Hematologic Malignancies

BACKGROUND

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel treatment for hematologic malignancies, with 6 FDA agents approved for commercial use. The Veterans Affairs (VA) Tennessee Valley Healthcare System (TVHS) is currently the only VA facility accredited to administer these agents and we are reporting the TVHS experience thus far.

METHODS

TVHS became an authorized treatment center for CAR-T therapy in September 2019 and performed its first CAR-T infusion in December 2019. This is a retrospective electronic chart review of all CAR-T veterans referred to TVHS from the program’s inception, December 1, 2019 through July 31, 2022 to evaluate at least one year of post infusion data. The primary objective is to evaluate the outcomes of veterans who received CAR-T therapy at TVHS including overall response rates (ORR), progression free survival (PFS), and overall survival (OS). Secondary objectives include assessment of toxicities, including rates and maximum grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

RESULTS

A total of 41 veterans have received CAR-T infusion at TVHS to date. Twenty-nine of these veterans have at least one year post-CAR-T infusion data and are included in this analysis. The majority of veterans were White (72%), male (93%), and were treated for diffuse large B-cell lymphoma (86%). Twenty-eight percent of veterans were under-represented minorities. Average age was 61 years with 62% being 65 years and older and five (17%) veterans being over the age of 74. Day 30 ORR was 90% (45% complete response [CR]). One-year PFS was 55.2% and 1-year OS was 65.5%. Of the 19 veterans who achieved CR by day 100, 79% remain in CR to date. CRS toxicity was observed in 66% of veterans (0% Grade 3 or higher). ICANS was observed in 27.5% of veterans (24% Grade 3 or higher). Only 5 (26%) veterans required transfer to the intensive care unit for additional monitoring.

CONCLUSIONS

CAR-T therapy has become a wellestablished practice at TVHS and is a safe and effective treatment option for veterans with aggressive lymphoid malignancies. Our outcomes are similar to that seen nationally with better access to under-represented minorities in an aging population.

BACKGROUND

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel treatment for hematologic malignancies, with 6 FDA agents approved for commercial use. The Veterans Affairs (VA) Tennessee Valley Healthcare System (TVHS) is currently the only VA facility accredited to administer these agents and we are reporting the TVHS experience thus far.

METHODS

TVHS became an authorized treatment center for CAR-T therapy in September 2019 and performed its first CAR-T infusion in December 2019. This is a retrospective electronic chart review of all CAR-T veterans referred to TVHS from the program’s inception, December 1, 2019 through July 31, 2022 to evaluate at least one year of post infusion data. The primary objective is to evaluate the outcomes of veterans who received CAR-T therapy at TVHS including overall response rates (ORR), progression free survival (PFS), and overall survival (OS). Secondary objectives include assessment of toxicities, including rates and maximum grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

RESULTS

A total of 41 veterans have received CAR-T infusion at TVHS to date. Twenty-nine of these veterans have at least one year post-CAR-T infusion data and are included in this analysis. The majority of veterans were White (72%), male (93%), and were treated for diffuse large B-cell lymphoma (86%). Twenty-eight percent of veterans were under-represented minorities. Average age was 61 years with 62% being 65 years and older and five (17%) veterans being over the age of 74. Day 30 ORR was 90% (45% complete response [CR]). One-year PFS was 55.2% and 1-year OS was 65.5%. Of the 19 veterans who achieved CR by day 100, 79% remain in CR to date. CRS toxicity was observed in 66% of veterans (0% Grade 3 or higher). ICANS was observed in 27.5% of veterans (24% Grade 3 or higher). Only 5 (26%) veterans required transfer to the intensive care unit for additional monitoring.

CONCLUSIONS

CAR-T therapy has become a wellestablished practice at TVHS and is a safe and effective treatment option for veterans with aggressive lymphoid malignancies. Our outcomes are similar to that seen nationally with better access to under-represented minorities in an aging population.

BACKGROUND

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel treatment for hematologic malignancies, with 6 FDA agents approved for commercial use. The Veterans Affairs (VA) Tennessee Valley Healthcare System (TVHS) is currently the only VA facility accredited to administer these agents and we are reporting the TVHS experience thus far.

METHODS

TVHS became an authorized treatment center for CAR-T therapy in September 2019 and performed its first CAR-T infusion in December 2019. This is a retrospective electronic chart review of all CAR-T veterans referred to TVHS from the program’s inception, December 1, 2019 through July 31, 2022 to evaluate at least one year of post infusion data. The primary objective is to evaluate the outcomes of veterans who received CAR-T therapy at TVHS including overall response rates (ORR), progression free survival (PFS), and overall survival (OS). Secondary objectives include assessment of toxicities, including rates and maximum grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

RESULTS

A total of 41 veterans have received CAR-T infusion at TVHS to date. Twenty-nine of these veterans have at least one year post-CAR-T infusion data and are included in this analysis. The majority of veterans were White (72%), male (93%), and were treated for diffuse large B-cell lymphoma (86%). Twenty-eight percent of veterans were under-represented minorities. Average age was 61 years with 62% being 65 years and older and five (17%) veterans being over the age of 74. Day 30 ORR was 90% (45% complete response [CR]). One-year PFS was 55.2% and 1-year OS was 65.5%. Of the 19 veterans who achieved CR by day 100, 79% remain in CR to date. CRS toxicity was observed in 66% of veterans (0% Grade 3 or higher). ICANS was observed in 27.5% of veterans (24% Grade 3 or higher). Only 5 (26%) veterans required transfer to the intensive care unit for additional monitoring.

