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Endothelial injury may play a major role in COVID-19–associated coagulopathy
A striking clinical feature of illness from SARS-CoV-2 is a marked increase in thrombotic and microvascular complications, or COVID-19–associated coagulopathy (CAC).
A new study suggests endothelial cell injury plays a major role in the pathogenesis of CAC, and blood levels of soluble thrombomodulin correlate with mortality.
George Goshua, MD, of Yale University, New Haven, Conn., presented this study as a late-breaking abstract at the virtual annual congress of the European Hematology Association.
Dr. Goshua cited past research showing CAC to be highly prevalent among hospitalized patients. Venous thromboembolism was found in 17% to 69% of patients, despite thromboprophylaxis.1-4 Arterial thrombosis has been seen in 3.6% to 4.0% of patients,1-3 and autopsy findings have shown microvascular thrombosis in as many as 87% of patients.5-7
For their study, Dr. Goshua and colleagues assessed endothelial cell damage, platelet activation, and hemostatic and fibrinolytic cascade effects of CAC.
The investigators measured markers of endothelial cell injury and platelet activation, plasminogen activation inhibitor 1 (PAI-1), and coagulation factors in stable and critically ill patients hospitalized with COVID-19. In addition, the team sought to identify biomarkers of mortality in hospitalized patients.
Dr. Goshua and colleagues studied 68 adults hospitalized for suspected COVID-19 – 48 in the ICU and 20 outside the ICU. Patients in the ICU received mechanical ventilation, while the non-ICU patients required supplemental oxygen (≤3 L/min per nasal cannula).
There were more men than women (69% vs. 31%) in the ICU population but not in the non-ICU population (40% vs. 60%). There were no statistically significant differences in age or comorbid conditions between the ICU and non-ICU patients.
Results and interpretation
Consistent with augmentation of the coagulation cascade – and as expected – D-dimer and thrombin-antithrombin levels were high in both the ICU and non-ICU populations, but levels were significantly higher (P < .001) among the ICU patients.
Endogenous anticoagulants (antithrombin and proteins C and S) and fibrinolytic enzymes (alpha 2-antiplasmin) were preserved, verifying that CAC is distinct from disseminated intravascular coagulation. Classic fibrinolysis did not occur, as PAI-1 was high in ICU and non-ICU patients, and lysis-30 was normal in nearly all ICU patients (96%).
Von Willebrand factor antigen and activity levels and factor VIII levels were markedly elevated in non-ICU and ICU patients, but they were significantly higher (P < .001) in the ICU cohort. This supports the hypothesis that endothelial cell damage and platelet activation play major roles in CAC.
Similarly, soluble P-selectin, which is shed from endothelial cells and platelets, was dramatically elevated in ICU patients in comparison with controls and non-ICU patients (P < .001 for both comparisons).
Levels of soluble thrombomodulin, which is released from endothelial cells, were not significantly different in ICU patients and controls. However, given thrombomodulin’s significant role in the coagulation cascade, Dr. Goshua and colleagues plotted receiver operating curves to see if soluble thrombomodulin levels were predictive of mortality.
The results showed that soluble thrombomodulin correlated with the probability of survival, both overall and in ICU patients. Soluble thrombomodulin levels greater than 3.26 ng/mL were associated with significantly worse survival in all patients (P = .0087) and ICU patients (P = .0309).
Influence on therapy
Laboratory perturbations were detected in both ICU and non-ICU patients, and otherwise healthy outpatients have exhibited potentially life-threatening CAC, according to Dr. Goshua.
These findings suggest the prothrombotic state occurs early in the pathogenesis of SARS-CoV-2 infection, is driven by platelet activation and endotheliopathy, and becomes more pronounced with worsening severity of infection.
The results of this study prompted a change in how Yale–New Haven Hospital manages COVID-19 patients. Patients without a clinical contraindication now receive aspirin at 81 mg daily in addition to the anticoagulation regimen typically used for all hospitalized COVID-19 patients.
Investigations regarding other medications that can influence platelet-endothelial cell interactions and modulate endothelial cell damage in CAC – such as dipyridamole, defibrotide, and eculizumab – are planned.
Challenges and unanswered questions
Virchow’s triad was described by the eminent German physician, Rudolf Virchow, MD, in the 19th century. It refers to the three broad categories of factors that can predispose patients to thrombosis — circulatory stasis, hypercoagulability, and endothelial injury.
Although all of these elements could be operative in CAC, the current study suggests platelet activation and endothelial cell injury in CAC may be of primary importance.
Because of the limited ability to test critically ill patients and concerns regarding exposure of additional hospital personnel to COVID-19 patients, the current report lacked clarity about the relationship of the detected laboratory abnormalities to confirmed thrombotic events.
It is unknown whether endothelial cells in different organs are damaged uniformly. It is also unclear if the laboratory abnormalities identified in this analysis can be used to monitor response to therapy, to guide follow-up management of discharged patients with CAC, or to identify infected outpatients who should receive prophylactic anticoagulation.
The mechanism by which SARS-CoV-2 injures endothelial cells is not explained by these data. Neutrophil defensins and other prothrombotic peptides or markers of inflammation could play key roles in pathogenesis, assessment of disease severity, or monitoring for therapeutic efficacy.
Today, we have more sophisticated diagnostic tools than Dr. Virchow had. We also have the ability to record and rapidly disseminate information globally. Still, with regard to the COVID-19 pandemic, clinicians face many of the same challenges that confronted Dr. Virchow in his era.
The analysis conducted by Dr. Goshua and colleagues goes a long way toward elucidating some of the mechanisms and therapeutic targets to meet these challenges.
Dr. Goshua disclosed no conflicts of interest.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Goshua G et al. EHA Congress. Abstract LB2605.
References
1. Klok FA et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-50. doi: 10.1016/j.thromres.2020.04.041.
2. Thomas W et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020;191:76-7. doi: 10.1016/j.thromres.2020.04.028
3. Lodigiani C et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi: 10.1016/j.thromres.2020.04.024
4. Llitjos JF et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi: 10.1111/jth.14869
5. Carsana L et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: 10.1101/2020.04.19.20054262v1.
6. Menter T et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4]. Histopathology. 2020;10.1111/his.14134. doi: 10.1111/his.14134
7. Lax SF, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series [published online ahead of print, 2020 May 14]. Ann Intern Med. 2020;M20-2566. doi: 10.7326/M20-2566.
A striking clinical feature of illness from SARS-CoV-2 is a marked increase in thrombotic and microvascular complications, or COVID-19–associated coagulopathy (CAC).
A new study suggests endothelial cell injury plays a major role in the pathogenesis of CAC, and blood levels of soluble thrombomodulin correlate with mortality.
George Goshua, MD, of Yale University, New Haven, Conn., presented this study as a late-breaking abstract at the virtual annual congress of the European Hematology Association.
Dr. Goshua cited past research showing CAC to be highly prevalent among hospitalized patients. Venous thromboembolism was found in 17% to 69% of patients, despite thromboprophylaxis.1-4 Arterial thrombosis has been seen in 3.6% to 4.0% of patients,1-3 and autopsy findings have shown microvascular thrombosis in as many as 87% of patients.5-7
For their study, Dr. Goshua and colleagues assessed endothelial cell damage, platelet activation, and hemostatic and fibrinolytic cascade effects of CAC.
The investigators measured markers of endothelial cell injury and platelet activation, plasminogen activation inhibitor 1 (PAI-1), and coagulation factors in stable and critically ill patients hospitalized with COVID-19. In addition, the team sought to identify biomarkers of mortality in hospitalized patients.
Dr. Goshua and colleagues studied 68 adults hospitalized for suspected COVID-19 – 48 in the ICU and 20 outside the ICU. Patients in the ICU received mechanical ventilation, while the non-ICU patients required supplemental oxygen (≤3 L/min per nasal cannula).
There were more men than women (69% vs. 31%) in the ICU population but not in the non-ICU population (40% vs. 60%). There were no statistically significant differences in age or comorbid conditions between the ICU and non-ICU patients.
Results and interpretation
Consistent with augmentation of the coagulation cascade – and as expected – D-dimer and thrombin-antithrombin levels were high in both the ICU and non-ICU populations, but levels were significantly higher (P < .001) among the ICU patients.
Endogenous anticoagulants (antithrombin and proteins C and S) and fibrinolytic enzymes (alpha 2-antiplasmin) were preserved, verifying that CAC is distinct from disseminated intravascular coagulation. Classic fibrinolysis did not occur, as PAI-1 was high in ICU and non-ICU patients, and lysis-30 was normal in nearly all ICU patients (96%).
Von Willebrand factor antigen and activity levels and factor VIII levels were markedly elevated in non-ICU and ICU patients, but they were significantly higher (P < .001) in the ICU cohort. This supports the hypothesis that endothelial cell damage and platelet activation play major roles in CAC.
Similarly, soluble P-selectin, which is shed from endothelial cells and platelets, was dramatically elevated in ICU patients in comparison with controls and non-ICU patients (P < .001 for both comparisons).
Levels of soluble thrombomodulin, which is released from endothelial cells, were not significantly different in ICU patients and controls. However, given thrombomodulin’s significant role in the coagulation cascade, Dr. Goshua and colleagues plotted receiver operating curves to see if soluble thrombomodulin levels were predictive of mortality.
The results showed that soluble thrombomodulin correlated with the probability of survival, both overall and in ICU patients. Soluble thrombomodulin levels greater than 3.26 ng/mL were associated with significantly worse survival in all patients (P = .0087) and ICU patients (P = .0309).
Influence on therapy
Laboratory perturbations were detected in both ICU and non-ICU patients, and otherwise healthy outpatients have exhibited potentially life-threatening CAC, according to Dr. Goshua.
These findings suggest the prothrombotic state occurs early in the pathogenesis of SARS-CoV-2 infection, is driven by platelet activation and endotheliopathy, and becomes more pronounced with worsening severity of infection.
The results of this study prompted a change in how Yale–New Haven Hospital manages COVID-19 patients. Patients without a clinical contraindication now receive aspirin at 81 mg daily in addition to the anticoagulation regimen typically used for all hospitalized COVID-19 patients.
Investigations regarding other medications that can influence platelet-endothelial cell interactions and modulate endothelial cell damage in CAC – such as dipyridamole, defibrotide, and eculizumab – are planned.
Challenges and unanswered questions
Virchow’s triad was described by the eminent German physician, Rudolf Virchow, MD, in the 19th century. It refers to the three broad categories of factors that can predispose patients to thrombosis — circulatory stasis, hypercoagulability, and endothelial injury.
Although all of these elements could be operative in CAC, the current study suggests platelet activation and endothelial cell injury in CAC may be of primary importance.
Because of the limited ability to test critically ill patients and concerns regarding exposure of additional hospital personnel to COVID-19 patients, the current report lacked clarity about the relationship of the detected laboratory abnormalities to confirmed thrombotic events.
It is unknown whether endothelial cells in different organs are damaged uniformly. It is also unclear if the laboratory abnormalities identified in this analysis can be used to monitor response to therapy, to guide follow-up management of discharged patients with CAC, or to identify infected outpatients who should receive prophylactic anticoagulation.
The mechanism by which SARS-CoV-2 injures endothelial cells is not explained by these data. Neutrophil defensins and other prothrombotic peptides or markers of inflammation could play key roles in pathogenesis, assessment of disease severity, or monitoring for therapeutic efficacy.
Today, we have more sophisticated diagnostic tools than Dr. Virchow had. We also have the ability to record and rapidly disseminate information globally. Still, with regard to the COVID-19 pandemic, clinicians face many of the same challenges that confronted Dr. Virchow in his era.
The analysis conducted by Dr. Goshua and colleagues goes a long way toward elucidating some of the mechanisms and therapeutic targets to meet these challenges.
Dr. Goshua disclosed no conflicts of interest.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Goshua G et al. EHA Congress. Abstract LB2605.
References
1. Klok FA et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-50. doi: 10.1016/j.thromres.2020.04.041.
2. Thomas W et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020;191:76-7. doi: 10.1016/j.thromres.2020.04.028
3. Lodigiani C et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi: 10.1016/j.thromres.2020.04.024
4. Llitjos JF et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi: 10.1111/jth.14869
5. Carsana L et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: 10.1101/2020.04.19.20054262v1.
6. Menter T et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4]. Histopathology. 2020;10.1111/his.14134. doi: 10.1111/his.14134
7. Lax SF, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series [published online ahead of print, 2020 May 14]. Ann Intern Med. 2020;M20-2566. doi: 10.7326/M20-2566.
A striking clinical feature of illness from SARS-CoV-2 is a marked increase in thrombotic and microvascular complications, or COVID-19–associated coagulopathy (CAC).
A new study suggests endothelial cell injury plays a major role in the pathogenesis of CAC, and blood levels of soluble thrombomodulin correlate with mortality.
George Goshua, MD, of Yale University, New Haven, Conn., presented this study as a late-breaking abstract at the virtual annual congress of the European Hematology Association.
Dr. Goshua cited past research showing CAC to be highly prevalent among hospitalized patients. Venous thromboembolism was found in 17% to 69% of patients, despite thromboprophylaxis.1-4 Arterial thrombosis has been seen in 3.6% to 4.0% of patients,1-3 and autopsy findings have shown microvascular thrombosis in as many as 87% of patients.5-7
For their study, Dr. Goshua and colleagues assessed endothelial cell damage, platelet activation, and hemostatic and fibrinolytic cascade effects of CAC.
The investigators measured markers of endothelial cell injury and platelet activation, plasminogen activation inhibitor 1 (PAI-1), and coagulation factors in stable and critically ill patients hospitalized with COVID-19. In addition, the team sought to identify biomarkers of mortality in hospitalized patients.
Dr. Goshua and colleagues studied 68 adults hospitalized for suspected COVID-19 – 48 in the ICU and 20 outside the ICU. Patients in the ICU received mechanical ventilation, while the non-ICU patients required supplemental oxygen (≤3 L/min per nasal cannula).
There were more men than women (69% vs. 31%) in the ICU population but not in the non-ICU population (40% vs. 60%). There were no statistically significant differences in age or comorbid conditions between the ICU and non-ICU patients.
Results and interpretation
Consistent with augmentation of the coagulation cascade – and as expected – D-dimer and thrombin-antithrombin levels were high in both the ICU and non-ICU populations, but levels were significantly higher (P < .001) among the ICU patients.
Endogenous anticoagulants (antithrombin and proteins C and S) and fibrinolytic enzymes (alpha 2-antiplasmin) were preserved, verifying that CAC is distinct from disseminated intravascular coagulation. Classic fibrinolysis did not occur, as PAI-1 was high in ICU and non-ICU patients, and lysis-30 was normal in nearly all ICU patients (96%).
Von Willebrand factor antigen and activity levels and factor VIII levels were markedly elevated in non-ICU and ICU patients, but they were significantly higher (P < .001) in the ICU cohort. This supports the hypothesis that endothelial cell damage and platelet activation play major roles in CAC.
Similarly, soluble P-selectin, which is shed from endothelial cells and platelets, was dramatically elevated in ICU patients in comparison with controls and non-ICU patients (P < .001 for both comparisons).
Levels of soluble thrombomodulin, which is released from endothelial cells, were not significantly different in ICU patients and controls. However, given thrombomodulin’s significant role in the coagulation cascade, Dr. Goshua and colleagues plotted receiver operating curves to see if soluble thrombomodulin levels were predictive of mortality.
The results showed that soluble thrombomodulin correlated with the probability of survival, both overall and in ICU patients. Soluble thrombomodulin levels greater than 3.26 ng/mL were associated with significantly worse survival in all patients (P = .0087) and ICU patients (P = .0309).
Influence on therapy
Laboratory perturbations were detected in both ICU and non-ICU patients, and otherwise healthy outpatients have exhibited potentially life-threatening CAC, according to Dr. Goshua.
These findings suggest the prothrombotic state occurs early in the pathogenesis of SARS-CoV-2 infection, is driven by platelet activation and endotheliopathy, and becomes more pronounced with worsening severity of infection.
The results of this study prompted a change in how Yale–New Haven Hospital manages COVID-19 patients. Patients without a clinical contraindication now receive aspirin at 81 mg daily in addition to the anticoagulation regimen typically used for all hospitalized COVID-19 patients.
Investigations regarding other medications that can influence platelet-endothelial cell interactions and modulate endothelial cell damage in CAC – such as dipyridamole, defibrotide, and eculizumab – are planned.
Challenges and unanswered questions
Virchow’s triad was described by the eminent German physician, Rudolf Virchow, MD, in the 19th century. It refers to the three broad categories of factors that can predispose patients to thrombosis — circulatory stasis, hypercoagulability, and endothelial injury.
Although all of these elements could be operative in CAC, the current study suggests platelet activation and endothelial cell injury in CAC may be of primary importance.
Because of the limited ability to test critically ill patients and concerns regarding exposure of additional hospital personnel to COVID-19 patients, the current report lacked clarity about the relationship of the detected laboratory abnormalities to confirmed thrombotic events.
It is unknown whether endothelial cells in different organs are damaged uniformly. It is also unclear if the laboratory abnormalities identified in this analysis can be used to monitor response to therapy, to guide follow-up management of discharged patients with CAC, or to identify infected outpatients who should receive prophylactic anticoagulation.
The mechanism by which SARS-CoV-2 injures endothelial cells is not explained by these data. Neutrophil defensins and other prothrombotic peptides or markers of inflammation could play key roles in pathogenesis, assessment of disease severity, or monitoring for therapeutic efficacy.
Today, we have more sophisticated diagnostic tools than Dr. Virchow had. We also have the ability to record and rapidly disseminate information globally. Still, with regard to the COVID-19 pandemic, clinicians face many of the same challenges that confronted Dr. Virchow in his era.
The analysis conducted by Dr. Goshua and colleagues goes a long way toward elucidating some of the mechanisms and therapeutic targets to meet these challenges.
Dr. Goshua disclosed no conflicts of interest.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Goshua G et al. EHA Congress. Abstract LB2605.
References
1. Klok FA et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-50. doi: 10.1016/j.thromres.2020.04.041.
2. Thomas W et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020;191:76-7. doi: 10.1016/j.thromres.2020.04.028
3. Lodigiani C et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi: 10.1016/j.thromres.2020.04.024
4. Llitjos JF et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi: 10.1111/jth.14869
5. Carsana L et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: 10.1101/2020.04.19.20054262v1.
6. Menter T et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4]. Histopathology. 2020;10.1111/his.14134. doi: 10.1111/his.14134
7. Lax SF, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series [published online ahead of print, 2020 May 14]. Ann Intern Med. 2020;M20-2566. doi: 10.7326/M20-2566.
FROM EHA CONGRESS
Inotuzumab / bosutinib treat R/R Ph+ ALL, CML in blast phase
Patients with Philadelphia chromosome–positive acute lymphoblastic or chronic myeloid leukemias in lymphoid blast phase may have longer event-free and overall survival with a combination of inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif) than with standard chemotherapy combined with a targeted agent, investigators in a phase 1/2 study reported.
Among patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or chronic myeloid leukemia (Ph+ CML) in lymphoid blast phase treated with inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif), the median overall survival was 15.4 months. In contrast, median overall survival for similar patients treated with chemotherapy and a tyrosine kinase inhibitor (TKI) was less than 6 months, reported Nitin Jain, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
The study was presented in a scientific poster session as part of the virtual annual congress of the European Hematology Association.
“Patients with relapsed/refractory Philadelphia chromosome–positive ALL/CML in lymphoid blast crisis are also best managed with a TKI targeting the constitutively active ABL kinase with the TKI selected based on presence of ABL kinase mutations and prior TKI history,” commented Marlise R. Luskin, MD, a leukemia specialist at the Dana-Farber Cancer Institute in Boston.
