2020. doi: 10.1136/bmj.l6794.
FROM BMJ
Are providers asking about menstrual bleeding before/during anticoagulant therapy?
ORLANDO – A small study suggests health care providers may fail to ask patients about heavy menstrual bleeding before or during treatment with oral anticoagulants.
Researchers performed a chart review at a single center, which indicated that 60% of women were not asked about heavy menstrual bleeding before they were prescribed an oral anticoagulant.
Six months after the women started anticoagulant therapy, 29% required treatment for heavy menstrual bleeding. Charts for the remaining 71% of women contained no information about heavy menstrual bleeding.
“We were unable to distinguish between true absence of heavy menstrual bleeding and absence of reporting,” said Bethany T. Samuelson Bannow, MD, of Oregon Health & Science University, Portland.
Dr. Samuelson Bannow presented these findings at the annual meeting of the American Society of Hematology.
She explained that heavy menstrual bleeding is defined as more than 80 mL of blood loss per cycle. It affects 10%-15% of women in their lifetime, and anticoagulants increase the risk of heavy menstrual bleeding.
Studies have shown that heavy menstrual bleeding occurs in 22%-65% of women treated with vitamin K agonists and 20%-27% of women treated with rivaroxaban (Blood. 2017;130[24]:2603-9). However, many anticoagulant studies don’t include heavy menstrual bleeding as an outcome.
To gain more insight, Dr. Samuelson Bannow and colleagues conducted a chart review. Their study included 236 women of reproductive age treated at Oregon Health & Science University between Jan. 1, 2012, and Dec. 31, 2018.
The patients’ median age was 37 years (range, 18-50 years). Most patients (67%) were receiving an oral anticoagulant for venous thromboembolism. The rest were on anticoagulant therapy for arterial thrombosis (6%), atrial fibrillation (6%), a mechanical valve (1%), or “other” reasons (20%).
Dr. Samuelson Bannow said the other group was “almost exclusively women who were receiving prophylaxis” postoperatively or for travel. Most women in this group were receiving rivaroxaban.
Rivaroxaban was the most commonly prescribed anticoagulant in the entire cohort (41%), followed by warfarin (34%) and apixaban (25%).
At the time of anticoagulant prescription, 12% of women reported a history of heavy menstrual bleeding, and 28% did not. For most patients – 60% – there was no discussion of menstrual history documented.
Six months after starting oral anticoagulant therapy, 29% of patients required treatment for heavy menstrual bleeding. For 71% of patients, there was no documentation on the treatment of heavy menstrual bleeding.
Treatment for heavy menstrual bleeding was required in 33% of patients on rivaroxaban, 24% of those on apixaban, and 29% of those on warfarin, a significant difference (P less than .001).
“Rates of heavy menstrual bleeding … are higher in rivaroxaban users,” Dr. Samuelson Bannow said. “This is not the first study to demonstrate this. However, [the rate of heavy menstrual bleeding in this study] is still a lot lower than we would expect based on past levels with warfarin. This tells us we’re probably missing a lot of heavy menstrual bleeding. That’s not too surprising considering how few providers are actually asking about the menses.”
Dr. Samuelson Bannow and colleagues disclosed no conflicts of interest.
SOURCE: Samuelson Bannow BT et al. ASH 2019, Abstract 60.
ORLANDO – A small study suggests health care providers may fail to ask patients about heavy menstrual bleeding before or during treatment with oral anticoagulants.
Researchers performed a chart review at a single center, which indicated that 60% of women were not asked about heavy menstrual bleeding before they were prescribed an oral anticoagulant.
Six months after the women started anticoagulant therapy, 29% required treatment for heavy menstrual bleeding. Charts for the remaining 71% of women contained no information about heavy menstrual bleeding.
“We were unable to distinguish between true absence of heavy menstrual bleeding and absence of reporting,” said Bethany T. Samuelson Bannow, MD, of Oregon Health & Science University, Portland.
Dr. Samuelson Bannow presented these findings at the annual meeting of the American Society of Hematology.
She explained that heavy menstrual bleeding is defined as more than 80 mL of blood loss per cycle. It affects 10%-15% of women in their lifetime, and anticoagulants increase the risk of heavy menstrual bleeding.
Studies have shown that heavy menstrual bleeding occurs in 22%-65% of women treated with vitamin K agonists and 20%-27% of women treated with rivaroxaban (Blood. 2017;130[24]:2603-9). However, many anticoagulant studies don’t include heavy menstrual bleeding as an outcome.