CONCLUSIONS

CAR-T therapy has become a wellestablished practice at TVHS and is a safe and effective treatment option for veterans with aggressive lymphoid malignancies. Our outcomes are similar to that seen nationally with better access to under-represented minorities in an aging population.

INTRODUCTION

Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.

CASE REPORT

A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.

DISCUSSION

Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.

CONCLUSIONS

Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.

INTRODUCTION

Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.

CASE REPORT

A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.

DISCUSSION

Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.

CONCLUSIONS

Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.

INTRODUCTION

Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.

CASE REPORT

A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.

DISCUSSION

Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.

CONCLUSIONS

Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.

INTRODUCTION

The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.

CASE PRESENTATIONS

(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.

DISCUSSION

In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.

CONCLUSIONS

For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.

INTRODUCTION

The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.

CASE PRESENTATIONS

(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.

DISCUSSION

In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.

CONCLUSIONS

For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.

INTRODUCTION

The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.

CASE PRESENTATIONS

(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.

DISCUSSION

In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.

CONCLUSIONS

For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.

BACKGROUND/PURPOSE

Tumor lysis syndrome (TLS) occurs when malignant cells rapidly break down. This may lead to hyperuricemia, hyperkalemia, hyperphosphatemia, and/or hypocalcemia. Rasburicase reduces uric acid in cancer patients undergoing anti-cancer therapy. However, caution is required as rasburicase is contraindicated for patients with glucose- 6-phosphate dehydrogenase (G6PD) deficiency due to the increased risk of hemolysis. G6PD deficiency is more prevalent among African Americans (AA), affecting approximately 12% of this population. The FDA recommends testing for G6PD deficiency in higher risk groups before administering rasburicase.

METHODS

A retrospective analysis was conducted at the Louis Stokes Cleveland VAMC from February 1, 2018, to January 31, 2023 addressing appropriate use of rasburicase and incidence of G6PD deficiency and hemolysis. Appropriate use was defined by: TLS (2 or more: uric acid ≥ 8 or 25% increase; K+ ≥ 6.0 or 25% increase; Phos > 4.5mg/dL, or 25% increase; or calcium < 7, or 25% decrease, from baseline) or at high risk for TLS (CLL: venetoclax use w/lymph node > 10cm or WBC > 25k and elevated uric acid; AML: WBC > 100k; ALL: WBC > 100k and LDH 2x ULN; Burkitt lymphoma: LDH 2x ULN).

RESULTS

50 patients were identified who received rasburicase. 21/50 (42%) did not meet criteria for appropriate use. 44/50 (88%) underwent G6PD testing. The average time from G6PD testing order to obtaining the results was 3.4 days; 18/50 patients (36%) had G6PD resulted prior to rasburicase administration, and 26 patients (52%) received rasburicase prior to G6PD results. Overall, 13/50 (26%) were AA. Of the AA pts, 12/13 (92%) were tested for G6PD. Of these 12, 1/12 was found to be G6PD deficient and this patient experienced G6PD deficiency-induced hemolysis after rasburicase. None of the non-AA pts (0/31) tested were found to be G6PD deficient.

IMPLICATIONS

There was a high (42%) level of inappropriate use of rasburicase. G6PD deficiency was uncommon and only found in the AA population. To reduce inappropriate use, rasburicase orders will be restricted to medical oncology. G6PD testing will be limited to AA pts, with pathology to develop a rapid turnaround time for results prior to rasburicase administration to prevent hemolysis.

BACKGROUND/PURPOSE

Tumor lysis syndrome (TLS) occurs when malignant cells rapidly break down. This may lead to hyperuricemia, hyperkalemia, hyperphosphatemia, and/or hypocalcemia. Rasburicase reduces uric acid in cancer patients undergoing anti-cancer therapy. However, caution is required as rasburicase is contraindicated for patients with glucose- 6-phosphate dehydrogenase (G6PD) deficiency due to the increased risk of hemolysis. G6PD deficiency is more prevalent among African Americans (AA), affecting approximately 12% of this population. The FDA recommends testing for G6PD deficiency in higher risk groups before administering rasburicase.