“A critical question for this patient population is whether these two approaches [TKI and inotuzumab ozogamicin] can be administered safely in combination. I congratulate MD Anderson for completion of this Phase I trial which demonstrates that inotuzumab and bosutinib can be safely combined with identification of a maximum tolerated dose of bosutinib 400 mg daily when administered in combination. I look forward to further studies that explore the efficacy of combination versus the approved single-agent regimen,” she said in an interview.
Study details
To see whether they could improve the dismal outcomes for patients with Ph+ ALL or Ph+ CML in lymphoid blast phase, they studied the combination of inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, and bosutinib, an inhibitor of the ABL kinase. Inotuzumab is approved in the United States for treatment of adults with relapsed or refractory B-cell precursor ALL, bosutinib is approved for the treatment of patients with newly-diagnosed chronic phase Ph+ CML and for adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
The investigators enrolled 16 patients with Ph+ ALL and 2 with Ph+ CML with bone marrow blasts greater than 5%, CD22 expressed on at least 20% of blasts, and good to fair performance status. The patients also had adequate organ function as measured by liver enzyme, total bilirubin, and serum creatinine levels. Patients with the T315I mutation, prior anti-CD22 therapy, active graft-versus-host disease, or liver disease were excluded.
The patients received inotuzumab 0.8 mg/m2 intravenously on day 1, they received 0.5 mg/m2 on days 8 and 15 of cycle 1, and they received 0.5 mg/m2 on days 1, 8, and 15 of cycles 2 through 6. Each cycle was 4 weeks. Patients who had a complete remission (CR), had complete cytogenetic remission (CCyR), or became negative for minimal residual disease (MRD) continued on 1 mg/m2 every 4 weeks. Bosutinib was dosed continuously day starting on the first day of cycle 1 and continued until disease progression or toxicity.
After a median follow-up of 36.7 months, 11 of the 18 patients had CRs, and 4 had CRs with incomplete recovery of hematologic counts. In addition, 13 of 16 patients with without diploid cytogenetics at the start of the study had CCyr; 14 patients had major molecular remission; 10 had complete molecular remission, and 11 were negative by flow cytometry.
As noted before, the median overall survival was 15.4 months. Event-free survival – time to lack of response, relapse, MRD relapse requiring therapy, or death – was 8 months. The event-free survival data were not censored for allogeneic stem cell transplant. Six patients underwent transplant while in remission.
The primary objective of the phase 1 trial was to evaluate safety of the combination and determine the maximum tolerated dose of bosutinib, which was determined to be 400 mg daily. At this dose level, one patient had a dose-limiting toxicity in the form of a grade 3 skin rash.
The most frequent adverse events were diarrhea and rash, in 50% of patients each, and nausea in 39% of patients. Grade 3 adverse events included were rash in three patients and reversible alanine aminotransferase and hyponatremia in one patient each. No patients developed veno-occlusive disease, and there no deaths within 30 days of the start of therapy.
Dr. Jain disclosed consultancy, honoraria, advisory board/committee activity, and research funding from Pfizer, maker of inotuzumab ozogamicin and bosutinib. Dr. Luskin reported no relevant disclosures.
SOURCE: Jain N et al. EHA25, Abstract EP396.
Patients with Philadelphia chromosome–positive acute lymphoblastic or chronic myeloid leukemias in lymphoid blast phase may have longer event-free and overall survival with a combination of inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif) than with standard chemotherapy combined with a targeted agent, investigators in a phase 1/2 study reported.
Among patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or chronic myeloid leukemia (Ph+ CML) in lymphoid blast phase treated with inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif), the median overall survival was 15.4 months. In contrast, median overall survival for similar patients treated with chemotherapy and a tyrosine kinase inhibitor (TKI) was less than 6 months, reported Nitin Jain, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
The study was presented in a scientific poster session as part of the virtual annual congress of the European Hematology Association.
“Patients with relapsed/refractory Philadelphia chromosome–positive ALL/CML in lymphoid blast crisis are also best managed with a TKI targeting the constitutively active ABL kinase with the TKI selected based on presence of ABL kinase mutations and prior TKI history,” commented Marlise R. Luskin, MD, a leukemia specialist at the Dana-Farber Cancer Institute in Boston.
“A critical question for this patient population is whether these two approaches [TKI and inotuzumab ozogamicin] can be administered safely in combination. I congratulate MD Anderson for completion of this Phase I trial which demonstrates that inotuzumab and bosutinib can be safely combined with identification of a maximum tolerated dose of bosutinib 400 mg daily when administered in combination. I look forward to further studies that explore the efficacy of combination versus the approved single-agent regimen,” she said in an interview.
Study details
To see whether they could improve the dismal outcomes for patients with Ph+ ALL or Ph+ CML in lymphoid blast phase, they studied the combination of inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, and bosutinib, an inhibitor of the ABL kinase. Inotuzumab is approved in the United States for treatment of adults with relapsed or refractory B-cell precursor ALL, bosutinib is approved for the treatment of patients with newly-diagnosed chronic phase Ph+ CML and for adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
The investigators enrolled 16 patients with Ph+ ALL and 2 with Ph+ CML with bone marrow blasts greater than 5%, CD22 expressed on at least 20% of blasts, and good to fair performance status. The patients also had adequate organ function as measured by liver enzyme, total bilirubin, and serum creatinine levels. Patients with the T315I mutation, prior anti-CD22 therapy, active graft-versus-host disease, or liver disease were excluded.
The patients received inotuzumab 0.8 mg/m2 intravenously on day 1, they received 0.5 mg/m2 on days 8 and 15 of cycle 1, and they received 0.5 mg/m2 on days 1, 8, and 15 of cycles 2 through 6. Each cycle was 4 weeks. Patients who had a complete remission (CR), had complete cytogenetic remission (CCyR), or became negative for minimal residual disease (MRD) continued on 1 mg/m2 every 4 weeks. Bosutinib was dosed continuously day starting on the first day of cycle 1 and continued until disease progression or toxicity.
After a median follow-up of 36.7 months, 11 of the 18 patients had CRs, and 4 had CRs with incomplete recovery of hematologic counts. In addition, 13 of 16 patients with without diploid cytogenetics at the start of the study had CCyr; 14 patients had major molecular remission; 10 had complete molecular remission, and 11 were negative by flow cytometry.
As noted before, the median overall survival was 15.4 months. Event-free survival – time to lack of response, relapse, MRD relapse requiring therapy, or death – was 8 months. The event-free survival data were not censored for allogeneic stem cell transplant. Six patients underwent transplant while in remission.
The primary objective of the phase 1 trial was to evaluate safety of the combination and determine the maximum tolerated dose of bosutinib, which was determined to be 400 mg daily. At this dose level, one patient had a dose-limiting toxicity in the form of a grade 3 skin rash.
The most frequent adverse events were diarrhea and rash, in 50% of patients each, and nausea in 39% of patients. Grade 3 adverse events included were rash in three patients and reversible alanine aminotransferase and hyponatremia in one patient each. No patients developed veno-occlusive disease, and there no deaths within 30 days of the start of therapy.
Dr. Jain disclosed consultancy, honoraria, advisory board/committee activity, and research funding from Pfizer, maker of inotuzumab ozogamicin and bosutinib. Dr. Luskin reported no relevant disclosures.
SOURCE: Jain N et al. EHA25, Abstract EP396.
Patients with Philadelphia chromosome–positive acute lymphoblastic or chronic myeloid leukemias in lymphoid blast phase may have longer event-free and overall survival with a combination of inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif) than with standard chemotherapy combined with a targeted agent, investigators in a phase 1/2 study reported.
Among patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or chronic myeloid leukemia (Ph+ CML) in lymphoid blast phase treated with inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif), the median overall survival was 15.4 months. In contrast, median overall survival for similar patients treated with chemotherapy and a tyrosine kinase inhibitor (TKI) was less than 6 months, reported Nitin Jain, MD, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
The study was presented in a scientific poster session as part of the virtual annual congress of the European Hematology Association.
“Patients with relapsed/refractory Philadelphia chromosome–positive ALL/CML in lymphoid blast crisis are also best managed with a TKI targeting the constitutively active ABL kinase with the TKI selected based on presence of ABL kinase mutations and prior TKI history,” commented Marlise R. Luskin, MD, a leukemia specialist at the Dana-Farber Cancer Institute in Boston.
“A critical question for this patient population is whether these two approaches [TKI and inotuzumab ozogamicin] can be administered safely in combination. I congratulate MD Anderson for completion of this Phase I trial which demonstrates that inotuzumab and bosutinib can be safely combined with identification of a maximum tolerated dose of bosutinib 400 mg daily when administered in combination. I look forward to further studies that explore the efficacy of combination versus the approved single-agent regimen,” she said in an interview.
Study details
To see whether they could improve the dismal outcomes for patients with Ph+ ALL or Ph+ CML in lymphoid blast phase, they studied the combination of inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, and bosutinib, an inhibitor of the ABL kinase. Inotuzumab is approved in the United States for treatment of adults with relapsed or refractory B-cell precursor ALL, bosutinib is approved for the treatment of patients with newly-diagnosed chronic phase Ph+ CML and for adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
The investigators enrolled 16 patients with Ph+ ALL and 2 with Ph+ CML with bone marrow blasts greater than 5%, CD22 expressed on at least 20% of blasts, and good to fair performance status. The patients also had adequate organ function as measured by liver enzyme, total bilirubin, and serum creatinine levels. Patients with the T315I mutation, prior anti-CD22 therapy, active graft-versus-host disease, or liver disease were excluded.
The patients received inotuzumab 0.8 mg/m2 intravenously on day 1, they received 0.5 mg/m2 on days 8 and 15 of cycle 1, and they received 0.5 mg/m2 on days 1, 8, and 15 of cycles 2 through 6. Each cycle was 4 weeks. Patients who had a complete remission (CR), had complete cytogenetic remission (CCyR), or became negative for minimal residual disease (MRD) continued on 1 mg/m2 every 4 weeks. Bosutinib was dosed continuously day starting on the first day of cycle 1 and continued until disease progression or toxicity.
After a median follow-up of 36.7 months, 11 of the 18 patients had CRs, and 4 had CRs with incomplete recovery of hematologic counts. In addition, 13 of 16 patients with without diploid cytogenetics at the start of the study had CCyr; 14 patients had major molecular remission; 10 had complete molecular remission, and 11 were negative by flow cytometry.
As noted before, the median overall survival was 15.4 months. Event-free survival – time to lack of response, relapse, MRD relapse requiring therapy, or death – was 8 months. The event-free survival data were not censored for allogeneic stem cell transplant. Six patients underwent transplant while in remission.
The primary objective of the phase 1 trial was to evaluate safety of the combination and determine the maximum tolerated dose of bosutinib, which was determined to be 400 mg daily. At this dose level, one patient had a dose-limiting toxicity in the form of a grade 3 skin rash.
The most frequent adverse events were diarrhea and rash, in 50% of patients each, and nausea in 39% of patients. Grade 3 adverse events included were rash in three patients and reversible alanine aminotransferase and hyponatremia in one patient each. No patients developed veno-occlusive disease, and there no deaths within 30 days of the start of therapy.
Dr. Jain disclosed consultancy, honoraria, advisory board/committee activity, and research funding from Pfizer, maker of inotuzumab ozogamicin and bosutinib. Dr. Luskin reported no relevant disclosures.
SOURCE: Jain N et al. EHA25, Abstract EP396.
FROM EHA CONGRESS
Venetoclax plus LDAC tops LDAC alone in AML
At about 18 months’ follow-up in treatment naive acute myelogenous leukemia (AML) patients who were 75 years or older or otherwise unfit for intensive chemotherapy, median overall survival (OS) was 8.4 months when they were randomized to low-dose cytarabine (LDAC) plus the BCL-2 inhibitor venetoclax versus 4.1 months with LDAC plus placebo. The results from the phase 3 trial were reported at the virtual annual congress of the European Hematology Association.
The combination also improved rates of remission, event-free survival, and patient reported outcomes and lessened transfusion requirements. Adverse events were manageable.
The findings position venetoclax add-on with LDAC “as a potential new standard of care” for untreated patients ineligible for intensive chemotherapy, lead investigator Andrew Wei, MD, PhD, an AML researcher at Monash University, Melbourne, said at the meeting.
The study addresses a substantial unmet need. The median age at AML diagnosis is over 68 years old and comorbidities such as heart failure and reduced creatinine clearance are common, which make the risk of toxicity with standard chemotherapy too high. Single-agent alternatives are of limited benefit, so Dr. Wei’s group and others are looking for better options to plug the treatment gap when standard chemotherapy is contraindicated.
Several combinations are under investigation, including LDAC plus venetoclax, which appears to have a synergistic effect greater than either agent on its own, Dr. Wei and colleagues explained in their journal report, which was published online to coincide with his presentation (Blood. 2020 Jun 11;135(24):2137-45).
In a commentary, Bob Lowenberg, Ph, a hematologist with the Erasmus University Medical Center in Rotterdam, and Gerwin Huls, MD, PhD, of the University Medical Center Groningen, both in the Netherlands, said the study “represents a valuable although moderate step forward on the way to a better therapeutic future for the ‘unfit’ patient with AML” (Blood. 2020. Jun 11;135(24): 2114-5).
“A challenging AML population”
In the study, 143 patients were randomized to oral venetoclax 600 mg daily and 68 to placebo in 28-day cycles, on a background of LDAC 20 mg/m2 administered subcutaneously on days 1-10 of each cycle.
“This study enrolled a challenging AML population, with nearly 60% age ≥75 years and a high proportion of patients with secondary disease (38%), prior hypomethylating agent (HMA) treatment (20%), poor cytogenetic risk (32%), and TP53 mutations (15%), which are known factors associated with dismal prognosis in AML,” the investigators noted in their report.
There was a numerical benefit in OS at 12 months – the preplanned primary outcome – but it was not statistically significant. At 18 months, however, and after adjustment for a higher rate of secondary AML in the venetoclax arm and other confounders in a post hoc analysis, survival differences reached significance. The 4.3-month OS benefit with the combination translated into a 30% reduction in the risk of death (hazard ratio, 0.70; 95% confidence interval, 0.50-0.99; P = .04)
Survival outcomes “were particularly promising for patient subgroups with NPM1- (median OS, not reached) and IDH1/2-mutant AML (median OS, 19.4 months),” the team noted.
Complete remission (CR) were 48% in the venetoclax arm, compared with 13% in the placebo group, and 34% of venetoclax patients versus 3% of placebo patients went into remission after their first cycle. Venetoclax subjects also had longer median event free survival (4.7 months vs. 2 months); higher rates of red blood cell and platelet transfusion independence (37% vs. 16%); and higher rates of cytometric minimal residual disease levels below 0.1% (6% vs. 1%).
The findings correlated with “strong improvements” in patient-reported outcomes, including fatigue and quality of life, the investigators reported.
Risk mitigation
Grade 3 or higher adverse events (AEs) included febrile neutropenia (32% in the venetoclax arm versus 29% in the placebo group), neutropenia (47% venetoclax vs. 16% placebo), thrombocytopenia (45% vs. 37%), and anemia (25% vs. 22%). The eight cases of tumor lysis syndrome (TLS) were all in the venetoclax arm. Grade 3 or higher bleeding was higher in the venetoclax arm (11% versus 7%), but the incidence of fatal bleeding was similar between the groups (1.4% venetoclax versus 1.5%).
“Although the venetoclax arm showed modest increases in hematologic AEs, the rate of AEs leading to treatment discontinuation (24% vs. 25%) and the rate of serious AEs such as pneumonia” and sepsis “were nearly identical between” the arms, the team said.
The combination “is more myelosuppressive,” but the effects “were mostly mitigated by venetoclax dose interruptions and reductions.” To mitigate the TLS risk, patients were hospitalized for TLS evaluation and prophylaxis during the 4-day venetoclax ramp-up in the first treatment cycle and for 24 hours after the 600-mg target was reached. “I think this is an extremely important measure to avoid this small but important complication,” Dr. Wei said at the meeting.
A moderate step forward
Dr. Lowenberg and Dr. Huls noted in their commentary that, despite the favorable outcomes, “the results are still sobering with a rapid drop of the survival curves to values of [around] 25% or less within 18 months, and event-free survival rates even falling to considerably lower levels.”
Also, there was a “weak correlation between the relatively wide differences in comparative CR/CRi rates and the much smaller differences in survival,” perhaps “due to a limited depth of the complete responses following venetoclax-LDAC therapy or the early development of therapeutic resistance,” they said.
The commentary also noted another option, adding the hedgehog pathway inhibitor glasdegib, instead of venetoclax, to LDAC. It also improved survival in a similar randomized study in unfit AML and high-risk myelodysplastic syndrome patients, from a median survival of 4.9 months with LDAC alone to 8.8 months with the combination (Leukemia. 2019 Feb;33(2):379-389. doi: 10.1038/s41375-018-0312-9).
Dueling regimens
Another alternative approach – venetoclax plus the HMA agent azacitidine – garnered a lot of attention at the meeting when it was reported that the combination had a median overall survival of 14.7 months, versus 9.6 months with azacitidine alone, in patients ineligible for intensive chemotherapy. CR/CRi rates were 66% with the combination, versus 28%.
“It seems like the results were better with the combination of venetoclax and azacitidine” than venetoclax plus LDAC, said Gunnar Juliusson, MD, PhD, of Lund (Sweden) University, who moderated Dr. Wei’s presentation.
He wanted to know if there was a way to identify patients who would do better on one regimen versus the other and was curious about the fact that the azacitidine study used a dose of 400 mg venetoclax, instead of 600 mg.
Dr. Wei noted the high incidence of poor prognostic factors in his study, including prior HMA treatment in 20%, but also that “we don’t know for sure” if there’s a clinically meaningful benefit with the higher dose.
He also said the optimal number of venetoclax cycles for best response is unknown. For now, treatment is “recommend until either [disease] progression, dose intolerance, or patient or physician preference,” he noted. Venetoclax subjects in his study had a median of four treatment cycles versus two in the placebo group. Combination patients in the azacitidine study had a median of seven cycles versus 4.5 with placebo.
Venetoclax already carries an indication in the United States in combination with azacitidine, decitabine, or LDAC for newly-diagnosed AML in adults 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy, at a daily dosage of 400 mg with HMAs and 600 mg with LDAC.
Labeling notes that “continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”
Both venetoclax trials were sponsored by the drug’s maker, AbbVie, which was involved with data interpretation and other matters. Dr. Wei is a consultant for and receives research funding from the company and also receives royalty payments in relation to venetoclax. The commentators did not have any competing financial interests. Disclosures, if any, were not reported for Dr. Juliusson.
SOURCE: Wei AH et al. EHA Congress, Abstract S136.
At about 18 months’ follow-up in treatment naive acute myelogenous leukemia (AML) patients who were 75 years or older or otherwise unfit for intensive chemotherapy, median overall survival (OS) was 8.4 months when they were randomized to low-dose cytarabine (LDAC) plus the BCL-2 inhibitor venetoclax versus 4.1 months with LDAC plus placebo. The results from the phase 3 trial were reported at the virtual annual congress of the European Hematology Association.
The combination also improved rates of remission, event-free survival, and patient reported outcomes and lessened transfusion requirements. Adverse events were manageable.
The findings position venetoclax add-on with LDAC “as a potential new standard of care” for untreated patients ineligible for intensive chemotherapy, lead investigator Andrew Wei, MD, PhD, an AML researcher at Monash University, Melbourne, said at the meeting.