To gain more insight, Dr. Samuelson Bannow and colleagues conducted a chart review. Their study included 236 women of reproductive age treated at Oregon Health & Science University between Jan. 1, 2012, and Dec. 31, 2018.
The patients’ median age was 37 years (range, 18-50 years). Most patients (67%) were receiving an oral anticoagulant for venous thromboembolism. The rest were on anticoagulant therapy for arterial thrombosis (6%), atrial fibrillation (6%), a mechanical valve (1%), or “other” reasons (20%).
Dr. Samuelson Bannow said the other group was “almost exclusively women who were receiving prophylaxis” postoperatively or for travel. Most women in this group were receiving rivaroxaban.
Rivaroxaban was the most commonly prescribed anticoagulant in the entire cohort (41%), followed by warfarin (34%) and apixaban (25%).
At the time of anticoagulant prescription, 12% of women reported a history of heavy menstrual bleeding, and 28% did not. For most patients – 60% – there was no discussion of menstrual history documented.
Six months after starting oral anticoagulant therapy, 29% of patients required treatment for heavy menstrual bleeding. For 71% of patients, there was no documentation on the treatment of heavy menstrual bleeding.
Treatment for heavy menstrual bleeding was required in 33% of patients on rivaroxaban, 24% of those on apixaban, and 29% of those on warfarin, a significant difference (P less than .001).
“Rates of heavy menstrual bleeding … are higher in rivaroxaban users,” Dr. Samuelson Bannow said. “This is not the first study to demonstrate this. However, [the rate of heavy menstrual bleeding in this study] is still a lot lower than we would expect based on past levels with warfarin. This tells us we’re probably missing a lot of heavy menstrual bleeding. That’s not too surprising considering how few providers are actually asking about the menses.”
Dr. Samuelson Bannow and colleagues disclosed no conflicts of interest.
SOURCE: Samuelson Bannow BT et al. ASH 2019, Abstract 60.
ORLANDO – A small study suggests health care providers may fail to ask patients about heavy menstrual bleeding before or during treatment with oral anticoagulants.
Researchers performed a chart review at a single center, which indicated that 60% of women were not asked about heavy menstrual bleeding before they were prescribed an oral anticoagulant.
Six months after the women started anticoagulant therapy, 29% required treatment for heavy menstrual bleeding. Charts for the remaining 71% of women contained no information about heavy menstrual bleeding.
“We were unable to distinguish between true absence of heavy menstrual bleeding and absence of reporting,” said Bethany T. Samuelson Bannow, MD, of Oregon Health & Science University, Portland.
Dr. Samuelson Bannow presented these findings at the annual meeting of the American Society of Hematology.
She explained that heavy menstrual bleeding is defined as more than 80 mL of blood loss per cycle. It affects 10%-15% of women in their lifetime, and anticoagulants increase the risk of heavy menstrual bleeding.
Studies have shown that heavy menstrual bleeding occurs in 22%-65% of women treated with vitamin K agonists and 20%-27% of women treated with rivaroxaban (Blood. 2017;130[24]:2603-9). However, many anticoagulant studies don’t include heavy menstrual bleeding as an outcome.
To gain more insight, Dr. Samuelson Bannow and colleagues conducted a chart review. Their study included 236 women of reproductive age treated at Oregon Health & Science University between Jan. 1, 2012, and Dec. 31, 2018.
The patients’ median age was 37 years (range, 18-50 years). Most patients (67%) were receiving an oral anticoagulant for venous thromboembolism. The rest were on anticoagulant therapy for arterial thrombosis (6%), atrial fibrillation (6%), a mechanical valve (1%), or “other” reasons (20%).
Dr. Samuelson Bannow said the other group was “almost exclusively women who were receiving prophylaxis” postoperatively or for travel. Most women in this group were receiving rivaroxaban.
Rivaroxaban was the most commonly prescribed anticoagulant in the entire cohort (41%), followed by warfarin (34%) and apixaban (25%).
At the time of anticoagulant prescription, 12% of women reported a history of heavy menstrual bleeding, and 28% did not. For most patients – 60% – there was no discussion of menstrual history documented.
Six months after starting oral anticoagulant therapy, 29% of patients required treatment for heavy menstrual bleeding. For 71% of patients, there was no documentation on the treatment of heavy menstrual bleeding.
Treatment for heavy menstrual bleeding was required in 33% of patients on rivaroxaban, 24% of those on apixaban, and 29% of those on warfarin, a significant difference (P less than .001).