The study addresses a substantial unmet need. The median age at AML diagnosis is over 68 years old and comorbidities such as heart failure and reduced creatinine clearance are common, which make the risk of toxicity with standard chemotherapy too high. Single-agent alternatives are of limited benefit, so Dr. Wei’s group and others are looking for better options to plug the treatment gap when standard chemotherapy is contraindicated.
Several combinations are under investigation, including LDAC plus venetoclax, which appears to have a synergistic effect greater than either agent on its own, Dr. Wei and colleagues explained in their journal report, which was published online to coincide with his presentation (Blood. 2020 Jun 11;135(24):2137-45).
In a commentary, Bob Lowenberg, Ph, a hematologist with the Erasmus University Medical Center in Rotterdam, and Gerwin Huls, MD, PhD, of the University Medical Center Groningen, both in the Netherlands, said the study “represents a valuable although moderate step forward on the way to a better therapeutic future for the ‘unfit’ patient with AML” (Blood. 2020. Jun 11;135(24): 2114-5).
“A challenging AML population”
In the study, 143 patients were randomized to oral venetoclax 600 mg daily and 68 to placebo in 28-day cycles, on a background of LDAC 20 mg/m2 administered subcutaneously on days 1-10 of each cycle.
“This study enrolled a challenging AML population, with nearly 60% age ≥75 years and a high proportion of patients with secondary disease (38%), prior hypomethylating agent (HMA) treatment (20%), poor cytogenetic risk (32%), and TP53 mutations (15%), which are known factors associated with dismal prognosis in AML,” the investigators noted in their report.
There was a numerical benefit in OS at 12 months – the preplanned primary outcome – but it was not statistically significant. At 18 months, however, and after adjustment for a higher rate of secondary AML in the venetoclax arm and other confounders in a post hoc analysis, survival differences reached significance. The 4.3-month OS benefit with the combination translated into a 30% reduction in the risk of death (hazard ratio, 0.70; 95% confidence interval, 0.50-0.99; P = .04)
Survival outcomes “were particularly promising for patient subgroups with NPM1- (median OS, not reached) and IDH1/2-mutant AML (median OS, 19.4 months),” the team noted.
Complete remission (CR) were 48% in the venetoclax arm, compared with 13% in the placebo group, and 34% of venetoclax patients versus 3% of placebo patients went into remission after their first cycle. Venetoclax subjects also had longer median event free survival (4.7 months vs. 2 months); higher rates of red blood cell and platelet transfusion independence (37% vs. 16%); and higher rates of cytometric minimal residual disease levels below 0.1% (6% vs. 1%).
The findings correlated with “strong improvements” in patient-reported outcomes, including fatigue and quality of life, the investigators reported.
Risk mitigation
Grade 3 or higher adverse events (AEs) included febrile neutropenia (32% in the venetoclax arm versus 29% in the placebo group), neutropenia (47% venetoclax vs. 16% placebo), thrombocytopenia (45% vs. 37%), and anemia (25% vs. 22%). The eight cases of tumor lysis syndrome (TLS) were all in the venetoclax arm. Grade 3 or higher bleeding was higher in the venetoclax arm (11% versus 7%), but the incidence of fatal bleeding was similar between the groups (1.4% venetoclax versus 1.5%).
“Although the venetoclax arm showed modest increases in hematologic AEs, the rate of AEs leading to treatment discontinuation (24% vs. 25%) and the rate of serious AEs such as pneumonia” and sepsis “were nearly identical between” the arms, the team said.
The combination “is more myelosuppressive,” but the effects “were mostly mitigated by venetoclax dose interruptions and reductions.” To mitigate the TLS risk, patients were hospitalized for TLS evaluation and prophylaxis during the 4-day venetoclax ramp-up in the first treatment cycle and for 24 hours after the 600-mg target was reached. “I think this is an extremely important measure to avoid this small but important complication,” Dr. Wei said at the meeting.
A moderate step forward
Dr. Lowenberg and Dr. Huls noted in their commentary that, despite the favorable outcomes, “the results are still sobering with a rapid drop of the survival curves to values of [around] 25% or less within 18 months, and event-free survival rates even falling to considerably lower levels.”
Also, there was a “weak correlation between the relatively wide differences in comparative CR/CRi rates and the much smaller differences in survival,” perhaps “due to a limited depth of the complete responses following venetoclax-LDAC therapy or the early development of therapeutic resistance,” they said.
The commentary also noted another option, adding the hedgehog pathway inhibitor glasdegib, instead of venetoclax, to LDAC. It also improved survival in a similar randomized study in unfit AML and high-risk myelodysplastic syndrome patients, from a median survival of 4.9 months with LDAC alone to 8.8 months with the combination (Leukemia. 2019 Feb;33(2):379-389. doi: 10.1038/s41375-018-0312-9).
Dueling regimens
Another alternative approach – venetoclax plus the HMA agent azacitidine – garnered a lot of attention at the meeting when it was reported that the combination had a median overall survival of 14.7 months, versus 9.6 months with azacitidine alone, in patients ineligible for intensive chemotherapy. CR/CRi rates were 66% with the combination, versus 28%.
“It seems like the results were better with the combination of venetoclax and azacitidine” than venetoclax plus LDAC, said Gunnar Juliusson, MD, PhD, of Lund (Sweden) University, who moderated Dr. Wei’s presentation.
He wanted to know if there was a way to identify patients who would do better on one regimen versus the other and was curious about the fact that the azacitidine study used a dose of 400 mg venetoclax, instead of 600 mg.
Dr. Wei noted the high incidence of poor prognostic factors in his study, including prior HMA treatment in 20%, but also that “we don’t know for sure” if there’s a clinically meaningful benefit with the higher dose.
He also said the optimal number of venetoclax cycles for best response is unknown. For now, treatment is “recommend until either [disease] progression, dose intolerance, or patient or physician preference,” he noted. Venetoclax subjects in his study had a median of four treatment cycles versus two in the placebo group. Combination patients in the azacitidine study had a median of seven cycles versus 4.5 with placebo.
Venetoclax already carries an indication in the United States in combination with azacitidine, decitabine, or LDAC for newly-diagnosed AML in adults 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy, at a daily dosage of 400 mg with HMAs and 600 mg with LDAC.
Labeling notes that “continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”
Both venetoclax trials were sponsored by the drug’s maker, AbbVie, which was involved with data interpretation and other matters. Dr. Wei is a consultant for and receives research funding from the company and also receives royalty payments in relation to venetoclax. The commentators did not have any competing financial interests. Disclosures, if any, were not reported for Dr. Juliusson.
SOURCE: Wei AH et al. EHA Congress, Abstract S136.
At about 18 months’ follow-up in treatment naive acute myelogenous leukemia (AML) patients who were 75 years or older or otherwise unfit for intensive chemotherapy, median overall survival (OS) was 8.4 months when they were randomized to low-dose cytarabine (LDAC) plus the BCL-2 inhibitor venetoclax versus 4.1 months with LDAC plus placebo. The results from the phase 3 trial were reported at the virtual annual congress of the European Hematology Association.
The combination also improved rates of remission, event-free survival, and patient reported outcomes and lessened transfusion requirements. Adverse events were manageable.
The findings position venetoclax add-on with LDAC “as a potential new standard of care” for untreated patients ineligible for intensive chemotherapy, lead investigator Andrew Wei, MD, PhD, an AML researcher at Monash University, Melbourne, said at the meeting.
The study addresses a substantial unmet need. The median age at AML diagnosis is over 68 years old and comorbidities such as heart failure and reduced creatinine clearance are common, which make the risk of toxicity with standard chemotherapy too high. Single-agent alternatives are of limited benefit, so Dr. Wei’s group and others are looking for better options to plug the treatment gap when standard chemotherapy is contraindicated.
Several combinations are under investigation, including LDAC plus venetoclax, which appears to have a synergistic effect greater than either agent on its own, Dr. Wei and colleagues explained in their journal report, which was published online to coincide with his presentation (Blood. 2020 Jun 11;135(24):2137-45).
In a commentary, Bob Lowenberg, Ph, a hematologist with the Erasmus University Medical Center in Rotterdam, and Gerwin Huls, MD, PhD, of the University Medical Center Groningen, both in the Netherlands, said the study “represents a valuable although moderate step forward on the way to a better therapeutic future for the ‘unfit’ patient with AML” (Blood. 2020. Jun 11;135(24): 2114-5).
“A challenging AML population”
In the study, 143 patients were randomized to oral venetoclax 600 mg daily and 68 to placebo in 28-day cycles, on a background of LDAC 20 mg/m2 administered subcutaneously on days 1-10 of each cycle.
“This study enrolled a challenging AML population, with nearly 60% age ≥75 years and a high proportion of patients with secondary disease (38%), prior hypomethylating agent (HMA) treatment (20%), poor cytogenetic risk (32%), and TP53 mutations (15%), which are known factors associated with dismal prognosis in AML,” the investigators noted in their report.
There was a numerical benefit in OS at 12 months – the preplanned primary outcome – but it was not statistically significant. At 18 months, however, and after adjustment for a higher rate of secondary AML in the venetoclax arm and other confounders in a post hoc analysis, survival differences reached significance. The 4.3-month OS benefit with the combination translated into a 30% reduction in the risk of death (hazard ratio, 0.70; 95% confidence interval, 0.50-0.99; P = .04)
Survival outcomes “were particularly promising for patient subgroups with NPM1- (median OS, not reached) and IDH1/2-mutant AML (median OS, 19.4 months),” the team noted.
Complete remission (CR) were 48% in the venetoclax arm, compared with 13% in the placebo group, and 34% of venetoclax patients versus 3% of placebo patients went into remission after their first cycle. Venetoclax subjects also had longer median event free survival (4.7 months vs. 2 months); higher rates of red blood cell and platelet transfusion independence (37% vs. 16%); and higher rates of cytometric minimal residual disease levels below 0.1% (6% vs. 1%).
The findings correlated with “strong improvements” in patient-reported outcomes, including fatigue and quality of life, the investigators reported.
Risk mitigation
Grade 3 or higher adverse events (AEs) included febrile neutropenia (32% in the venetoclax arm versus 29% in the placebo group), neutropenia (47% venetoclax vs. 16% placebo), thrombocytopenia (45% vs. 37%), and anemia (25% vs. 22%). The eight cases of tumor lysis syndrome (TLS) were all in the venetoclax arm. Grade 3 or higher bleeding was higher in the venetoclax arm (11% versus 7%), but the incidence of fatal bleeding was similar between the groups (1.4% venetoclax versus 1.5%).
“Although the venetoclax arm showed modest increases in hematologic AEs, the rate of AEs leading to treatment discontinuation (24% vs. 25%) and the rate of serious AEs such as pneumonia” and sepsis “were nearly identical between” the arms, the team said.
The combination “is more myelosuppressive,” but the effects “were mostly mitigated by venetoclax dose interruptions and reductions.” To mitigate the TLS risk, patients were hospitalized for TLS evaluation and prophylaxis during the 4-day venetoclax ramp-up in the first treatment cycle and for 24 hours after the 600-mg target was reached. “I think this is an extremely important measure to avoid this small but important complication,” Dr. Wei said at the meeting.
A moderate step forward
Dr. Lowenberg and Dr. Huls noted in their commentary that, despite the favorable outcomes, “the results are still sobering with a rapid drop of the survival curves to values of [around] 25% or less within 18 months, and event-free survival rates even falling to considerably lower levels.”
Also, there was a “weak correlation between the relatively wide differences in comparative CR/CRi rates and the much smaller differences in survival,” perhaps “due to a limited depth of the complete responses following venetoclax-LDAC therapy or the early development of therapeutic resistance,” they said.
The commentary also noted another option, adding the hedgehog pathway inhibitor glasdegib, instead of venetoclax, to LDAC. It also improved survival in a similar randomized study in unfit AML and high-risk myelodysplastic syndrome patients, from a median survival of 4.9 months with LDAC alone to 8.8 months with the combination (Leukemia. 2019 Feb;33(2):379-389. doi: 10.1038/s41375-018-0312-9).
Dueling regimens
Another alternative approach – venetoclax plus the HMA agent azacitidine – garnered a lot of attention at the meeting when it was reported that the combination had a median overall survival of 14.7 months, versus 9.6 months with azacitidine alone, in patients ineligible for intensive chemotherapy. CR/CRi rates were 66% with the combination, versus 28%.
“It seems like the results were better with the combination of venetoclax and azacitidine” than venetoclax plus LDAC, said Gunnar Juliusson, MD, PhD, of Lund (Sweden) University, who moderated Dr. Wei’s presentation.
He wanted to know if there was a way to identify patients who would do better on one regimen versus the other and was curious about the fact that the azacitidine study used a dose of 400 mg venetoclax, instead of 600 mg.
Dr. Wei noted the high incidence of poor prognostic factors in his study, including prior HMA treatment in 20%, but also that “we don’t know for sure” if there’s a clinically meaningful benefit with the higher dose.
He also said the optimal number of venetoclax cycles for best response is unknown. For now, treatment is “recommend until either [disease] progression, dose intolerance, or patient or physician preference,” he noted. Venetoclax subjects in his study had a median of four treatment cycles versus two in the placebo group. Combination patients in the azacitidine study had a median of seven cycles versus 4.5 with placebo.
Venetoclax already carries an indication in the United States in combination with azacitidine, decitabine, or LDAC for newly-diagnosed AML in adults 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy, at a daily dosage of 400 mg with HMAs and 600 mg with LDAC.
Labeling notes that “continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”
Both venetoclax trials were sponsored by the drug’s maker, AbbVie, which was involved with data interpretation and other matters. Dr. Wei is a consultant for and receives research funding from the company and also receives royalty payments in relation to venetoclax. The commentators did not have any competing financial interests. Disclosures, if any, were not reported for Dr. Juliusson.
SOURCE: Wei AH et al. EHA Congress, Abstract S136.
REPORTING FROM EHA CONGRESS
Azacitidine plus enasidenib improves response, but not survival, in mIDH2 AML
Azacitidine plus enasidenib improved complete and overall responses in newly diagnosed acute myelogenous leukemia with isocitrate dehydrogenase 2 gene mutations, compared with azacitidine alone, but it did not improve overall survival in an open-label, phase 2 trial reported at the virtual annual congress of the European Hematology Association.
“Given the very high cost of” enasidenib, and the lack of survival benefit, Gunnar Juliusson, MD, PhD, of Lund University, Sweden, who moderated the study presentation, wondered if it might make more sense to hold enasidenib in reserve until after progression on azacitidine.
“The challenge is going to be exactly” that, “trying to figure out [if] you use both things together” or in sequence. “You can look at it in both ways,” said lead investigator Courtney DiNardo, MD, associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.
“We do know” that with enasidenib monotherapy, there’s “a decrement in the rates of remission and in the duration of response” and overall survival in the salvage setting, so there’s “a clear rationale to give it earlier rather than later,” but “I think this study in some ways provides a few more questions than it really answers,” she said at the meeting.
About 15% of AML patients have leukemogenic isocitrate dehydrogenase 2 (IDH2) mutations; enasidenib, an oral small molecule, inhibits the mutant enzyme. The older AML patients are, the more likely they are to have an IDH2 mutation, so the work “is relevant to our older chemotherapy ineligible population,” Dr. DiNardo said.
The trial was prompted by preclinical indications of synergy with azacitidine; alone, each agent has an overall response rate of about 30% in newly diagnosed AML, and a complete remission (CR) rate of about 20%, she explained.
Her team randomized 68 adults with newly diagnosed AML and an IDH2 mutation to enasidenib 100 mg daily on a 28-day cycle with subcutaneous azacitidine 75 mg/m2 for 7 days during the cycle, and 33 others to just the azacitidine alone.
Their subjects were ineligible for intensive chemotherapy and had intermediate to poor risk cytogenetics. The median age was 75 years, and Eastern Cooperative Oncology Group performance scores were 2 or less.
The overall response rate was 71% with the combination and 42% in the azacitidine alone arm (P = .0064). Fifty-three percent of combination patients, but 12% of azacitidine alone subjects, had complete remissions (P = .0001). The median duration of response with combination therapy was 24.1 months, versus 12.1 months.
Enasidenib plus azacitidine subjects also had greater drops in mutant IDH2 variant allele frequency (median 83.4% versus 17.7%, P < .01) and levels of the downstream oncometabolite 2-hydroxyglutarate (97.8% versus 54.3%; P < .01).
However, median OS was 22 months in both arms (HR 0.99, 95% CI 0.52, 1.87, P = .97). Although median event-free survival favored the combination – 17.2 months versus 10.8 – the results were not statistically significant (HR 0.59, 95% CI 0.30, 1.17, P = .13).
A possible reason for the lack of survival benefit, Dr. DiNardo said, was that seven azacitidine-alone patients (21%) went on to enasidenib after leaving the study, most commonly for disease progression, which occurred in 31% of combination patients versus 52% in the azacitidine-alone arm.
Combination subjects had a median of 10 treatment cycles, vs. 7 in the azacitidine-alone group. Grade 3-4 adverse events included thrombocytopenia (37% combination, 19% azacitidine-alone), neutropenia (35% vs. 22%), anemia (19% vs. 22%), and febrile neutropenia (15% vs. 16%). Grade 3-4 infections were more common with azacitidine monotherapy (31% vs. 18%).
Twelve enasidenib/azacitidine subjects (18%) developed isocitrate dehydrogenase differentiation syndrome, a complication that carries a black box warning in enasidenib’s label.
The work was funded by enasidenib marketer Celgene. Dr. DiNardo is an adviser to, and receives research funding from, the company. Dr. Juliusson’s disclosures, if any, were not reported.
SOURCE: DiNardo CD et al. EHA Congress, abstract S139.
Azacitidine plus enasidenib improved complete and overall responses in newly diagnosed acute myelogenous leukemia with isocitrate dehydrogenase 2 gene mutations, compared with azacitidine alone, but it did not improve overall survival in an open-label, phase 2 trial reported at the virtual annual congress of the European Hematology Association.
“Given the very high cost of” enasidenib, and the lack of survival benefit, Gunnar Juliusson, MD, PhD, of Lund University, Sweden, who moderated the study presentation, wondered if it might make more sense to hold enasidenib in reserve until after progression on azacitidine.
“The challenge is going to be exactly” that, “trying to figure out [if] you use both things together” or in sequence. “You can look at it in both ways,” said lead investigator Courtney DiNardo, MD, associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.
“We do know” that with enasidenib monotherapy, there’s “a decrement in the rates of remission and in the duration of response” and overall survival in the salvage setting, so there’s “a clear rationale to give it earlier rather than later,” but “I think this study in some ways provides a few more questions than it really answers,” she said at the meeting.
About 15% of AML patients have leukemogenic isocitrate dehydrogenase 2 (IDH2) mutations; enasidenib, an oral small molecule, inhibits the mutant enzyme. The older AML patients are, the more likely they are to have an IDH2 mutation, so the work “is relevant to our older chemotherapy ineligible population,” Dr. DiNardo said.
The trial was prompted by preclinical indications of synergy with azacitidine; alone, each agent has an overall response rate of about 30% in newly diagnosed AML, and a complete remission (CR) rate of about 20%, she explained.
Her team randomized 68 adults with newly diagnosed AML and an IDH2 mutation to enasidenib 100 mg daily on a 28-day cycle with subcutaneous azacitidine 75 mg/m2 for 7 days during the cycle, and 33 others to just the azacitidine alone.
Their subjects were ineligible for intensive chemotherapy and had intermediate to poor risk cytogenetics. The median age was 75 years, and Eastern Cooperative Oncology Group performance scores were 2 or less.
The overall response rate was 71% with the combination and 42% in the azacitidine alone arm (P = .0064). Fifty-three percent of combination patients, but 12% of azacitidine alone subjects, had complete remissions (P = .0001). The median duration of response with combination therapy was 24.1 months, versus 12.1 months.
Enasidenib plus azacitidine subjects also had greater drops in mutant IDH2 variant allele frequency (median 83.4% versus 17.7%, P < .01) and levels of the downstream oncometabolite 2-hydroxyglutarate (97.8% versus 54.3%; P < .01).
However, median OS was 22 months in both arms (HR 0.99, 95% CI 0.52, 1.87, P = .97). Although median event-free survival favored the combination – 17.2 months versus 10.8 – the results were not statistically significant (HR 0.59, 95% CI 0.30, 1.17, P = .13).
A possible reason for the lack of survival benefit, Dr. DiNardo said, was that seven azacitidine-alone patients (21%) went on to enasidenib after leaving the study, most commonly for disease progression, which occurred in 31% of combination patients versus 52% in the azacitidine-alone arm.
Combination subjects had a median of 10 treatment cycles, vs. 7 in the azacitidine-alone group. Grade 3-4 adverse events included thrombocytopenia (37% combination, 19% azacitidine-alone), neutropenia (35% vs. 22%), anemia (19% vs. 22%), and febrile neutropenia (15% vs. 16%). Grade 3-4 infections were more common with azacitidine monotherapy (31% vs. 18%).
Twelve enasidenib/azacitidine subjects (18%) developed isocitrate dehydrogenase differentiation syndrome, a complication that carries a black box warning in enasidenib’s label.
The work was funded by enasidenib marketer Celgene. Dr. DiNardo is an adviser to, and receives research funding from, the company. Dr. Juliusson’s disclosures, if any, were not reported.
SOURCE: DiNardo CD et al. EHA Congress, abstract S139.
Azacitidine plus enasidenib improved complete and overall responses in newly diagnosed acute myelogenous leukemia with isocitrate dehydrogenase 2 gene mutations, compared with azacitidine alone, but it did not improve overall survival in an open-label, phase 2 trial reported at the virtual annual congress of the European Hematology Association.
“Given the very high cost of” enasidenib, and the lack of survival benefit, Gunnar Juliusson, MD, PhD, of Lund University, Sweden, who moderated the study presentation, wondered if it might make more sense to hold enasidenib in reserve until after progression on azacitidine.
“The challenge is going to be exactly” that, “trying to figure out [if] you use both things together” or in sequence. “You can look at it in both ways,” said lead investigator Courtney DiNardo, MD, associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.
“We do know” that with enasidenib monotherapy, there’s “a decrement in the rates of remission and in the duration of response” and overall survival in the salvage setting, so there’s “a clear rationale to give it earlier rather than later,” but “I think this study in some ways provides a few more questions than it really answers,” she said at the meeting.
About 15% of AML patients have leukemogenic isocitrate dehydrogenase 2 (IDH2) mutations; enasidenib, an oral small molecule, inhibits the mutant enzyme. The older AML patients are, the more likely they are to have an IDH2 mutation, so the work “is relevant to our older chemotherapy ineligible population,” Dr. DiNardo said.
The trial was prompted by preclinical indications of synergy with azacitidine; alone, each agent has an overall response rate of about 30% in newly diagnosed AML, and a complete remission (CR) rate of about 20%, she explained.
Her team randomized 68 adults with newly diagnosed AML and an IDH2 mutation to enasidenib 100 mg daily on a 28-day cycle with subcutaneous azacitidine 75 mg/m2 for 7 days during the cycle, and 33 others to just the azacitidine alone.
Their subjects were ineligible for intensive chemotherapy and had intermediate to poor risk cytogenetics. The median age was 75 years, and Eastern Cooperative Oncology Group performance scores were 2 or less.
The overall response rate was 71% with the combination and 42% in the azacitidine alone arm (P = .0064). Fifty-three percent of combination patients, but 12% of azacitidine alone subjects, had complete remissions (P = .0001). The median duration of response with combination therapy was 24.1 months, versus 12.1 months.
Enasidenib plus azacitidine subjects also had greater drops in mutant IDH2 variant allele frequency (median 83.4% versus 17.7%, P < .01) and levels of the downstream oncometabolite 2-hydroxyglutarate (97.8% versus 54.3%; P < .01).
However, median OS was 22 months in both arms (HR 0.99, 95% CI 0.52, 1.87, P = .97). Although median event-free survival favored the combination – 17.2 months versus 10.8 – the results were not statistically significant (HR 0.59, 95% CI 0.30, 1.17, P = .13).
A possible reason for the lack of survival benefit, Dr. DiNardo said, was that seven azacitidine-alone patients (21%) went on to enasidenib after leaving the study, most commonly for disease progression, which occurred in 31% of combination patients versus 52% in the azacitidine-alone arm.
Combination subjects had a median of 10 treatment cycles, vs. 7 in the azacitidine-alone group. Grade 3-4 adverse events included thrombocytopenia (37% combination, 19% azacitidine-alone), neutropenia (35% vs. 22%), anemia (19% vs. 22%), and febrile neutropenia (15% vs. 16%). Grade 3-4 infections were more common with azacitidine monotherapy (31% vs. 18%).
Twelve enasidenib/azacitidine subjects (18%) developed isocitrate dehydrogenase differentiation syndrome, a complication that carries a black box warning in enasidenib’s label.
The work was funded by enasidenib marketer Celgene. Dr. DiNardo is an adviser to, and receives research funding from, the company. Dr. Juliusson’s disclosures, if any, were not reported.
SOURCE: DiNardo CD et al. EHA Congress, abstract S139.
FROM EHA CONGRESS
HSCT may be best option for therapy-related ALL
Therapy-related acute lymphoblastic leukemia (tALL) is less common and less well known than therapy-related acute myeloid leukemia, but tALL also appears to be associated with poor-prognosis features, compared with de novo ALL, investigators said.
“Currently, this condition is not fully recognized by the [World Health Organization] classification, but it has emerged as a relevant and increasingly common form of ALL. There is no standardized therapy for tALL at this time due to the rarity of the condition. Therefore, more information regarding characteristics, prognosis, and treatment is needed,” wrote Brayan Merchán, MD, and colleagues at Princess Margaret Hospital in Toronto.
At their center, the median overall survival (OS) among 58 patients with tALL who received front line induction therapy was 13 months, although patients who were able to undergo hematopoietic stem cell transplant had a 400% longer OS than patients who did not receive HSCT, they reported in an electronic poster presented as part of the virtual annual congress of the European Hematology Association.
A hematologist-oncologist who has studied tALL agreed that it appears to be a distinct clinical entity from de novo ALL.
“It is distinct from the other ALL because the age [at diagnosis] is different, the cytogenetic and molecular profiles are different, and while responses are the same, it seems that survival is lower in cases who don’t go through bone marrow transplant as consolidation,” said Ibrahim Aldoss, MD, from City of Hope Medical Center in Duarte, Calif.
Dr. Aldoss, who was not involved in the study, was the lead author of a study published in 2018 which found that, “[a]lthough survival of therapy-related acute lymphoblastic leukemia was inferior to de novo cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities” (Haematologica. 2018 Oct; 103[10]:1662-8).
He noted that induction regimen options for patients with tALL may be limited because some patients may had previous exposures to cytotoxic chemotherapy agents – such as anthracyclines used in standard regimens for breast cancer – that have cumulative toxicities and lifetime dose limits.
In addition, “these patients tend to be older, because they went through another cancer and then developed therapy-related ALL, and usually they’re not eligible for pediatric-inspired regimens that we use more frequently in younger patients,” he said.
Retrospective study
Dr. Merchán and colleagues conducted a retrospective study of all consecutive adults with ALL treated at their center from 1999 to 2019 and followed until January 2020. Of this group, they identified 59 patients who had been exposed to chemotherapy or radiation for other diseases prior to their ALL diagnosis.
The mean age of the 59 patients (31 women and 28 men) was 54.7 years. In all, 34 had solid cancers and 25 had hematologic malignancies before their ALL diagnosis. The most common diagnosis was breast cancer in 15 patients, followed by multiple myeloma in 11, lymphoma in 7, and AML in 5. Other prior diagnoses were not specified.
Prior therapies included chemotherapy alone in 18 patients, radiotherapy alone in 19, and 20 had both treatment modalities (information about 2 remaining patients was not presented).
For the overall population the median time to tALL diagnosis was 5 years, but for 9 patients with the poor-prognosis MLL gene rearrangement the median time to tALL was just 21 months. The disease latency period was 21 months for patients who received chemotherapy, compared with 117 months for patients treated with radiotherapy.
The majority of patients (53) had B-phenotype ALL. Of the 49 for whom cytogenetic data were available, 41 had cytogenetic abnormalities, including the MLL rearrangement in 9, and complex karyotype in 7. Of all 59 patients, 12 had translocation t(9;22).
One patient did not undergo induction therapy for ALL because of poor performance status. All of the other patients received induction therapy, either a Dana-Farber Cancer Institute protocol in 44 patients, hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in 5, or blinatumomab in 3.
A complete response was seen in 41 patients (70%); 7 patients died during induction from causes attributed to therapy.
The mean follow-up for all patients was 27 months, and median overall survival was 13 months.
Median overall survival was 98 months for patients who underwent allogeneic HSCT versus a median of 19 months for patients who did not undergo transplant. This difference was not statistically significant, however, likely because of the small sample size.
Causes of death in 11 patients after transplant included relapse in 4 and graft-versus-host disease in 2 (other causes were not specified). Among the 34 patients who did not undergo HSCT following induction, 15 died from disease progression.
“From our results, tALL patients who were able to receive HSCT had better OS. Our data also supports the notion that tALL may be distinct entity with poor prognosis features compared to de novo ALL,” the investigators concluded.
The authors did not disclose a funding source. Dr. Merchán and Dr. Aldoss reported no relevant disclosures.
SOURCE: Merchán B et al. EHA25, Abstract EP391.
Therapy-related acute lymphoblastic leukemia (tALL) is less common and less well known than therapy-related acute myeloid leukemia, but tALL also appears to be associated with poor-prognosis features, compared with de novo ALL, investigators said.
“Currently, this condition is not fully recognized by the [World Health Organization] classification, but it has emerged as a relevant and increasingly common form of ALL. There is no standardized therapy for tALL at this time due to the rarity of the condition. Therefore, more information regarding characteristics, prognosis, and treatment is needed,” wrote Brayan Merchán, MD, and colleagues at Princess Margaret Hospital in Toronto.
At their center, the median overall survival (OS) among 58 patients with tALL who received front line induction therapy was 13 months, although patients who were able to undergo hematopoietic stem cell transplant had a 400% longer OS than patients who did not receive HSCT, they reported in an electronic poster presented as part of the virtual annual congress of the European Hematology Association.
A hematologist-oncologist who has studied tALL agreed that it appears to be a distinct clinical entity from de novo ALL.
“It is distinct from the other ALL because the age [at diagnosis] is different, the cytogenetic and molecular profiles are different, and while responses are the same, it seems that survival is lower in cases who don’t go through bone marrow transplant as consolidation,” said Ibrahim Aldoss, MD, from City of Hope Medical Center in Duarte, Calif.
Dr. Aldoss, who was not involved in the study, was the lead author of a study published in 2018 which found that, “[a]lthough survival of therapy-related acute lymphoblastic leukemia was inferior to de novo cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities” (Haematologica. 2018 Oct; 103[10]:1662-8).
He noted that induction regimen options for patients with tALL may be limited because some patients may had previous exposures to cytotoxic chemotherapy agents – such as anthracyclines used in standard regimens for breast cancer – that have cumulative toxicities and lifetime dose limits.
In addition, “these patients tend to be older, because they went through another cancer and then developed therapy-related ALL, and usually they’re not eligible for pediatric-inspired regimens that we use more frequently in younger patients,” he said.
Retrospective study
Dr. Merchán and colleagues conducted a retrospective study of all consecutive adults with ALL treated at their center from 1999 to 2019 and followed until January 2020. Of this group, they identified 59 patients who had been exposed to chemotherapy or radiation for other diseases prior to their ALL diagnosis.
The mean age of the 59 patients (31 women and 28 men) was 54.7 years. In all, 34 had solid cancers and 25 had hematologic malignancies before their ALL diagnosis. The most common diagnosis was breast cancer in 15 patients, followed by multiple myeloma in 11, lymphoma in 7, and AML in 5. Other prior diagnoses were not specified.
Prior therapies included chemotherapy alone in 18 patients, radiotherapy alone in 19, and 20 had both treatment modalities (information about 2 remaining patients was not presented).
For the overall population the median time to tALL diagnosis was 5 years, but for 9 patients with the poor-prognosis MLL gene rearrangement the median time to tALL was just 21 months. The disease latency period was 21 months for patients who received chemotherapy, compared with 117 months for patients treated with radiotherapy.
The majority of patients (53) had B-phenotype ALL. Of the 49 for whom cytogenetic data were available, 41 had cytogenetic abnormalities, including the MLL rearrangement in 9, and complex karyotype in 7. Of all 59 patients, 12 had translocation t(9;22).
One patient did not undergo induction therapy for ALL because of poor performance status. All of the other patients received induction therapy, either a Dana-Farber Cancer Institute protocol in 44 patients, hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in 5, or blinatumomab in 3.
A complete response was seen in 41 patients (70%); 7 patients died during induction from causes attributed to therapy.
The mean follow-up for all patients was 27 months, and median overall survival was 13 months.
Median overall survival was 98 months for patients who underwent allogeneic HSCT versus a median of 19 months for patients who did not undergo transplant. This difference was not statistically significant, however, likely because of the small sample size.
Causes of death in 11 patients after transplant included relapse in 4 and graft-versus-host disease in 2 (other causes were not specified). Among the 34 patients who did not undergo HSCT following induction, 15 died from disease progression.
“From our results, tALL patients who were able to receive HSCT had better OS. Our data also supports the notion that tALL may be distinct entity with poor prognosis features compared to de novo ALL,” the investigators concluded.
The authors did not disclose a funding source. Dr. Merchán and Dr. Aldoss reported no relevant disclosures.
SOURCE: Merchán B et al. EHA25, Abstract EP391.
Therapy-related acute lymphoblastic leukemia (tALL) is less common and less well known than therapy-related acute myeloid leukemia, but tALL also appears to be associated with poor-prognosis features, compared with de novo ALL, investigators said.
“Currently, this condition is not fully recognized by the [World Health Organization] classification, but it has emerged as a relevant and increasingly common form of ALL. There is no standardized therapy for tALL at this time due to the rarity of the condition. Therefore, more information regarding characteristics, prognosis, and treatment is needed,” wrote Brayan Merchán, MD, and colleagues at Princess Margaret Hospital in Toronto.
At their center, the median overall survival (OS) among 58 patients with tALL who received front line induction therapy was 13 months, although patients who were able to undergo hematopoietic stem cell transplant had a 400% longer OS than patients who did not receive HSCT, they reported in an electronic poster presented as part of the virtual annual congress of the European Hematology Association.
A hematologist-oncologist who has studied tALL agreed that it appears to be a distinct clinical entity from de novo ALL.
“It is distinct from the other ALL because the age [at diagnosis] is different, the cytogenetic and molecular profiles are different, and while responses are the same, it seems that survival is lower in cases who don’t go through bone marrow transplant as consolidation,” said Ibrahim Aldoss, MD, from City of Hope Medical Center in Duarte, Calif.
Dr. Aldoss, who was not involved in the study, was the lead author of a study published in 2018 which found that, “[a]lthough survival of therapy-related acute lymphoblastic leukemia was inferior to de novo cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities” (Haematologica. 2018 Oct; 103[10]:1662-8).
He noted that induction regimen options for patients with tALL may be limited because some patients may had previous exposures to cytotoxic chemotherapy agents – such as anthracyclines used in standard regimens for breast cancer – that have cumulative toxicities and lifetime dose limits.
In addition, “these patients tend to be older, because they went through another cancer and then developed therapy-related ALL, and usually they’re not eligible for pediatric-inspired regimens that we use more frequently in younger patients,” he said.
Retrospective study
Dr. Merchán and colleagues conducted a retrospective study of all consecutive adults with ALL treated at their center from 1999 to 2019 and followed until January 2020. Of this group, they identified 59 patients who had been exposed to chemotherapy or radiation for other diseases prior to their ALL diagnosis.
The mean age of the 59 patients (31 women and 28 men) was 54.7 years. In all, 34 had solid cancers and 25 had hematologic malignancies before their ALL diagnosis. The most common diagnosis was breast cancer in 15 patients, followed by multiple myeloma in 11, lymphoma in 7, and AML in 5. Other prior diagnoses were not specified.
Prior therapies included chemotherapy alone in 18 patients, radiotherapy alone in 19, and 20 had both treatment modalities (information about 2 remaining patients was not presented).
For the overall population the median time to tALL diagnosis was 5 years, but for 9 patients with the poor-prognosis MLL gene rearrangement the median time to tALL was just 21 months. The disease latency period was 21 months for patients who received chemotherapy, compared with 117 months for patients treated with radiotherapy.
The majority of patients (53) had B-phenotype ALL. Of the 49 for whom cytogenetic data were available, 41 had cytogenetic abnormalities, including the MLL rearrangement in 9, and complex karyotype in 7. Of all 59 patients, 12 had translocation t(9;22).
One patient did not undergo induction therapy for ALL because of poor performance status. All of the other patients received induction therapy, either a Dana-Farber Cancer Institute protocol in 44 patients, hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in 5, or blinatumomab in 3.
A complete response was seen in 41 patients (70%); 7 patients died during induction from causes attributed to therapy.
The mean follow-up for all patients was 27 months, and median overall survival was 13 months.
Median overall survival was 98 months for patients who underwent allogeneic HSCT versus a median of 19 months for patients who did not undergo transplant. This difference was not statistically significant, however, likely because of the small sample size.
Causes of death in 11 patients after transplant included relapse in 4 and graft-versus-host disease in 2 (other causes were not specified). Among the 34 patients who did not undergo HSCT following induction, 15 died from disease progression.
“From our results, tALL patients who were able to receive HSCT had better OS. Our data also supports the notion that tALL may be distinct entity with poor prognosis features compared to de novo ALL,” the investigators concluded.
The authors did not disclose a funding source. Dr. Merchán and Dr. Aldoss reported no relevant disclosures.
SOURCE: Merchán B et al. EHA25, Abstract EP391.
FROM EHA CONGRESS
Isa-Kd improves PFS in relapsed/refractory multiple myeloma
The risk of progression or death for patients with relapsed or refractory multiple myeloma was nearly halved with the addition of isatuximab to carfilzomib and dexamethasone, according to an interim analysis of the phase 3 IKEMA trial (NCT03275285).
After a median follow-up of 20.7 months, the median progression-free survival had not been reached for 179 patients treated with isatuximab (Sarclisa), carfilzomib (Kyprolis), and dexamethasone (together, known as Isa-Kd), compared with 19.5 months for 123 patients treated with carfilzomib and dexamethasone alone (Kd). The hazard ratio for progression free survival with the triple combination was 0.531 (P = .0007), reported coprincipal investigator Phillipe Moreau, MD, from the University Hospital Hôtel-Dieu in Nantes, France.
“The benefit of the triplet combination was observed across subgroups, including patients difficult to treat, such as [those with] high-risk cytogenetics or elderly patients,” he said in a late-breaking abstract presentation during the virtual annual congress of the European Hematology Association.
Isatuximab is an immunoglobulin G1 monoclonal antibody targeting a CD38 transmembrane glycoprotein on multiple myeloma cells, with a mechanism of action similar to that of another anti-CD38 antibody, daratumumab (Darzalex). Isatuximab is approved in the United States and Europe in combination with pomalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma after at least two prior lines of therapy.