“Rates of heavy menstrual bleeding … are higher in rivaroxaban users,” Dr. Samuelson Bannow said. “This is not the first study to demonstrate this. However, [the rate of heavy menstrual bleeding in this study] is still a lot lower than we would expect based on past levels with warfarin. This tells us we’re probably missing a lot of heavy menstrual bleeding. That’s not too surprising considering how few providers are actually asking about the menses.”
Dr. Samuelson Bannow and colleagues disclosed no conflicts of interest.
SOURCE: Samuelson Bannow BT et al. ASH 2019, Abstract 60.
REPORTING FROM ASH 2019
NCCN guidelines highlight ‘complicated’ treatment for pediatric lymphomas
The National Comprehensive Cancer Network (NCCN) has released its first set of guidelines for managing pediatric aggressive mature B-cell lymphomas.
The guidelines highlight the complexities of treating pediatric Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as recommendations include a range of multiagent regimens for different patient groups at various time points.
“The treatment of this disease is relatively complicated,” said Kimberly J. Davies, MD, a pediatric hematologist/oncologist at Dana-Farber Cancer Institute in Boston and chair of the guidelines panel. “The chemotherapy regimens have a lot of drugs, a lot of nuances to how they’re supposed to be given. These guidelines delineate that treatment and help the provider … make sure they are delivering the treatment a patient needs.”
The guidelines recommend different regimens according to a patient’s risk group, but the same treatment approach should be used for patients with BL and those with DLBCL.
“The biggest difference between pediatric and adult patients is that pediatric patients are more uniformly treated, regardless of what type of aggressive B-cell lymphoma they have,” said Matthew Barth, MD, a pediatric hematologist/oncologist at Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and vice chair of the NCCN guidelines panel.
“Adults with diffuse large B-cell lymphoma and Burkitt lymphoma are generally treated with different chemotherapy regimens, but, in pediatrics, we use the same treatment regimens for both diffuse large B-cell lymphoma and Burkitt lymphoma,” he added.
As an example, the new guidelines recommend that pediatric patients with low-risk BL/DLBCL receive the POG9219 regimen (N Engl J Med. 1997 Oct 30;337[18]:1259-66) or FAB/LMB96 regimen A (Br J Haematol. 2008 Jun;141[6]:840-7) as induction, or they should be enrolled in a clinical trial.
On the other hand, induction for high-risk pediatric BL/DLBCL patients should consist of rituximab and a chemotherapy regimen used in the COG ANHL1131 trial. The recommendation to incorporate rituximab in high-risk pediatric patients is based on results from that trial (J Clin Oncol. 2016 May 20. doi: 10.1200/JCO.2016.34.15_suppl.10507).
“Until recent clinical trial data was available, we weren’t really sure how to incorporate rituximab into the treatment of pediatric patients with mature B-cell lymphomas,” Dr. Barth said. “We now have evidence that rituximab is clearly beneficial for patients who are in higher-risk groups.”
Dr. Barth and Dr. Davies both noted that pediatric BL and DLBCL have high cure rates. Long-term survival rates range from about 80% to more than 90%, according to the American Cancer Society. However, the patients who do relapse or progress can be difficult to treat.
“We have quite good cure rates at this point in time, which is a great success, but that means that a very small population of patients don’t respond to initial therapy, and … it’s hard to know what the best treatment for those patients is,” Dr. Davies said.
She noted that studies are underway to determine if immunotherapies, including chimeric antigen receptor T-cell therapy, might improve outcomes in patients with relapsed or refractory disease.
For now, the NCCN guidelines recommend clinical trial enrollment for relapsed/refractory patients. Alternatively, these patients can receive additional chemotherapy, and responders can proceed to transplant. Patients who don’t achieve at least a partial response may go on to a clinical trial or receive best supportive care.
Dr. Davies and Dr. Barth reported having no conflicts of interest.
The National Comprehensive Cancer Network (NCCN) has released its first set of guidelines for managing pediatric aggressive mature B-cell lymphomas.
The guidelines highlight the complexities of treating pediatric Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as recommendations include a range of multiagent regimens for different patient groups at various time points.
“The treatment of this disease is relatively complicated,” said Kimberly J. Davies, MD, a pediatric hematologist/oncologist at Dana-Farber Cancer Institute in Boston and chair of the guidelines panel. “The chemotherapy regimens have a lot of drugs, a lot of nuances to how they’re supposed to be given. These guidelines delineate that treatment and help the provider … make sure they are delivering the treatment a patient needs.”
The guidelines recommend different regimens according to a patient’s risk group, but the same treatment approach should be used for patients with BL and those with DLBCL.