A ‘me too’ agent?
It’s unclear, however, whether isatuximab offers any additional benefit over daratumumab, an agent approved for use both in front line therapy combinations and for patients with relapsed/refractory disease, said Brea C. Lipe, MD, a multiple myeloma specialist at the University of Rochester (N.Y.) Wilmot Cancer Institute, who was not involved in the study.
“Every time we get a new drug it’s nice to have another option, but it doesn’t really add anything different from daratumumab at this point,” she said in an interview.
Dr. Lipe noted the IKEMA results are similar to those seen in the phase 3 CANDOR trial, comparing carfilzomib, dexamethasone, and daratumumab to carfilzomib/dexamethasone alone in patients with relapsed/refractory myeloma. In addition, it’s unknown whether patients with disease that is refractory to daratumumab could benefit from isatuximab, she said.
Although isatuximab has been touted as offering more rapid and more convenient dosing than daratumumab, the introduction of rapid infusion and subcutaneous administration of daratumumab has negated any theoretical advantage of the newcomer, Dr. Lipe added.
Study details
In the IKEMA trial, 302 patients with relapsed/refractory multiple myeloma who’d received one to three prior lines of therapy were stratified by the number of prior lines and by revised Multiple Myeloma International Staging System (R-ISS) and were then randomized on a 3:2 basis to treatment with carfilzomib 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of cycle 1 and 56 mg/m2 on the corresponding days of each subsequent cycle plus dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle, with or without isatuximab. The antibody was dosed 10 mg/kg on days 1, 8, 15, and 22 in cycle 1 then every 2 weeks thereafter.
Treatments were continued until disease progression, unacceptable toxicity, or patient choice intervened.
At a prespecified interim analysis, the trial met its primary endpoint of a minimum 41% risk reduction in the hazard rate for progression free survival (PFS), with an actual risk reduction of 47%.
An analysis of PFS by subgroup showed significant benefits with the triple combination for patients aged 65 years and older, those with baseline estimated glomerular filtration rates below 60 mL/min per 1.73 m2, those with more than one prior line of therapy, those who had not previously received a proteasome inhibitor (e.g., bortezomib) or immunomodulatory agent (e.g., lenalidomide), those with high-risk cytogenetic status, and those with R-ISS stage II at study entry.
Overall response rates were similar between the study arms, at 86.6% with Isa-Kd and 82.9% with Kd, but the rate of very good partial responses or better was significantly higher with the triplet, at 72.6% versus 56.1% (P = .0011). The rate of minimal residual disease negativity was also significantly lower with Isa-Kd in the intent-to-treat population, at 29.6% versus 13%, respectively (P = .0004).
Overall survival data were not mature at the time of data cutoff and will be reported later, Dr. Moreau said.
Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 76.8% of patients on the triplet and 67.2% of those on Kd. The incidences of death, serious TEAEs, or adverse events leading to discontinuation of therapy did not differ markedly between the treatment arms, however. Grade 3 or greater cardiac failure occurred in seven patients treated with the triplet (4%) and five treated with Kd (4.1%); respective rates of grade 3 or greater hematologic abnormalities included anemia in 22% and 19.7%, neutropenia in 19.2% and 7.4%, and thrombocytopenia in 29.9% and 23.8%.
The primary completion date for the trial is estimated to occur in November 2020, with final results in November 2023.
The study was sponsored by Sanofi. Dr. Moreau disclosed honoraria and a consulting or advisory role with several companies, not including Sanofi. Dr. Lipe disclosed impending advisory board activity for Janssen.
SOURCE: Moreau P et al. EHA Congress, Abstract LB2603.
The risk of progression or death for patients with relapsed or refractory multiple myeloma was nearly halved with the addition of isatuximab to carfilzomib and dexamethasone, according to an interim analysis of the phase 3 IKEMA trial (NCT03275285).
After a median follow-up of 20.7 months, the median progression-free survival had not been reached for 179 patients treated with isatuximab (Sarclisa), carfilzomib (Kyprolis), and dexamethasone (together, known as Isa-Kd), compared with 19.5 months for 123 patients treated with carfilzomib and dexamethasone alone (Kd). The hazard ratio for progression free survival with the triple combination was 0.531 (P = .0007), reported coprincipal investigator Phillipe Moreau, MD, from the University Hospital Hôtel-Dieu in Nantes, France.
“The benefit of the triplet combination was observed across subgroups, including patients difficult to treat, such as [those with] high-risk cytogenetics or elderly patients,” he said in a late-breaking abstract presentation during the virtual annual congress of the European Hematology Association.
Isatuximab is an immunoglobulin G1 monoclonal antibody targeting a CD38 transmembrane glycoprotein on multiple myeloma cells, with a mechanism of action similar to that of another anti-CD38 antibody, daratumumab (Darzalex). Isatuximab is approved in the United States and Europe in combination with pomalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma after at least two prior lines of therapy.
A ‘me too’ agent?
It’s unclear, however, whether isatuximab offers any additional benefit over daratumumab, an agent approved for use both in front line therapy combinations and for patients with relapsed/refractory disease, said Brea C. Lipe, MD, a multiple myeloma specialist at the University of Rochester (N.Y.) Wilmot Cancer Institute, who was not involved in the study.
“Every time we get a new drug it’s nice to have another option, but it doesn’t really add anything different from daratumumab at this point,” she said in an interview.
Dr. Lipe noted the IKEMA results are similar to those seen in the phase 3 CANDOR trial, comparing carfilzomib, dexamethasone, and daratumumab to carfilzomib/dexamethasone alone in patients with relapsed/refractory myeloma. In addition, it’s unknown whether patients with disease that is refractory to daratumumab could benefit from isatuximab, she said.
Although isatuximab has been touted as offering more rapid and more convenient dosing than daratumumab, the introduction of rapid infusion and subcutaneous administration of daratumumab has negated any theoretical advantage of the newcomer, Dr. Lipe added.
Study details
In the IKEMA trial, 302 patients with relapsed/refractory multiple myeloma who’d received one to three prior lines of therapy were stratified by the number of prior lines and by revised Multiple Myeloma International Staging System (R-ISS) and were then randomized on a 3:2 basis to treatment with carfilzomib 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of cycle 1 and 56 mg/m2 on the corresponding days of each subsequent cycle plus dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle, with or without isatuximab. The antibody was dosed 10 mg/kg on days 1, 8, 15, and 22 in cycle 1 then every 2 weeks thereafter.
Treatments were continued until disease progression, unacceptable toxicity, or patient choice intervened.
At a prespecified interim analysis, the trial met its primary endpoint of a minimum 41% risk reduction in the hazard rate for progression free survival (PFS), with an actual risk reduction of 47%.
An analysis of PFS by subgroup showed significant benefits with the triple combination for patients aged 65 years and older, those with baseline estimated glomerular filtration rates below 60 mL/min per 1.73 m2, those with more than one prior line of therapy, those who had not previously received a proteasome inhibitor (e.g., bortezomib) or immunomodulatory agent (e.g., lenalidomide), those with high-risk cytogenetic status, and those with R-ISS stage II at study entry.
Overall response rates were similar between the study arms, at 86.6% with Isa-Kd and 82.9% with Kd, but the rate of very good partial responses or better was significantly higher with the triplet, at 72.6% versus 56.1% (P = .0011). The rate of minimal residual disease negativity was also significantly lower with Isa-Kd in the intent-to-treat population, at 29.6% versus 13%, respectively (P = .0004).
Overall survival data were not mature at the time of data cutoff and will be reported later, Dr. Moreau said.
Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 76.8% of patients on the triplet and 67.2% of those on Kd. The incidences of death, serious TEAEs, or adverse events leading to discontinuation of therapy did not differ markedly between the treatment arms, however. Grade 3 or greater cardiac failure occurred in seven patients treated with the triplet (4%) and five treated with Kd (4.1%); respective rates of grade 3 or greater hematologic abnormalities included anemia in 22% and 19.7%, neutropenia in 19.2% and 7.4%, and thrombocytopenia in 29.9% and 23.8%.
The primary completion date for the trial is estimated to occur in November 2020, with final results in November 2023.
The study was sponsored by Sanofi. Dr. Moreau disclosed honoraria and a consulting or advisory role with several companies, not including Sanofi. Dr. Lipe disclosed impending advisory board activity for Janssen.
SOURCE: Moreau P et al. EHA Congress, Abstract LB2603.
The risk of progression or death for patients with relapsed or refractory multiple myeloma was nearly halved with the addition of isatuximab to carfilzomib and dexamethasone, according to an interim analysis of the phase 3 IKEMA trial (NCT03275285).
After a median follow-up of 20.7 months, the median progression-free survival had not been reached for 179 patients treated with isatuximab (Sarclisa), carfilzomib (Kyprolis), and dexamethasone (together, known as Isa-Kd), compared with 19.5 months for 123 patients treated with carfilzomib and dexamethasone alone (Kd). The hazard ratio for progression free survival with the triple combination was 0.531 (P = .0007), reported coprincipal investigator Phillipe Moreau, MD, from the University Hospital Hôtel-Dieu in Nantes, France.
“The benefit of the triplet combination was observed across subgroups, including patients difficult to treat, such as [those with] high-risk cytogenetics or elderly patients,” he said in a late-breaking abstract presentation during the virtual annual congress of the European Hematology Association.
Isatuximab is an immunoglobulin G1 monoclonal antibody targeting a CD38 transmembrane glycoprotein on multiple myeloma cells, with a mechanism of action similar to that of another anti-CD38 antibody, daratumumab (Darzalex). Isatuximab is approved in the United States and Europe in combination with pomalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma after at least two prior lines of therapy.
A ‘me too’ agent?
It’s unclear, however, whether isatuximab offers any additional benefit over daratumumab, an agent approved for use both in front line therapy combinations and for patients with relapsed/refractory disease, said Brea C. Lipe, MD, a multiple myeloma specialist at the University of Rochester (N.Y.) Wilmot Cancer Institute, who was not involved in the study.
“Every time we get a new drug it’s nice to have another option, but it doesn’t really add anything different from daratumumab at this point,” she said in an interview.
Dr. Lipe noted the IKEMA results are similar to those seen in the phase 3 CANDOR trial, comparing carfilzomib, dexamethasone, and daratumumab to carfilzomib/dexamethasone alone in patients with relapsed/refractory myeloma. In addition, it’s unknown whether patients with disease that is refractory to daratumumab could benefit from isatuximab, she said.
Although isatuximab has been touted as offering more rapid and more convenient dosing than daratumumab, the introduction of rapid infusion and subcutaneous administration of daratumumab has negated any theoretical advantage of the newcomer, Dr. Lipe added.
Study details
In the IKEMA trial, 302 patients with relapsed/refractory multiple myeloma who’d received one to three prior lines of therapy were stratified by the number of prior lines and by revised Multiple Myeloma International Staging System (R-ISS) and were then randomized on a 3:2 basis to treatment with carfilzomib 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of cycle 1 and 56 mg/m2 on the corresponding days of each subsequent cycle plus dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle, with or without isatuximab. The antibody was dosed 10 mg/kg on days 1, 8, 15, and 22 in cycle 1 then every 2 weeks thereafter.
Treatments were continued until disease progression, unacceptable toxicity, or patient choice intervened.
At a prespecified interim analysis, the trial met its primary endpoint of a minimum 41% risk reduction in the hazard rate for progression free survival (PFS), with an actual risk reduction of 47%.
An analysis of PFS by subgroup showed significant benefits with the triple combination for patients aged 65 years and older, those with baseline estimated glomerular filtration rates below 60 mL/min per 1.73 m2, those with more than one prior line of therapy, those who had not previously received a proteasome inhibitor (e.g., bortezomib) or immunomodulatory agent (e.g., lenalidomide), those with high-risk cytogenetic status, and those with R-ISS stage II at study entry.
Overall response rates were similar between the study arms, at 86.6% with Isa-Kd and 82.9% with Kd, but the rate of very good partial responses or better was significantly higher with the triplet, at 72.6% versus 56.1% (P = .0011). The rate of minimal residual disease negativity was also significantly lower with Isa-Kd in the intent-to-treat population, at 29.6% versus 13%, respectively (P = .0004).
Overall survival data were not mature at the time of data cutoff and will be reported later, Dr. Moreau said.
Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 76.8% of patients on the triplet and 67.2% of those on Kd. The incidences of death, serious TEAEs, or adverse events leading to discontinuation of therapy did not differ markedly between the treatment arms, however. Grade 3 or greater cardiac failure occurred in seven patients treated with the triplet (4%) and five treated with Kd (4.1%); respective rates of grade 3 or greater hematologic abnormalities included anemia in 22% and 19.7%, neutropenia in 19.2% and 7.4%, and thrombocytopenia in 29.9% and 23.8%.
The primary completion date for the trial is estimated to occur in November 2020, with final results in November 2023.
The study was sponsored by Sanofi. Dr. Moreau disclosed honoraria and a consulting or advisory role with several companies, not including Sanofi. Dr. Lipe disclosed impending advisory board activity for Janssen.
SOURCE: Moreau P et al. EHA Congress, Abstract LB2603.
FROM EHA CONGRESS
Ibrutinib-venetoclax produces high MRD-negative rates in CLL/SLL
In patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a once-daily oral regimen of ibrutinib and venetoclax was associated with deep molecular remissions in both bone marrow and peripheral blood, including in patients with high-risk disease, according to investigators in the phase 2 CAPTIVATE MRD trial.
An intention-to-treat analysis of 164 patients with CLL/SLL treated with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed a 75% rate of minimal residual disease (MRD) negativity in peripheral blood, and a 68% rate of MRD negativity in bone marrow among patients who received up to 12 cycles of the combination, reported Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif., and colleagues.
“This phase 2 study supports synergistic antitumor activity of the combination with notable deep responses across multiple compartments,” she said in an oral presentation during the virtual annual congress of the European Hematology Association.
Not ready to change practice
A hematologist/oncologist who was not involved in the study said that the data from CAPTIVATE MRD look good, but it’s still not known whether concurrent or sequential administration of the agents is optimal, and whether other regimens may be more effective in the first line.
“I think this is promising, but the informative and practice-changing study would be to compare this combination to ibrutinib monotherapy or to venetoclax and obinutuzumab, and that’s actually the subject of the next large German cooperative group study, CLL17,” said Catherine C. Coombs, MD, assistant professor of medicine at the University of North Carolina, and the UNC Lineberger Cancer Center, Chapel Hill.
She noted that the combination of venetoclax and obinutuzumab (Gazyva) is also associated with high rates of MRD negativity in the first-line setting, and that use of this regimen allows clinicians to reserve ibrutinib or acalabrutinib (Calquence) for patients in the relapsed setting.
Prerandomization results
Dr. Siddiqi presented prerandomization results from the MRD cohort of the CAPTIVATE trial (NCT02910583), which is evaluating the combination of ibrutinib and venetoclax for depth of MRD response. Following 12 cycles of the combinations, patients in this cohort are then randomized based on confirmed MRD status, with patients who are MRD negative randomized to maintenance with either ibrutinib or placebo, and patients with residual disease (MRD positive) randomized to maintenance with either ibrutinib alone or with venetoclax.
A total of 164 patients with previously untreated CLL/SLL and active disease requiring treatment who were under age 70 and had good performance status were enrolled. Following an ibrutinib lead-in period with the drug given at 420 mg once daily for three cycles of 28 days, the patients were continued on ibrutinib, and were started on venetoclax with a ramp up to 400 mg once daily, for 12 additional cycles.
As planned, patients were assessed after 15 cycles for tumor lysis syndrome (TLS) risk assessment, MRD, and hematologic, clinical, imaging, and bone marrow exams for response.
The median patient age was 58, with poor-risk features such as deletion 17p seen in 16%, complex karyotype in 19%, and unmutated immunoglobulin heavy chain variable (IGHV) in 59%.
A total of 152 patients (90%) completed all 12 cycles of the combined agents, with a median treatment duration of 14.7 months on ibrutinib and 12 months on venetoclax. Eight patients had adverse events leading to discontinuation, but there were no treatment-related deaths.
A majority of patients had reductions in lymph node burden after the three-cycle ibrutinib lead in. TLS risk also decreased during the lead-in period, with 90% of patients who had a high baseline TLS risk shifting to medium or low-risk categories, and no patients moved into the high-risk category.
“Hospitalization because of this was no longer required in 66% of at-risk patients after three cycles of ibrutinib lead in, and 82% of patients initiated venetoclax ramp up without the need for hospitalization,” Dr. Siddiqi said.
The best response of undetectable MRD was seen in peripheral blood of 75% of 163 evaluable patients, and in bone marrow of 72% of 155 patients. As noted before, the respective rates of MRD negativity in the intention-to-treat population were 75% and 68%. The proportion of patients with undetectable MRD in peripheral blood increased over time, from 57% after six cycles of the combination, she said.
The overall response rate was 97%, including 51% complete responses (CR) or CR with incomplete bone marrow recovery (CRi), and 46% partial (PR) or nodular PR (nPR). Among patients with CR/CRi, 85% had undetectable MRD in peripheral blood and 80% were MRD negative in bone marrow. In patients with PR/nPR, the respective rates were 69% and 59%. The high rates of undetectable MRD were seen irrespective of baseline disease characteristics, including bulky disease, cytogenetic risk category, del(17p) or TP53 mutation, and complex karyotype.
The most common adverse events with the combination were grade 1 or 2 diarrhea, arthralgia, fatigue, headache, and nausea. Grade 3 neutropenia was seen in 17% of patients, and grade 4 neutropenia was seen in 16%. Grade 3 febrile neutropenia and laboratory confirmed TLS occurred in 2 patients each (1%), and there were no grade 4 instances of either adverse event.
Postrandomization follow-up and analyses are currently being conducted, and results will be reported at a future meeting, real or virtual. An analysis of data on a separate cohort of 159 patients treated with the ibrutinib-venetoclax combination for a fixed duration is currently ongoing.
Dr. Siddiqi disclosed research funding and speakers bureau activity for Pharmacyclics, which sponsored the study, and others, as well as consulting/advising for several companies. Dr. Coombs disclosed consulting for AbbVie.
SOURCE: Siddiqi T et al. EHA25. Abstract S158.
In patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a once-daily oral regimen of ibrutinib and venetoclax was associated with deep molecular remissions in both bone marrow and peripheral blood, including in patients with high-risk disease, according to investigators in the phase 2 CAPTIVATE MRD trial.
An intention-to-treat analysis of 164 patients with CLL/SLL treated with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed a 75% rate of minimal residual disease (MRD) negativity in peripheral blood, and a 68% rate of MRD negativity in bone marrow among patients who received up to 12 cycles of the combination, reported Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif., and colleagues.
“This phase 2 study supports synergistic antitumor activity of the combination with notable deep responses across multiple compartments,” she said in an oral presentation during the virtual annual congress of the European Hematology Association.
Not ready to change practice
A hematologist/oncologist who was not involved in the study said that the data from CAPTIVATE MRD look good, but it’s still not known whether concurrent or sequential administration of the agents is optimal, and whether other regimens may be more effective in the first line.
“I think this is promising, but the informative and practice-changing study would be to compare this combination to ibrutinib monotherapy or to venetoclax and obinutuzumab, and that’s actually the subject of the next large German cooperative group study, CLL17,” said Catherine C. Coombs, MD, assistant professor of medicine at the University of North Carolina, and the UNC Lineberger Cancer Center, Chapel Hill.
She noted that the combination of venetoclax and obinutuzumab (Gazyva) is also associated with high rates of MRD negativity in the first-line setting, and that use of this regimen allows clinicians to reserve ibrutinib or acalabrutinib (Calquence) for patients in the relapsed setting.
Prerandomization results
Dr. Siddiqi presented prerandomization results from the MRD cohort of the CAPTIVATE trial (NCT02910583), which is evaluating the combination of ibrutinib and venetoclax for depth of MRD response. Following 12 cycles of the combinations, patients in this cohort are then randomized based on confirmed MRD status, with patients who are MRD negative randomized to maintenance with either ibrutinib or placebo, and patients with residual disease (MRD positive) randomized to maintenance with either ibrutinib alone or with venetoclax.
A total of 164 patients with previously untreated CLL/SLL and active disease requiring treatment who were under age 70 and had good performance status were enrolled. Following an ibrutinib lead-in period with the drug given at 420 mg once daily for three cycles of 28 days, the patients were continued on ibrutinib, and were started on venetoclax with a ramp up to 400 mg once daily, for 12 additional cycles.
As planned, patients were assessed after 15 cycles for tumor lysis syndrome (TLS) risk assessment, MRD, and hematologic, clinical, imaging, and bone marrow exams for response.
The median patient age was 58, with poor-risk features such as deletion 17p seen in 16%, complex karyotype in 19%, and unmutated immunoglobulin heavy chain variable (IGHV) in 59%.
A total of 152 patients (90%) completed all 12 cycles of the combined agents, with a median treatment duration of 14.7 months on ibrutinib and 12 months on venetoclax. Eight patients had adverse events leading to discontinuation, but there were no treatment-related deaths.
A majority of patients had reductions in lymph node burden after the three-cycle ibrutinib lead in. TLS risk also decreased during the lead-in period, with 90% of patients who had a high baseline TLS risk shifting to medium or low-risk categories, and no patients moved into the high-risk category.
“Hospitalization because of this was no longer required in 66% of at-risk patients after three cycles of ibrutinib lead in, and 82% of patients initiated venetoclax ramp up without the need for hospitalization,” Dr. Siddiqi said.
The best response of undetectable MRD was seen in peripheral blood of 75% of 163 evaluable patients, and in bone marrow of 72% of 155 patients. As noted before, the respective rates of MRD negativity in the intention-to-treat population were 75% and 68%. The proportion of patients with undetectable MRD in peripheral blood increased over time, from 57% after six cycles of the combination, she said.
The overall response rate was 97%, including 51% complete responses (CR) or CR with incomplete bone marrow recovery (CRi), and 46% partial (PR) or nodular PR (nPR). Among patients with CR/CRi, 85% had undetectable MRD in peripheral blood and 80% were MRD negative in bone marrow. In patients with PR/nPR, the respective rates were 69% and 59%. The high rates of undetectable MRD were seen irrespective of baseline disease characteristics, including bulky disease, cytogenetic risk category, del(17p) or TP53 mutation, and complex karyotype.
The most common adverse events with the combination were grade 1 or 2 diarrhea, arthralgia, fatigue, headache, and nausea. Grade 3 neutropenia was seen in 17% of patients, and grade 4 neutropenia was seen in 16%. Grade 3 febrile neutropenia and laboratory confirmed TLS occurred in 2 patients each (1%), and there were no grade 4 instances of either adverse event.
Postrandomization follow-up and analyses are currently being conducted, and results will be reported at a future meeting, real or virtual. An analysis of data on a separate cohort of 159 patients treated with the ibrutinib-venetoclax combination for a fixed duration is currently ongoing.
Dr. Siddiqi disclosed research funding and speakers bureau activity for Pharmacyclics, which sponsored the study, and others, as well as consulting/advising for several companies. Dr. Coombs disclosed consulting for AbbVie.
SOURCE: Siddiqi T et al. EHA25. Abstract S158.
In patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a once-daily oral regimen of ibrutinib and venetoclax was associated with deep molecular remissions in both bone marrow and peripheral blood, including in patients with high-risk disease, according to investigators in the phase 2 CAPTIVATE MRD trial.
An intention-to-treat analysis of 164 patients with CLL/SLL treated with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed a 75% rate of minimal residual disease (MRD) negativity in peripheral blood, and a 68% rate of MRD negativity in bone marrow among patients who received up to 12 cycles of the combination, reported Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif., and colleagues.
“This phase 2 study supports synergistic antitumor activity of the combination with notable deep responses across multiple compartments,” she said in an oral presentation during the virtual annual congress of the European Hematology Association.
Not ready to change practice
A hematologist/oncologist who was not involved in the study said that the data from CAPTIVATE MRD look good, but it’s still not known whether concurrent or sequential administration of the agents is optimal, and whether other regimens may be more effective in the first line.
“I think this is promising, but the informative and practice-changing study would be to compare this combination to ibrutinib monotherapy or to venetoclax and obinutuzumab, and that’s actually the subject of the next large German cooperative group study, CLL17,” said Catherine C. Coombs, MD, assistant professor of medicine at the University of North Carolina, and the UNC Lineberger Cancer Center, Chapel Hill.
She noted that the combination of venetoclax and obinutuzumab (Gazyva) is also associated with high rates of MRD negativity in the first-line setting, and that use of this regimen allows clinicians to reserve ibrutinib or acalabrutinib (Calquence) for patients in the relapsed setting.
Prerandomization results
Dr. Siddiqi presented prerandomization results from the MRD cohort of the CAPTIVATE trial (NCT02910583), which is evaluating the combination of ibrutinib and venetoclax for depth of MRD response. Following 12 cycles of the combinations, patients in this cohort are then randomized based on confirmed MRD status, with patients who are MRD negative randomized to maintenance with either ibrutinib or placebo, and patients with residual disease (MRD positive) randomized to maintenance with either ibrutinib alone or with venetoclax.
A total of 164 patients with previously untreated CLL/SLL and active disease requiring treatment who were under age 70 and had good performance status were enrolled. Following an ibrutinib lead-in period with the drug given at 420 mg once daily for three cycles of 28 days, the patients were continued on ibrutinib, and were started on venetoclax with a ramp up to 400 mg once daily, for 12 additional cycles.
As planned, patients were assessed after 15 cycles for tumor lysis syndrome (TLS) risk assessment, MRD, and hematologic, clinical, imaging, and bone marrow exams for response.
The median patient age was 58, with poor-risk features such as deletion 17p seen in 16%, complex karyotype in 19%, and unmutated immunoglobulin heavy chain variable (IGHV) in 59%.
A total of 152 patients (90%) completed all 12 cycles of the combined agents, with a median treatment duration of 14.7 months on ibrutinib and 12 months on venetoclax. Eight patients had adverse events leading to discontinuation, but there were no treatment-related deaths.
A majority of patients had reductions in lymph node burden after the three-cycle ibrutinib lead in. TLS risk also decreased during the lead-in period, with 90% of patients who had a high baseline TLS risk shifting to medium or low-risk categories, and no patients moved into the high-risk category.
“Hospitalization because of this was no longer required in 66% of at-risk patients after three cycles of ibrutinib lead in, and 82% of patients initiated venetoclax ramp up without the need for hospitalization,” Dr. Siddiqi said.
The best response of undetectable MRD was seen in peripheral blood of 75% of 163 evaluable patients, and in bone marrow of 72% of 155 patients. As noted before, the respective rates of MRD negativity in the intention-to-treat population were 75% and 68%. The proportion of patients with undetectable MRD in peripheral blood increased over time, from 57% after six cycles of the combination, she said.
The overall response rate was 97%, including 51% complete responses (CR) or CR with incomplete bone marrow recovery (CRi), and 46% partial (PR) or nodular PR (nPR). Among patients with CR/CRi, 85% had undetectable MRD in peripheral blood and 80% were MRD negative in bone marrow. In patients with PR/nPR, the respective rates were 69% and 59%. The high rates of undetectable MRD were seen irrespective of baseline disease characteristics, including bulky disease, cytogenetic risk category, del(17p) or TP53 mutation, and complex karyotype.
The most common adverse events with the combination were grade 1 or 2 diarrhea, arthralgia, fatigue, headache, and nausea. Grade 3 neutropenia was seen in 17% of patients, and grade 4 neutropenia was seen in 16%. Grade 3 febrile neutropenia and laboratory confirmed TLS occurred in 2 patients each (1%), and there were no grade 4 instances of either adverse event.
Postrandomization follow-up and analyses are currently being conducted, and results will be reported at a future meeting, real or virtual. An analysis of data on a separate cohort of 159 patients treated with the ibrutinib-venetoclax combination for a fixed duration is currently ongoing.
Dr. Siddiqi disclosed research funding and speakers bureau activity for Pharmacyclics, which sponsored the study, and others, as well as consulting/advising for several companies. Dr. Coombs disclosed consulting for AbbVie.
SOURCE: Siddiqi T et al. EHA25. Abstract S158.
FROM EHA 2020
VIALE-A confirms survival benefit for venetoclax-azacitidine in hard-to-treat AML
Adding venetoclax to azacitidine significantly extended survival of patients with previously untreated acute myeloid leukemia (AML) who were ineligible for standard induction therapy, results of the phase 3 VIALE-A trial showed.
Median overall survival for patients treated with venetoclax (Venclexta) and azacitidine was 14.7 months, compared with 9.6 months for patients who received azacitidine with a placebo, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Cancer Center, Houston.
“The combination of [azacitidine] and [venetoclax] was associated with statistically significant and clinically meaningful improvements in overall survival, response rates, duration of remission, and transfusion independence, representing a true paradigm shift in the treatment of our older patients with AML,” she said in a late-breaking abstract presentation at the virtual annual congress of the European Hematology Association.
Patients with newly diagnosed AML who are aged 75 years and older or have significant comorbidities are often not able to withstand the rigors of standard induction therapy for AML and have instead been treated with low-dose hypomethylating agents or cytarabine, but these therapies typically are associated with inferior outcomes, Dr. DiNardo said.
Venetoclax has shown good single-agent activity against relapsed/refractory AML. Early efficacy results of a phase 1b study, reported at the 2017 EHA Congress, showed that, among 100 patients age 65 years and older with previously untreated AML, the combination of venetoclax with either decitabine or azacitidine was associated with a 69% overall response rate, and that older patients were able to tolerate the regimen.
No surprise
The results of the VIALE-A study merely confirm what hematologists/oncologists have known for several years, said Joshua F. Zeidner, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
“Most leukemia clinicians have been using this regimen as a standard of care prior to these results,” he said in an interview. Dr. Zeidner was not involved in the study.
In November 2018, the Food and Drug Administration granted accelerated approval to venetoclax in combination with either azacitidine or decitabine or low-dose cytarabine in adults with newly diagnosed AML who because of age or comorbidities were ineligible for standard intensive induction regimens. Dr. Zeidner noted, however, that there are still questions about the combination in this population that need further exploration.
Despite being labeled as a “low-intensity” therapy, “I think low intensity is sort of a misnomer here,” he said. “It’s very challenging to give this regimen in the community because of all of the cytopenias, a high degree of transfusion dependence that these patients have, at least in the first few cycles, and all the rigorous laboratory monitoring and drug interactions that are common with venetoclax really lead to a lot of challenges in the community.”
Also still unanswered are questions about how to dose patients with early responses who have potential dose-limiting toxicities such as neutropenia and thrombocytopenia, he said.
It’s also unclear whether patients will require hospitalization during the ramp-up phase of venetoclax, as was done in some clinical trials, because of risk of tumor lysis syndrome. In the VIALE-A study, however, there were only three minor biochemical cases of tumor lysis syndrome in the experimental arm, and none of these cases required dose modification or treatment discontinuation.
“This begets the question whether patients need to be hospitalized at for the initiation of this treatment,” Dr. Zeidner said. Additional studies will also be needed to see whether certain subgroups of patients would be likely to derive particular benefit from venetoclax plus azacitidine, such as patients with IDH1 or IDH2 somatic mutations.
Randomized confirmatory trial
The VIALE-A study was a randomized, placebo-controlled trial designed to put the early promise of the combination to the test.
Investigators enrolled 433 adults with newly diagnosed AML who were ineligible for induction therapy either because they were 75 or older or were younger than 75 but had one or more of the following comorbidities: heart failure requiring treatment or a left ventricular ejection fraction of 50% or less, chronic stable angina, diffusion lung capacity for carbon monoxide of 65% or less or forced expiratory volume in 1 second of 65% or less, or Eastern Cooperative Oncology Group performance status score of 2-3.
After stratification by age, cytogenetic risk, and geographic region, the patients were randomized in a 2:1 fashion to receive azacitidine 75 mg/m2 either subcutaneously or intravenously on days 1-7 of each 28-day cycle, plus either oral venetoclax 400 mg daily following a 3-day ramp up in the first cycle (286 patients) or placebo (145 patients).
The median age in each arm was 76 years. Approximately 75% of patients in each arm had de novo AML.
Approximately half of all patients in each arm has bone marrow blast counts of 50% or greater. Two-thirds of patients had intermediate cytogenetic risk and one-third had poor risk disease. Somatic mutation rates, including mutations in IDH1/2, FLT3, NPM1 and TP53, were roughly comparable between the arms.
As noted before, median overall survival, the primary endpoint, was significantly longer with venetoclax, at 14.7 versus 9.6 months, translating into a hazard ratio for death with venetoclax of 0.66 (P < .001).
Although the numbers were relatively small, an analysis of overall survival by subgroups showed either a significant advantage or trend favoring venetoclax in all subgroups, notably among patients with difficult-to-treat disease, including patients 75 years and older and those with secondary AML, Dr. DiNardo said.
The combined complete response and CR with incomplete recovery (CRi) response rate was 66.4% with venetoclax, compared with 28.3% with azacitidine alone. The median time to a CR/CRi was shorter with the combination at 1.3 versus 2.8 months for azacitidine plus placebo, and the median duration of a CR/CRi response was longer, at 17.5 versus 13.4 months, respectively.
Response rates were also notably higher with venetoclax in all cytogenetic risk, AML subtype, molecular mutation, age, ECOG score, and bone marrow blast subgroups.
Additionally, significantly more patients treated with venetoclax/azacitidine were transfusion independent for a minimum of 8 weeks for platelets or combined red cells and platelets, Dr. DiNardo noted.
Median event-free survival – time from randomization to relapse, death, or treatment failure – was 9.8 months in the venetoclax arm versus 7 months in the placebo arm (HR, 0.63; P < .001).
All patients experienced at least one treatment-emergent adverse event. Grade 3 or greater hematologic adverse events were seen 82% of patients in the venetoclax arm and 68% in the placebo arm. The respective rates of grade 3 or greater neutropenia were 42% versus 29%, and febrile neutropenia were 42% versus 19%. Thrombocytopenia, anemia, and leukopenia rates were also higher among patients who received venetoclax.
Grade 1-2 gastrointestinal events were the most frequent nonhematologic adverse events. There was no increase in early deaths seen with the study combination.
The study was supported by AbbVie and Genentech. Dr. DiNardo disclosed research funding from and advisory board activities for those companies and from others. Dr. Zeidner disclosed serving on an independent review committee for AbbVie and advisory board activity for Genentech and others.
SOURCE: DiNardo C et al. EHA25, Abstract LB2601.
Adding venetoclax to azacitidine significantly extended survival of patients with previously untreated acute myeloid leukemia (AML) who were ineligible for standard induction therapy, results of the phase 3 VIALE-A trial showed.
Median overall survival for patients treated with venetoclax (Venclexta) and azacitidine was 14.7 months, compared with 9.6 months for patients who received azacitidine with a placebo, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Cancer Center, Houston.
“The combination of [azacitidine] and [venetoclax] was associated with statistically significant and clinically meaningful improvements in overall survival, response rates, duration of remission, and transfusion independence, representing a true paradigm shift in the treatment of our older patients with AML,” she said in a late-breaking abstract presentation at the virtual annual congress of the European Hematology Association.
Patients with newly diagnosed AML who are aged 75 years and older or have significant comorbidities are often not able to withstand the rigors of standard induction therapy for AML and have instead been treated with low-dose hypomethylating agents or cytarabine, but these therapies typically are associated with inferior outcomes, Dr. DiNardo said.
Venetoclax has shown good single-agent activity against relapsed/refractory AML. Early efficacy results of a phase 1b study, reported at the 2017 EHA Congress, showed that, among 100 patients age 65 years and older with previously untreated AML, the combination of venetoclax with either decitabine or azacitidine was associated with a 69% overall response rate, and that older patients were able to tolerate the regimen.
No surprise
The results of the VIALE-A study merely confirm what hematologists/oncologists have known for several years, said Joshua F. Zeidner, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
“Most leukemia clinicians have been using this regimen as a standard of care prior to these results,” he said in an interview. Dr. Zeidner was not involved in the study.
In November 2018, the Food and Drug Administration granted accelerated approval to venetoclax in combination with either azacitidine or decitabine or low-dose cytarabine in adults with newly diagnosed AML who because of age or comorbidities were ineligible for standard intensive induction regimens. Dr. Zeidner noted, however, that there are still questions about the combination in this population that need further exploration.
Despite being labeled as a “low-intensity” therapy, “I think low intensity is sort of a misnomer here,” he said. “It’s very challenging to give this regimen in the community because of all of the cytopenias, a high degree of transfusion dependence that these patients have, at least in the first few cycles, and all the rigorous laboratory monitoring and drug interactions that are common with venetoclax really lead to a lot of challenges in the community.”
Also still unanswered are questions about how to dose patients with early responses who have potential dose-limiting toxicities such as neutropenia and thrombocytopenia, he said.
It’s also unclear whether patients will require hospitalization during the ramp-up phase of venetoclax, as was done in some clinical trials, because of risk of tumor lysis syndrome. In the VIALE-A study, however, there were only three minor biochemical cases of tumor lysis syndrome in the experimental arm, and none of these cases required dose modification or treatment discontinuation.
“This begets the question whether patients need to be hospitalized at for the initiation of this treatment,” Dr. Zeidner said. Additional studies will also be needed to see whether certain subgroups of patients would be likely to derive particular benefit from venetoclax plus azacitidine, such as patients with IDH1 or IDH2 somatic mutations.
Randomized confirmatory trial
The VIALE-A study was a randomized, placebo-controlled trial designed to put the early promise of the combination to the test.
Investigators enrolled 433 adults with newly diagnosed AML who were ineligible for induction therapy either because they were 75 or older or were younger than 75 but had one or more of the following comorbidities: heart failure requiring treatment or a left ventricular ejection fraction of 50% or less, chronic stable angina, diffusion lung capacity for carbon monoxide of 65% or less or forced expiratory volume in 1 second of 65% or less, or Eastern Cooperative Oncology Group performance status score of 2-3.
After stratification by age, cytogenetic risk, and geographic region, the patients were randomized in a 2:1 fashion to receive azacitidine 75 mg/m2 either subcutaneously or intravenously on days 1-7 of each 28-day cycle, plus either oral venetoclax 400 mg daily following a 3-day ramp up in the first cycle (286 patients) or placebo (145 patients).
The median age in each arm was 76 years. Approximately 75% of patients in each arm had de novo AML.
Approximately half of all patients in each arm has bone marrow blast counts of 50% or greater. Two-thirds of patients had intermediate cytogenetic risk and one-third had poor risk disease. Somatic mutation rates, including mutations in IDH1/2, FLT3, NPM1 and TP53, were roughly comparable between the arms.
As noted before, median overall survival, the primary endpoint, was significantly longer with venetoclax, at 14.7 versus 9.6 months, translating into a hazard ratio for death with venetoclax of 0.66 (P < .001).
Although the numbers were relatively small, an analysis of overall survival by subgroups showed either a significant advantage or trend favoring venetoclax in all subgroups, notably among patients with difficult-to-treat disease, including patients 75 years and older and those with secondary AML, Dr. DiNardo said.