“The biggest difference between pediatric and adult patients is that pediatric patients are more uniformly treated, regardless of what type of aggressive B-cell lymphoma they have,” said Matthew Barth, MD, a pediatric hematologist/oncologist at Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and vice chair of the NCCN guidelines panel.
“Adults with diffuse large B-cell lymphoma and Burkitt lymphoma are generally treated with different chemotherapy regimens, but, in pediatrics, we use the same treatment regimens for both diffuse large B-cell lymphoma and Burkitt lymphoma,” he added.
As an example, the new guidelines recommend that pediatric patients with low-risk BL/DLBCL receive the POG9219 regimen (N Engl J Med. 1997 Oct 30;337[18]:1259-66) or FAB/LMB96 regimen A (Br J Haematol. 2008 Jun;141[6]:840-7) as induction, or they should be enrolled in a clinical trial.
On the other hand, induction for high-risk pediatric BL/DLBCL patients should consist of rituximab and a chemotherapy regimen used in the COG ANHL1131 trial. The recommendation to incorporate rituximab in high-risk pediatric patients is based on results from that trial (J Clin Oncol. 2016 May 20. doi: 10.1200/JCO.2016.34.15_suppl.10507).
“Until recent clinical trial data was available, we weren’t really sure how to incorporate rituximab into the treatment of pediatric patients with mature B-cell lymphomas,” Dr. Barth said. “We now have evidence that rituximab is clearly beneficial for patients who are in higher-risk groups.”
Dr. Barth and Dr. Davies both noted that pediatric BL and DLBCL have high cure rates. Long-term survival rates range from about 80% to more than 90%, according to the American Cancer Society. However, the patients who do relapse or progress can be difficult to treat.
“We have quite good cure rates at this point in time, which is a great success, but that means that a very small population of patients don’t respond to initial therapy, and … it’s hard to know what the best treatment for those patients is,” Dr. Davies said.
She noted that studies are underway to determine if immunotherapies, including chimeric antigen receptor T-cell therapy, might improve outcomes in patients with relapsed or refractory disease.
For now, the NCCN guidelines recommend clinical trial enrollment for relapsed/refractory patients. Alternatively, these patients can receive additional chemotherapy, and responders can proceed to transplant. Patients who don’t achieve at least a partial response may go on to a clinical trial or receive best supportive care.
Dr. Davies and Dr. Barth reported having no conflicts of interest.
The National Comprehensive Cancer Network (NCCN) has released its first set of guidelines for managing pediatric aggressive mature B-cell lymphomas.
The guidelines highlight the complexities of treating pediatric Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), as recommendations include a range of multiagent regimens for different patient groups at various time points.
“The treatment of this disease is relatively complicated,” said Kimberly J. Davies, MD, a pediatric hematologist/oncologist at Dana-Farber Cancer Institute in Boston and chair of the guidelines panel. “The chemotherapy regimens have a lot of drugs, a lot of nuances to how they’re supposed to be given. These guidelines delineate that treatment and help the provider … make sure they are delivering the treatment a patient needs.”
The guidelines recommend different regimens according to a patient’s risk group, but the same treatment approach should be used for patients with BL and those with DLBCL.
“The biggest difference between pediatric and adult patients is that pediatric patients are more uniformly treated, regardless of what type of aggressive B-cell lymphoma they have,” said Matthew Barth, MD, a pediatric hematologist/oncologist at Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and vice chair of the NCCN guidelines panel.
“Adults with diffuse large B-cell lymphoma and Burkitt lymphoma are generally treated with different chemotherapy regimens, but, in pediatrics, we use the same treatment regimens for both diffuse large B-cell lymphoma and Burkitt lymphoma,” he added.
As an example, the new guidelines recommend that pediatric patients with low-risk BL/DLBCL receive the POG9219 regimen (N Engl J Med. 1997 Oct 30;337[18]:1259-66) or FAB/LMB96 regimen A (Br J Haematol. 2008 Jun;141[6]:840-7) as induction, or they should be enrolled in a clinical trial.
On the other hand, induction for high-risk pediatric BL/DLBCL patients should consist of rituximab and a chemotherapy regimen used in the COG ANHL1131 trial. The recommendation to incorporate rituximab in high-risk pediatric patients is based on results from that trial (J Clin Oncol. 2016 May 20. doi: 10.1200/JCO.2016.34.15_suppl.10507).
“Until recent clinical trial data was available, we weren’t really sure how to incorporate rituximab into the treatment of pediatric patients with mature B-cell lymphomas,” Dr. Barth said. “We now have evidence that rituximab is clearly beneficial for patients who are in higher-risk groups.”