The combined complete response and CR with incomplete recovery (CRi) response rate was 66.4% with venetoclax, compared with 28.3% with azacitidine alone. The median time to a CR/CRi was shorter with the combination at 1.3 versus 2.8 months for azacitidine plus placebo, and the median duration of a CR/CRi response was longer, at 17.5 versus 13.4 months, respectively.
Response rates were also notably higher with venetoclax in all cytogenetic risk, AML subtype, molecular mutation, age, ECOG score, and bone marrow blast subgroups.
Additionally, significantly more patients treated with venetoclax/azacitidine were transfusion independent for a minimum of 8 weeks for platelets or combined red cells and platelets, Dr. DiNardo noted.
Median event-free survival – time from randomization to relapse, death, or treatment failure – was 9.8 months in the venetoclax arm versus 7 months in the placebo arm (HR, 0.63; P < .001).
All patients experienced at least one treatment-emergent adverse event. Grade 3 or greater hematologic adverse events were seen 82% of patients in the venetoclax arm and 68% in the placebo arm. The respective rates of grade 3 or greater neutropenia were 42% versus 29%, and febrile neutropenia were 42% versus 19%. Thrombocytopenia, anemia, and leukopenia rates were also higher among patients who received venetoclax.
Grade 1-2 gastrointestinal events were the most frequent nonhematologic adverse events. There was no increase in early deaths seen with the study combination.
The study was supported by AbbVie and Genentech. Dr. DiNardo disclosed research funding from and advisory board activities for those companies and from others. Dr. Zeidner disclosed serving on an independent review committee for AbbVie and advisory board activity for Genentech and others.
SOURCE: DiNardo C et al. EHA25, Abstract LB2601.
Adding venetoclax to azacitidine significantly extended survival of patients with previously untreated acute myeloid leukemia (AML) who were ineligible for standard induction therapy, results of the phase 3 VIALE-A trial showed.
Median overall survival for patients treated with venetoclax (Venclexta) and azacitidine was 14.7 months, compared with 9.6 months for patients who received azacitidine with a placebo, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Cancer Center, Houston.
“The combination of [azacitidine] and [venetoclax] was associated with statistically significant and clinically meaningful improvements in overall survival, response rates, duration of remission, and transfusion independence, representing a true paradigm shift in the treatment of our older patients with AML,” she said in a late-breaking abstract presentation at the virtual annual congress of the European Hematology Association.
Patients with newly diagnosed AML who are aged 75 years and older or have significant comorbidities are often not able to withstand the rigors of standard induction therapy for AML and have instead been treated with low-dose hypomethylating agents or cytarabine, but these therapies typically are associated with inferior outcomes, Dr. DiNardo said.
Venetoclax has shown good single-agent activity against relapsed/refractory AML. Early efficacy results of a phase 1b study, reported at the 2017 EHA Congress, showed that, among 100 patients age 65 years and older with previously untreated AML, the combination of venetoclax with either decitabine or azacitidine was associated with a 69% overall response rate, and that older patients were able to tolerate the regimen.
No surprise
The results of the VIALE-A study merely confirm what hematologists/oncologists have known for several years, said Joshua F. Zeidner, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
“Most leukemia clinicians have been using this regimen as a standard of care prior to these results,” he said in an interview. Dr. Zeidner was not involved in the study.
In November 2018, the Food and Drug Administration granted accelerated approval to venetoclax in combination with either azacitidine or decitabine or low-dose cytarabine in adults with newly diagnosed AML who because of age or comorbidities were ineligible for standard intensive induction regimens. Dr. Zeidner noted, however, that there are still questions about the combination in this population that need further exploration.
Despite being labeled as a “low-intensity” therapy, “I think low intensity is sort of a misnomer here,” he said. “It’s very challenging to give this regimen in the community because of all of the cytopenias, a high degree of transfusion dependence that these patients have, at least in the first few cycles, and all the rigorous laboratory monitoring and drug interactions that are common with venetoclax really lead to a lot of challenges in the community.”
Also still unanswered are questions about how to dose patients with early responses who have potential dose-limiting toxicities such as neutropenia and thrombocytopenia, he said.
It’s also unclear whether patients will require hospitalization during the ramp-up phase of venetoclax, as was done in some clinical trials, because of risk of tumor lysis syndrome. In the VIALE-A study, however, there were only three minor biochemical cases of tumor lysis syndrome in the experimental arm, and none of these cases required dose modification or treatment discontinuation.
“This begets the question whether patients need to be hospitalized at for the initiation of this treatment,” Dr. Zeidner said. Additional studies will also be needed to see whether certain subgroups of patients would be likely to derive particular benefit from venetoclax plus azacitidine, such as patients with IDH1 or IDH2 somatic mutations.
Randomized confirmatory trial
The VIALE-A study was a randomized, placebo-controlled trial designed to put the early promise of the combination to the test.
Investigators enrolled 433 adults with newly diagnosed AML who were ineligible for induction therapy either because they were 75 or older or were younger than 75 but had one or more of the following comorbidities: heart failure requiring treatment or a left ventricular ejection fraction of 50% or less, chronic stable angina, diffusion lung capacity for carbon monoxide of 65% or less or forced expiratory volume in 1 second of 65% or less, or Eastern Cooperative Oncology Group performance status score of 2-3.
After stratification by age, cytogenetic risk, and geographic region, the patients were randomized in a 2:1 fashion to receive azacitidine 75 mg/m2 either subcutaneously or intravenously on days 1-7 of each 28-day cycle, plus either oral venetoclax 400 mg daily following a 3-day ramp up in the first cycle (286 patients) or placebo (145 patients).
The median age in each arm was 76 years. Approximately 75% of patients in each arm had de novo AML.
Approximately half of all patients in each arm has bone marrow blast counts of 50% or greater. Two-thirds of patients had intermediate cytogenetic risk and one-third had poor risk disease. Somatic mutation rates, including mutations in IDH1/2, FLT3, NPM1 and TP53, were roughly comparable between the arms.
As noted before, median overall survival, the primary endpoint, was significantly longer with venetoclax, at 14.7 versus 9.6 months, translating into a hazard ratio for death with venetoclax of 0.66 (P < .001).
Although the numbers were relatively small, an analysis of overall survival by subgroups showed either a significant advantage or trend favoring venetoclax in all subgroups, notably among patients with difficult-to-treat disease, including patients 75 years and older and those with secondary AML, Dr. DiNardo said.
The combined complete response and CR with incomplete recovery (CRi) response rate was 66.4% with venetoclax, compared with 28.3% with azacitidine alone. The median time to a CR/CRi was shorter with the combination at 1.3 versus 2.8 months for azacitidine plus placebo, and the median duration of a CR/CRi response was longer, at 17.5 versus 13.4 months, respectively.
Response rates were also notably higher with venetoclax in all cytogenetic risk, AML subtype, molecular mutation, age, ECOG score, and bone marrow blast subgroups.
Additionally, significantly more patients treated with venetoclax/azacitidine were transfusion independent for a minimum of 8 weeks for platelets or combined red cells and platelets, Dr. DiNardo noted.
Median event-free survival – time from randomization to relapse, death, or treatment failure – was 9.8 months in the venetoclax arm versus 7 months in the placebo arm (HR, 0.63; P < .001).
All patients experienced at least one treatment-emergent adverse event. Grade 3 or greater hematologic adverse events were seen 82% of patients in the venetoclax arm and 68% in the placebo arm. The respective rates of grade 3 or greater neutropenia were 42% versus 29%, and febrile neutropenia were 42% versus 19%. Thrombocytopenia, anemia, and leukopenia rates were also higher among patients who received venetoclax.
Grade 1-2 gastrointestinal events were the most frequent nonhematologic adverse events. There was no increase in early deaths seen with the study combination.
The study was supported by AbbVie and Genentech. Dr. DiNardo disclosed research funding from and advisory board activities for those companies and from others. Dr. Zeidner disclosed serving on an independent review committee for AbbVie and advisory board activity for Genentech and others.
SOURCE: DiNardo C et al. EHA25, Abstract LB2601.
FROM EHA CONGRESS
Safe to skip radiotherapy with negative PET in Hodgkin lymphoma
and can skip the additional radiotherapy that is normally included in the combined modality treatment, say experts reporting the final results from an international phase 3 randomized trial dubbed HD17.
“Most patients with this disease will not need radiotherapy any longer,” concluded first author Peter Borchmann, MD, assistant medical director in the department of hematology/oncology at the University Hospital Cologne (Germany).
Dr. Borchmann was speaking online as part of the virtual edition of the European Hematology Association 25th Annual Congress 2020.
“Importantly, the mortality of patients with early-stage unfavorable Hodgkin lymphoma in the HD17 study did not differ from the normal healthy German population, and this is the first time we have had this finding in one of our studies,” he emphasized.
Dr. Borchmann added that positron emission tomography imaging is key in deciding which patients can skip radiation.
“We conclude from the HD17 trial that the combined modality concept can and should be replaced by a PET-guided omission of radiotherapy for patients with newly diagnosed early-stage unfavorable Hodgkin lymphoma,” he said.
“The vast majority of early-stage unfavorable Hodgkin lymphoma patients can be treated with the brief and highly effective 2+2 chemotherapy alone,” he added.
Therefore, he continued, “PET-guided 2+2 chemotherapy is the new standard of care for the German Hodgkin study group,” which conducted the trial.
The use of both chemotherapy and radiation has long been a standard approach to treatment, and this combined modality treatment is highly effective, Dr. Borchmann explained. But it can cause long-term damage, and the known longer-term negative effects of radiotherapy, such as cardiovascular disease and second malignancies, are a particular concern because patients with early-stage Hodgkin lymphoma are relatively young, with a median age of around 30 years at disease onset.
An expert approached for comment said that the momentum to skip radiotherapy when possible is an ongoing issue, and importantly, this study adds to those efforts.
“The treatment of Hodgkin lymphoma has moved for many years now to less radiation therapy, and this trend will continue with the results of this study,” commented John G. Gribben, MD, director of the Stem Cell Transplantation Program and medical director of the North East London Cancer Research Network Centre at Barts Cancer Center of Excellence and the London School of Medicine.
“We have moved to lower doses and involved fields with the intent of decreasing toxicity, and particularly long-term toxicity from radiotherapy,” he said in an interview.
HD17 study details
For the multicenter, phase 3 HD17 trial, Dr. Borchmann and colleagues turned to PET to identify patients who had and had not responded well to chemotherapy (PET negative and PET positive) and to determine if those who had responded well could safely avoid radiotherapy without compromising efficacy.
“We wanted to determine if we could reduce the treatment intensity by omission of radiotherapy in patients who respond very well to the systemic treatment, so who have a complete metabolic remission after the chemotherapy,” Dr. Borchmann said.
The 2+2 treatment approach includes two cycles of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and two subsequent cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).
The trial enrolled 1,100 patients with newly diagnosed Hodgkin lymphoma between January 2012 and March 2017. Of these, 979 patients had confirmed PET results, with 651 (66.5%) found to be PET negative, defined as having a Deauville score (DS) of less than 3 (DS3); 238 (24.3%) were DS3, and 90 (9.2%) were DS4.
The study met its primary endpoint of noninferiority in progression-free survival (PFS) at 5 years, with a PFS of 95.1% in the PET-guided group (n = 447), compared with 97.3% in the standard combined-modality treatment group (n = 428), over a median observation time of 45 months, for a difference of 2.2% (P = .12).
“We found that the survival levels were very high, and we can safely conclude the noninferiority of the PET-guided approach in PET-negative patients,” Dr. Borchmann said.
A further analysis showed that the 597 PET-negative patients who did not receive radiotherapy because of their PET status had 5-year PFS that was noninferior to the combined modality group (95.9% vs. 97.7%, respectively; P = .20).
And among 646 patients who received the 2+2 regimen plus radiotherapy, of those confirmed as PET positive (n = 328), the estimated 5-year PFS was significantly lower (94.2%), compared with those determined to be PET negative (n = 318; 97.6%; hazard ratio, 3.03).
A cut-off of DS4 for positivity was associated with a stronger effect, with a lower estimated 5-year PFS of 81.6% vs. 98.8% for DS3 patients and 97.6% for DS less than 3 (P < .0001).
“Only DS4 has a prognostic impact, but not DS3,” Dr. Borchmann said. “DS4 positivity indicates a relevant risk for treatment failure, however, there are few patients in this risk group (9.2% in this trial).”
The 5-year overall survival rates in an intent-to-treat analysis were 98.8% in the standard combined modality group and 98.4% in the PET-guided group.
With a median observation time of 47 months, there have been 10 fatal events in the trial out of 1,100 patients, including two Hodgkin lymphoma-related events and one treatment-related death.
“Overall, Hodgkin lymphoma or treatment-related mortality rates were extremely low,” Dr. Borchmann said.
The study was funded by Deutsche Krebshilfe. Dr. Borchmann and Dr. Gribben have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
and can skip the additional radiotherapy that is normally included in the combined modality treatment, say experts reporting the final results from an international phase 3 randomized trial dubbed HD17.
“Most patients with this disease will not need radiotherapy any longer,” concluded first author Peter Borchmann, MD, assistant medical director in the department of hematology/oncology at the University Hospital Cologne (Germany).
Dr. Borchmann was speaking online as part of the virtual edition of the European Hematology Association 25th Annual Congress 2020.
“Importantly, the mortality of patients with early-stage unfavorable Hodgkin lymphoma in the HD17 study did not differ from the normal healthy German population, and this is the first time we have had this finding in one of our studies,” he emphasized.
Dr. Borchmann added that positron emission tomography imaging is key in deciding which patients can skip radiation.
“We conclude from the HD17 trial that the combined modality concept can and should be replaced by a PET-guided omission of radiotherapy for patients with newly diagnosed early-stage unfavorable Hodgkin lymphoma,” he said.
“The vast majority of early-stage unfavorable Hodgkin lymphoma patients can be treated with the brief and highly effective 2+2 chemotherapy alone,” he added.
Therefore, he continued, “PET-guided 2+2 chemotherapy is the new standard of care for the German Hodgkin study group,” which conducted the trial.
The use of both chemotherapy and radiation has long been a standard approach to treatment, and this combined modality treatment is highly effective, Dr. Borchmann explained. But it can cause long-term damage, and the known longer-term negative effects of radiotherapy, such as cardiovascular disease and second malignancies, are a particular concern because patients with early-stage Hodgkin lymphoma are relatively young, with a median age of around 30 years at disease onset.
An expert approached for comment said that the momentum to skip radiotherapy when possible is an ongoing issue, and importantly, this study adds to those efforts.
“The treatment of Hodgkin lymphoma has moved for many years now to less radiation therapy, and this trend will continue with the results of this study,” commented John G. Gribben, MD, director of the Stem Cell Transplantation Program and medical director of the North East London Cancer Research Network Centre at Barts Cancer Center of Excellence and the London School of Medicine.
“We have moved to lower doses and involved fields with the intent of decreasing toxicity, and particularly long-term toxicity from radiotherapy,” he said in an interview.
HD17 study details
For the multicenter, phase 3 HD17 trial, Dr. Borchmann and colleagues turned to PET to identify patients who had and had not responded well to chemotherapy (PET negative and PET positive) and to determine if those who had responded well could safely avoid radiotherapy without compromising efficacy.
“We wanted to determine if we could reduce the treatment intensity by omission of radiotherapy in patients who respond very well to the systemic treatment, so who have a complete metabolic remission after the chemotherapy,” Dr. Borchmann said.
The 2+2 treatment approach includes two cycles of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and two subsequent cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).
The trial enrolled 1,100 patients with newly diagnosed Hodgkin lymphoma between January 2012 and March 2017. Of these, 979 patients had confirmed PET results, with 651 (66.5%) found to be PET negative, defined as having a Deauville score (DS) of less than 3 (DS3); 238 (24.3%) were DS3, and 90 (9.2%) were DS4.
The study met its primary endpoint of noninferiority in progression-free survival (PFS) at 5 years, with a PFS of 95.1% in the PET-guided group (n = 447), compared with 97.3% in the standard combined-modality treatment group (n = 428), over a median observation time of 45 months, for a difference of 2.2% (P = .12).
“We found that the survival levels were very high, and we can safely conclude the noninferiority of the PET-guided approach in PET-negative patients,” Dr. Borchmann said.
A further analysis showed that the 597 PET-negative patients who did not receive radiotherapy because of their PET status had 5-year PFS that was noninferior to the combined modality group (95.9% vs. 97.7%, respectively; P = .20).
And among 646 patients who received the 2+2 regimen plus radiotherapy, of those confirmed as PET positive (n = 328), the estimated 5-year PFS was significantly lower (94.2%), compared with those determined to be PET negative (n = 318; 97.6%; hazard ratio, 3.03).
A cut-off of DS4 for positivity was associated with a stronger effect, with a lower estimated 5-year PFS of 81.6% vs. 98.8% for DS3 patients and 97.6% for DS less than 3 (P < .0001).
“Only DS4 has a prognostic impact, but not DS3,” Dr. Borchmann said. “DS4 positivity indicates a relevant risk for treatment failure, however, there are few patients in this risk group (9.2% in this trial).”
The 5-year overall survival rates in an intent-to-treat analysis were 98.8% in the standard combined modality group and 98.4% in the PET-guided group.
With a median observation time of 47 months, there have been 10 fatal events in the trial out of 1,100 patients, including two Hodgkin lymphoma-related events and one treatment-related death.
“Overall, Hodgkin lymphoma or treatment-related mortality rates were extremely low,” Dr. Borchmann said.
The study was funded by Deutsche Krebshilfe. Dr. Borchmann and Dr. Gribben have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
and can skip the additional radiotherapy that is normally included in the combined modality treatment, say experts reporting the final results from an international phase 3 randomized trial dubbed HD17.
“Most patients with this disease will not need radiotherapy any longer,” concluded first author Peter Borchmann, MD, assistant medical director in the department of hematology/oncology at the University Hospital Cologne (Germany).
Dr. Borchmann was speaking online as part of the virtual edition of the European Hematology Association 25th Annual Congress 2020.
“Importantly, the mortality of patients with early-stage unfavorable Hodgkin lymphoma in the HD17 study did not differ from the normal healthy German population, and this is the first time we have had this finding in one of our studies,” he emphasized.
Dr. Borchmann added that positron emission tomography imaging is key in deciding which patients can skip radiation.
“We conclude from the HD17 trial that the combined modality concept can and should be replaced by a PET-guided omission of radiotherapy for patients with newly diagnosed early-stage unfavorable Hodgkin lymphoma,” he said.
“The vast majority of early-stage unfavorable Hodgkin lymphoma patients can be treated with the brief and highly effective 2+2 chemotherapy alone,” he added.
Therefore, he continued, “PET-guided 2+2 chemotherapy is the new standard of care for the German Hodgkin study group,” which conducted the trial.
The use of both chemotherapy and radiation has long been a standard approach to treatment, and this combined modality treatment is highly effective, Dr. Borchmann explained. But it can cause long-term damage, and the known longer-term negative effects of radiotherapy, such as cardiovascular disease and second malignancies, are a particular concern because patients with early-stage Hodgkin lymphoma are relatively young, with a median age of around 30 years at disease onset.
An expert approached for comment said that the momentum to skip radiotherapy when possible is an ongoing issue, and importantly, this study adds to those efforts.
“The treatment of Hodgkin lymphoma has moved for many years now to less radiation therapy, and this trend will continue with the results of this study,” commented John G. Gribben, MD, director of the Stem Cell Transplantation Program and medical director of the North East London Cancer Research Network Centre at Barts Cancer Center of Excellence and the London School of Medicine.
“We have moved to lower doses and involved fields with the intent of decreasing toxicity, and particularly long-term toxicity from radiotherapy,” he said in an interview.
HD17 study details
For the multicenter, phase 3 HD17 trial, Dr. Borchmann and colleagues turned to PET to identify patients who had and had not responded well to chemotherapy (PET negative and PET positive) and to determine if those who had responded well could safely avoid radiotherapy without compromising efficacy.
“We wanted to determine if we could reduce the treatment intensity by omission of radiotherapy in patients who respond very well to the systemic treatment, so who have a complete metabolic remission after the chemotherapy,” Dr. Borchmann said.
The 2+2 treatment approach includes two cycles of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and two subsequent cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).
The trial enrolled 1,100 patients with newly diagnosed Hodgkin lymphoma between January 2012 and March 2017. Of these, 979 patients had confirmed PET results, with 651 (66.5%) found to be PET negative, defined as having a Deauville score (DS) of less than 3 (DS3); 238 (24.3%) were DS3, and 90 (9.2%) were DS4.
The study met its primary endpoint of noninferiority in progression-free survival (PFS) at 5 years, with a PFS of 95.1% in the PET-guided group (n = 447), compared with 97.3% in the standard combined-modality treatment group (n = 428), over a median observation time of 45 months, for a difference of 2.2% (P = .12).
“We found that the survival levels were very high, and we can safely conclude the noninferiority of the PET-guided approach in PET-negative patients,” Dr. Borchmann said.
A further analysis showed that the 597 PET-negative patients who did not receive radiotherapy because of their PET status had 5-year PFS that was noninferior to the combined modality group (95.9% vs. 97.7%, respectively; P = .20).
And among 646 patients who received the 2+2 regimen plus radiotherapy, of those confirmed as PET positive (n = 328), the estimated 5-year PFS was significantly lower (94.2%), compared with those determined to be PET negative (n = 318; 97.6%; hazard ratio, 3.03).
A cut-off of DS4 for positivity was associated with a stronger effect, with a lower estimated 5-year PFS of 81.6% vs. 98.8% for DS3 patients and 97.6% for DS less than 3 (P < .0001).
“Only DS4 has a prognostic impact, but not DS3,” Dr. Borchmann said. “DS4 positivity indicates a relevant risk for treatment failure, however, there are few patients in this risk group (9.2% in this trial).”
The 5-year overall survival rates in an intent-to-treat analysis were 98.8% in the standard combined modality group and 98.4% in the PET-guided group.
With a median observation time of 47 months, there have been 10 fatal events in the trial out of 1,100 patients, including two Hodgkin lymphoma-related events and one treatment-related death.
“Overall, Hodgkin lymphoma or treatment-related mortality rates were extremely low,” Dr. Borchmann said.
The study was funded by Deutsche Krebshilfe. Dr. Borchmann and Dr. Gribben have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Omitting whole body irradiation before HSCT: Trial stopped early
Hematopoietic stem cell transplantation (HSCT) may offer the chance of a cure for patients with leukemia and other blood cancers, but the process of preparing the body to receive such a transplant can be brutal, involving whole body irradiation as well as chemotherapy conditioning. New results show that both steps are needed: a trial that omitted whole body irradiation in young patients with acute lymphoblastic leukemia (ALL) was stopped early because of significantly poorer outcomes.
The multicenter, global FORUM (For Omitting Radiation Under Majority Age) trial involved 75 centers in 17 countries between 2013 and 2018.
“Our study shows significantly better outcomes for total body irradiation compared to myeloablative chemo-conditioning arms, with no differences between the [two] chemo-conditioning groups,” concluded Christina Peters, MD, professor of pediatrics in the department of stem cell transplantation at St Anna Children’s Hospital in Vienna.
, she added.
Dr. Peters presented the findings as part of the virtual annual congress of the European Hematology Association.
Describing the results as “sobering,” session comoderator Shai Izraeli, MD, director of the department of hematology-oncology at Schneider Children’s Medical Center, in Petah Tikva, Israel, said an online comment from the virtual meeting audience reflected the reaction to these unwelcome results: “So we are still stuck with total body irradiation?”
Dr. Peters said the good news is that the number of patients needing to undergo stem cell transplants is low, and with research advances, may hopefully drop even further.
“Only 10% of patients under the age of 18 nowadays undergo allogeneic HSCT, and perhaps in the future that will become even less if we are able to rescue some of the groups with other immunological measures such as CAR-T cells and antibodies,” she said.
“I think it is very important to better identify those who really need total body irradiation in the future,” she added.
In an interview, Dr. Izraeli agreed.
“The prognosis of children after bone marrow transplantation is excellent – the majority are cured from their leukemia,” he said. “And we have to remember that those who undergo bone marrow transplant have the worst leukemias.”
He pointed out that, in fact, contemporary chemotherapy alone is effective in the treatment of more than 90% of patients with ALL younger than aged 18.
For the 10% of patients who do not respond to chemotherapy alone and undergo allogeneic HSCT, about 50%-80% of pediatric patients who have resistant leukemia are cured. However, the total body irradiation used to prepare the body to receive the transplant is linked to potentially serious consequences later in life, including sterility, lung problems, growth retardation, and secondary cancer.
To determine if the irradiation component could be safely replaced with a chemotherapy-based conditioning approach, Dr. Peters and colleagues conducted the FORUM trial.
In total 413 patients undergoing HSCT were enrolled and randomized to pretransplant conditioning with total body irradiation and etoposide (n = 202) or a chemotherapy-only approach with fludarabine/thiotepa/busulfan (flu/thio/bu; n = 99) or fludarabine/thiotepa/treosulfan (treo; n = 93).
Most patients (72%) had B-cell precursor ALL and 23% had T-cell ALL. Just over half (54%) were transplanted in first complete remission (CR1), 40% in CR2, and 4% in CR3.
The source of stem cells was bone marrow for most patients (82%); peripheral blood stem cell for 12%, and cord blood for 4%.
Study stopped early
The aim of the study was to demonstrate noninferiority with the chemotherapy approach.
However, the significantly inferior outcome observed in the chemotherapy-only group led to randomization being halted in March 2019.
The 2-year overall survival in the intent-to-treat (ITT) analysis, with a mean observation time of 2.1 years, was 0.75 ± 0.04 for chemo-conditioning versus 0.91 ± 0.02 for total body irradiation/etoposide (ITT P < .001).
The ITT analysis showed relapses were significantly higher in the chemo-conditioning group (2-year cumulative incidence of relapse [CIR], 0.33) compared with the total body irradiation group (CIR, 0.12; P < .001).
The 2-year event-free survival (EFS) rate was also significantly higher in the total body irradiation group (0.86 vs 0.58; P < .001), and transplant-related mortality over 2 years was lower with total body irradiation (0.02 vs 0.09; P = .02).
A per-protocol analysis showed the 2-year overall survival to be the same in the two chemotherapy groups (both 0.77 ± 0.05) compared with 0.91 ± 0.02 in the total body irradiation group (P = .003).
“In this cohort [the 91% overall survival rate] may even be lower than contemporary intensive frontline therapy results that are achieved nowadays,” Dr. Peters said.
In looking at subgroups, there were no significant differences according to age group or cancer phenotype, while MLL rearrangement was associated with higher relapse incidence.
Remission status was found to notably influence EFS, dropping from 0.91 in CR1 patients with total body irradiation to 0.76 in CR2 patients. However, total body irradiation remained significantly higher compared with the chemo-conditioning groups in CR1 (P = .004) and CR2 (P < .001).
Transplant-related mortality was not significantly different between the total body irradiation and chemo-conditioning groups in the CR1 or CR2 groups (P = .09 and P = .18, respectively), despite the significant difference when remission status was not included.
Overall, “we tried to identify subgroups in which total body irradiation might be eliminated, however in all analyses, total body irradiation was better than chemo-conditioning in all arms,” Dr. Peters said.
Meanwhile, the findings underscore that even when patients cannot receive total body irradiation, the alternative chemo-conditioning therapy in fact shows favorable efficacy on its own, Dr. Izraeli said.
“The prognosis of the chemotherapy group is also quite remarkably good, although less than the total body irradiation arm. This means that if for some reason total body irradiation cannot be given, the chemotherapy is a very reasonable alternative.”
Dr. Peters has reported relationships with Amgen, Novartis, Pfizer, Medac, Jazz, and Neovii. Dr. Izraeli has reported no relevant financial relationships.
SOURCE: EHA Congress. Abstract S102.
A version of this article originally appeared on Medscape.com.
Hematopoietic stem cell transplantation (HSCT) may offer the chance of a cure for patients with leukemia and other blood cancers, but the process of preparing the body to receive such a transplant can be brutal, involving whole body irradiation as well as chemotherapy conditioning. New results show that both steps are needed: a trial that omitted whole body irradiation in young patients with acute lymphoblastic leukemia (ALL) was stopped early because of significantly poorer outcomes.
The multicenter, global FORUM (For Omitting Radiation Under Majority Age) trial involved 75 centers in 17 countries between 2013 and 2018.
“Our study shows significantly better outcomes for total body irradiation compared to myeloablative chemo-conditioning arms, with no differences between the [two] chemo-conditioning groups,” concluded Christina Peters, MD, professor of pediatrics in the department of stem cell transplantation at St Anna Children’s Hospital in Vienna.
, she added.
Dr. Peters presented the findings as part of the virtual annual congress of the European Hematology Association.
Describing the results as “sobering,” session comoderator Shai Izraeli, MD, director of the department of hematology-oncology at Schneider Children’s Medical Center, in Petah Tikva, Israel, said an online comment from the virtual meeting audience reflected the reaction to these unwelcome results: “So we are still stuck with total body irradiation?”
Dr. Peters said the good news is that the number of patients needing to undergo stem cell transplants is low, and with research advances, may hopefully drop even further.
“Only 10% of patients under the age of 18 nowadays undergo allogeneic HSCT, and perhaps in the future that will become even less if we are able to rescue some of the groups with other immunological measures such as CAR-T cells and antibodies,” she said.
“I think it is very important to better identify those who really need total body irradiation in the future,” she added.
In an interview, Dr. Izraeli agreed.
“The prognosis of children after bone marrow transplantation is excellent – the majority are cured from their leukemia,” he said. “And we have to remember that those who undergo bone marrow transplant have the worst leukemias.”
He pointed out that, in fact, contemporary chemotherapy alone is effective in the treatment of more than 90% of patients with ALL younger than aged 18.
For the 10% of patients who do not respond to chemotherapy alone and undergo allogeneic HSCT, about 50%-80% of pediatric patients who have resistant leukemia are cured. However, the total body irradiation used to prepare the body to receive the transplant is linked to potentially serious consequences later in life, including sterility, lung problems, growth retardation, and secondary cancer.
To determine if the irradiation component could be safely replaced with a chemotherapy-based conditioning approach, Dr. Peters and colleagues conducted the FORUM trial.
In total 413 patients undergoing HSCT were enrolled and randomized to pretransplant conditioning with total body irradiation and etoposide (n = 202) or a chemotherapy-only approach with fludarabine/thiotepa/busulfan (flu/thio/bu; n = 99) or fludarabine/thiotepa/treosulfan (treo; n = 93).
Most patients (72%) had B-cell precursor ALL and 23% had T-cell ALL. Just over half (54%) were transplanted in first complete remission (CR1), 40% in CR2, and 4% in CR3.
The source of stem cells was bone marrow for most patients (82%); peripheral blood stem cell for 12%, and cord blood for 4%.
Study stopped early
The aim of the study was to demonstrate noninferiority with the chemotherapy approach.
However, the significantly inferior outcome observed in the chemotherapy-only group led to randomization being halted in March 2019.
The 2-year overall survival in the intent-to-treat (ITT) analysis, with a mean observation time of 2.1 years, was 0.75 ± 0.04 for chemo-conditioning versus 0.91 ± 0.02 for total body irradiation/etoposide (ITT P < .001).
The ITT analysis showed relapses were significantly higher in the chemo-conditioning group (2-year cumulative incidence of relapse [CIR], 0.33) compared with the total body irradiation group (CIR, 0.12; P < .001).
The 2-year event-free survival (EFS) rate was also significantly higher in the total body irradiation group (0.86 vs 0.58; P < .001), and transplant-related mortality over 2 years was lower with total body irradiation (0.02 vs 0.09; P = .02).
A per-protocol analysis showed the 2-year overall survival to be the same in the two chemotherapy groups (both 0.77 ± 0.05) compared with 0.91 ± 0.02 in the total body irradiation group (P = .003).
“In this cohort [the 91% overall survival rate] may even be lower than contemporary intensive frontline therapy results that are achieved nowadays,” Dr. Peters said.
In looking at subgroups, there were no significant differences according to age group or cancer phenotype, while MLL rearrangement was associated with higher relapse incidence.
Remission status was found to notably influence EFS, dropping from 0.91 in CR1 patients with total body irradiation to 0.76 in CR2 patients. However, total body irradiation remained significantly higher compared with the chemo-conditioning groups in CR1 (P = .004) and CR2 (P < .001).
Transplant-related mortality was not significantly different between the total body irradiation and chemo-conditioning groups in the CR1 or CR2 groups (P = .09 and P = .18, respectively), despite the significant difference when remission status was not included.
Overall, “we tried to identify subgroups in which total body irradiation might be eliminated, however in all analyses, total body irradiation was better than chemo-conditioning in all arms,” Dr. Peters said.
Meanwhile, the findings underscore that even when patients cannot receive total body irradiation, the alternative chemo-conditioning therapy in fact shows favorable efficacy on its own, Dr. Izraeli said.
“The prognosis of the chemotherapy group is also quite remarkably good, although less than the total body irradiation arm. This means that if for some reason total body irradiation cannot be given, the chemotherapy is a very reasonable alternative.”
Dr. Peters has reported relationships with Amgen, Novartis, Pfizer, Medac, Jazz, and Neovii. Dr. Izraeli has reported no relevant financial relationships.
SOURCE: EHA Congress. Abstract S102.
A version of this article originally appeared on Medscape.com.
Hematopoietic stem cell transplantation (HSCT) may offer the chance of a cure for patients with leukemia and other blood cancers, but the process of preparing the body to receive such a transplant can be brutal, involving whole body irradiation as well as chemotherapy conditioning. New results show that both steps are needed: a trial that omitted whole body irradiation in young patients with acute lymphoblastic leukemia (ALL) was stopped early because of significantly poorer outcomes.
The multicenter, global FORUM (For Omitting Radiation Under Majority Age) trial involved 75 centers in 17 countries between 2013 and 2018.
“Our study shows significantly better outcomes for total body irradiation compared to myeloablative chemo-conditioning arms, with no differences between the [two] chemo-conditioning groups,” concluded Christina Peters, MD, professor of pediatrics in the department of stem cell transplantation at St Anna Children’s Hospital in Vienna.
, she added.
Dr. Peters presented the findings as part of the virtual annual congress of the European Hematology Association.
Describing the results as “sobering,” session comoderator Shai Izraeli, MD, director of the department of hematology-oncology at Schneider Children’s Medical Center, in Petah Tikva, Israel, said an online comment from the virtual meeting audience reflected the reaction to these unwelcome results: “So we are still stuck with total body irradiation?”
Dr. Peters said the good news is that the number of patients needing to undergo stem cell transplants is low, and with research advances, may hopefully drop even further.
“Only 10% of patients under the age of 18 nowadays undergo allogeneic HSCT, and perhaps in the future that will become even less if we are able to rescue some of the groups with other immunological measures such as CAR-T cells and antibodies,” she said.
“I think it is very important to better identify those who really need total body irradiation in the future,” she added.
In an interview, Dr. Izraeli agreed.
“The prognosis of children after bone marrow transplantation is excellent – the majority are cured from their leukemia,” he said. “And we have to remember that those who undergo bone marrow transplant have the worst leukemias.”
He pointed out that, in fact, contemporary chemotherapy alone is effective in the treatment of more than 90% of patients with ALL younger than aged 18.
For the 10% of patients who do not respond to chemotherapy alone and undergo allogeneic HSCT, about 50%-80% of pediatric patients who have resistant leukemia are cured. However, the total body irradiation used to prepare the body to receive the transplant is linked to potentially serious consequences later in life, including sterility, lung problems, growth retardation, and secondary cancer.
To determine if the irradiation component could be safely replaced with a chemotherapy-based conditioning approach, Dr. Peters and colleagues conducted the FORUM trial.
In total 413 patients undergoing HSCT were enrolled and randomized to pretransplant conditioning with total body irradiation and etoposide (n = 202) or a chemotherapy-only approach with fludarabine/thiotepa/busulfan (flu/thio/bu; n = 99) or fludarabine/thiotepa/treosulfan (treo; n = 93).
Most patients (72%) had B-cell precursor ALL and 23% had T-cell ALL. Just over half (54%) were transplanted in first complete remission (CR1), 40% in CR2, and 4% in CR3.
The source of stem cells was bone marrow for most patients (82%); peripheral blood stem cell for 12%, and cord blood for 4%.
Study stopped early
The aim of the study was to demonstrate noninferiority with the chemotherapy approach.
However, the significantly inferior outcome observed in the chemotherapy-only group led to randomization being halted in March 2019.
The 2-year overall survival in the intent-to-treat (ITT) analysis, with a mean observation time of 2.1 years, was 0.75 ± 0.04 for chemo-conditioning versus 0.91 ± 0.02 for total body irradiation/etoposide (ITT P < .001).
The ITT analysis showed relapses were significantly higher in the chemo-conditioning group (2-year cumulative incidence of relapse [CIR], 0.33) compared with the total body irradiation group (CIR, 0.12; P < .001).
The 2-year event-free survival (EFS) rate was also significantly higher in the total body irradiation group (0.86 vs 0.58; P < .001), and transplant-related mortality over 2 years was lower with total body irradiation (0.02 vs 0.09; P = .02).
A per-protocol analysis showed the 2-year overall survival to be the same in the two chemotherapy groups (both 0.77 ± 0.05) compared with 0.91 ± 0.02 in the total body irradiation group (P = .003).
“In this cohort [the 91% overall survival rate] may even be lower than contemporary intensive frontline therapy results that are achieved nowadays,” Dr. Peters said.
In looking at subgroups, there were no significant differences according to age group or cancer phenotype, while MLL rearrangement was associated with higher relapse incidence.
Remission status was found to notably influence EFS, dropping from 0.91 in CR1 patients with total body irradiation to 0.76 in CR2 patients. However, total body irradiation remained significantly higher compared with the chemo-conditioning groups in CR1 (P = .004) and CR2 (P < .001).
Transplant-related mortality was not significantly different between the total body irradiation and chemo-conditioning groups in the CR1 or CR2 groups (P = .09 and P = .18, respectively), despite the significant difference when remission status was not included.
Overall, “we tried to identify subgroups in which total body irradiation might be eliminated, however in all analyses, total body irradiation was better than chemo-conditioning in all arms,” Dr. Peters said.
Meanwhile, the findings underscore that even when patients cannot receive total body irradiation, the alternative chemo-conditioning therapy in fact shows favorable efficacy on its own, Dr. Izraeli said.
“The prognosis of the chemotherapy group is also quite remarkably good, although less than the total body irradiation arm. This means that if for some reason total body irradiation cannot be given, the chemotherapy is a very reasonable alternative.”
Dr. Peters has reported relationships with Amgen, Novartis, Pfizer, Medac, Jazz, and Neovii. Dr. Izraeli has reported no relevant financial relationships.
SOURCE: EHA Congress. Abstract S102.
A version of this article originally appeared on Medscape.com.
FROM EHA CONGRESS