Dr. Barth and Dr. Davies both noted that pediatric BL and DLBCL have high cure rates. Long-term survival rates range from about 80% to more than 90%, according to the American Cancer Society. However, the patients who do relapse or progress can be difficult to treat.
“We have quite good cure rates at this point in time, which is a great success, but that means that a very small population of patients don’t respond to initial therapy, and … it’s hard to know what the best treatment for those patients is,” Dr. Davies said.
She noted that studies are underway to determine if immunotherapies, including chimeric antigen receptor T-cell therapy, might improve outcomes in patients with relapsed or refractory disease.
For now, the NCCN guidelines recommend clinical trial enrollment for relapsed/refractory patients. Alternatively, these patients can receive additional chemotherapy, and responders can proceed to transplant. Patients who don’t achieve at least a partial response may go on to a clinical trial or receive best supportive care.
Dr. Davies and Dr. Barth reported having no conflicts of interest.
FDA Awards Grant To Study Temozolomide in Gist
A phase 2 study of temozolomide in gastrointestinal stromal tumors (GIST) received one of the 12 grants awarded in October by the US Food and Drug Administration (FDA) to enhance the development of medical products for patients with rare diseases. Jason Sicklick, MD, and the University of California San Diego in La Jolla will receive $1.5 million over 3 years to conduct the phase 2 study (NCT03556384). The objective of the study is to determine the efficacy at 6 months of temozolomide therapy in patients with the SDH-mutant/deficient subtype. Temozolomide is approved by the FDA to treat newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytomas. It is not approved for the treatment of SDH-mutant/deficient GIST.
The FDA awarded the grants through the Orphan Products Clinical Trials Grants Program. Other orphan diseases receiving grants included glomerulopathy, gliomas, Fanconi anemia, sickle cell respiratory complications, Duchenne muscular dystrophy, HPV associated respiratory papillomatosis, refractory viral infections and T-cell immunodeficiency, oral cancer, retinoblastoma, cerebellar brain tumors, and acute myeloid leukemia.
A phase 2 study of temozolomide in gastrointestinal stromal tumors (GIST) received one of the 12 grants awarded in October by the US Food and Drug Administration (FDA) to enhance the development of medical products for patients with rare diseases. Jason Sicklick, MD, and the University of California San Diego in La Jolla will receive $1.5 million over 3 years to conduct the phase 2 study (NCT03556384). The objective of the study is to determine the efficacy at 6 months of temozolomide therapy in patients with the SDH-mutant/deficient subtype. Temozolomide is approved by the FDA to treat newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytomas. It is not approved for the treatment of SDH-mutant/deficient GIST.
The FDA awarded the grants through the Orphan Products Clinical Trials Grants Program. Other orphan diseases receiving grants included glomerulopathy, gliomas, Fanconi anemia, sickle cell respiratory complications, Duchenne muscular dystrophy, HPV associated respiratory papillomatosis, refractory viral infections and T-cell immunodeficiency, oral cancer, retinoblastoma, cerebellar brain tumors, and acute myeloid leukemia.
A phase 2 study of temozolomide in gastrointestinal stromal tumors (GIST) received one of the 12 grants awarded in October by the US Food and Drug Administration (FDA) to enhance the development of medical products for patients with rare diseases. Jason Sicklick, MD, and the University of California San Diego in La Jolla will receive $1.5 million over 3 years to conduct the phase 2 study (NCT03556384). The objective of the study is to determine the efficacy at 6 months of temozolomide therapy in patients with the SDH-mutant/deficient subtype. Temozolomide is approved by the FDA to treat newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytomas. It is not approved for the treatment of SDH-mutant/deficient GIST.
The FDA awarded the grants through the Orphan Products Clinical Trials Grants Program. Other orphan diseases receiving grants included glomerulopathy, gliomas, Fanconi anemia, sickle cell respiratory complications, Duchenne muscular dystrophy, HPV associated respiratory papillomatosis, refractory viral infections and T-cell immunodeficiency, oral cancer, retinoblastoma, cerebellar brain tumors, and acute myeloid leukemia.
Genomic profiling of AML and MDS yields prognostic clues
ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.
“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).
The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.
The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.
The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.
Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.
The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.
For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.
In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.
They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.
At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.
“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.
In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.
“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.
The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.
SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.
ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.
“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).
The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.
The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.
The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.
Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.
The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.
For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.
In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.
They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.
At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.
“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.
In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.
“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.
The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.
SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.
ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.
“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).
The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.
The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.
The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.
Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.
The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.
For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.
In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.
They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.
At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.
“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.
In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.
“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.
The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.
SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.
REPORTING FROM ASH 2019