METHODS

A retrospective analysis was conducted at the Louis Stokes Cleveland VAMC from February 1, 2018, to January 31, 2023 addressing appropriate use of rasburicase and incidence of G6PD deficiency and hemolysis. Appropriate use was defined by: TLS (2 or more: uric acid ≥ 8 or 25% increase; K+ ≥ 6.0 or 25% increase; Phos > 4.5mg/dL, or 25% increase; or calcium < 7, or 25% decrease, from baseline) or at high risk for TLS (CLL: venetoclax use w/lymph node > 10cm or WBC > 25k and elevated uric acid; AML: WBC > 100k; ALL: WBC > 100k and LDH 2x ULN; Burkitt lymphoma: LDH 2x ULN).

RESULTS

50 patients were identified who received rasburicase. 21/50 (42%) did not meet criteria for appropriate use. 44/50 (88%) underwent G6PD testing. The average time from G6PD testing order to obtaining the results was 3.4 days; 18/50 patients (36%) had G6PD resulted prior to rasburicase administration, and 26 patients (52%) received rasburicase prior to G6PD results. Overall, 13/50 (26%) were AA. Of the AA pts, 12/13 (92%) were tested for G6PD. Of these 12, 1/12 was found to be G6PD deficient and this patient experienced G6PD deficiency-induced hemolysis after rasburicase. None of the non-AA pts (0/31) tested were found to be G6PD deficient.

IMPLICATIONS

There was a high (42%) level of inappropriate use of rasburicase. G6PD deficiency was uncommon and only found in the AA population. To reduce inappropriate use, rasburicase orders will be restricted to medical oncology. G6PD testing will be limited to AA pts, with pathology to develop a rapid turnaround time for results prior to rasburicase administration to prevent hemolysis.

BACKGROUND/PURPOSE

Tumor lysis syndrome (TLS) occurs when malignant cells rapidly break down. This may lead to hyperuricemia, hyperkalemia, hyperphosphatemia, and/or hypocalcemia. Rasburicase reduces uric acid in cancer patients undergoing anti-cancer therapy. However, caution is required as rasburicase is contraindicated for patients with glucose- 6-phosphate dehydrogenase (G6PD) deficiency due to the increased risk of hemolysis. G6PD deficiency is more prevalent among African Americans (AA), affecting approximately 12% of this population. The FDA recommends testing for G6PD deficiency in higher risk groups before administering rasburicase.

METHODS

A retrospective analysis was conducted at the Louis Stokes Cleveland VAMC from February 1, 2018, to January 31, 2023 addressing appropriate use of rasburicase and incidence of G6PD deficiency and hemolysis. Appropriate use was defined by: TLS (2 or more: uric acid ≥ 8 or 25% increase; K+ ≥ 6.0 or 25% increase; Phos > 4.5mg/dL, or 25% increase; or calcium < 7, or 25% decrease, from baseline) or at high risk for TLS (CLL: venetoclax use w/lymph node > 10cm or WBC > 25k and elevated uric acid; AML: WBC > 100k; ALL: WBC > 100k and LDH 2x ULN; Burkitt lymphoma: LDH 2x ULN).

RESULTS

50 patients were identified who received rasburicase. 21/50 (42%) did not meet criteria for appropriate use. 44/50 (88%) underwent G6PD testing. The average time from G6PD testing order to obtaining the results was 3.4 days; 18/50 patients (36%) had G6PD resulted prior to rasburicase administration, and 26 patients (52%) received rasburicase prior to G6PD results. Overall, 13/50 (26%) were AA. Of the AA pts, 12/13 (92%) were tested for G6PD. Of these 12, 1/12 was found to be G6PD deficient and this patient experienced G6PD deficiency-induced hemolysis after rasburicase. None of the non-AA pts (0/31) tested were found to be G6PD deficient.

IMPLICATIONS

There was a high (42%) level of inappropriate use of rasburicase. G6PD deficiency was uncommon and only found in the AA population. To reduce inappropriate use, rasburicase orders will be restricted to medical oncology. G6PD testing will be limited to AA pts, with pathology to develop a rapid turnaround time for results prior to rasburicase administration to prevent hemolysis.

BACKGROUND

Multiple myeloma, an incurable plasma cell malignancy, has an average age of diagnosis over 65 years. For transplant-eligible patients, high-dose melphalan 200 mg/m2 (MEL200), followed by autologous stem cell rescue (ASCR) is the standard in consolidation therapy. Most clinical trials evaluating MEL200 with ASCR excluded patients over 65 due to concerns for toxicity and treatment-related mortality, leading to use of reduced dose melphalan 140 mg/m2 (MEL140) in clinical practice for older patients. As this dose has limited studies surrounding its reduction, the purpose of this study was to compare outcomes and toxicities of MEL140 in patients over the age of 65 to MEL200 in patients 65 and under.

METHODS

This single-center institutional review board approved retrospective study was conducted at VA Tennessee Valley Healthcare System. All multiple myeloma patients greater than 18 years of age who received melphalan with ASCR from January 1, 2018, to December 31, 2021, were included. Patients were divided into two arms: age < 65 treated with MEL200 and age >65 treated with MEL140. The primary endpoint was oneyear progression-free survival (PFS). The secondary endpoints were one-year overall survival (OS), treatment related mortality, time to neutrophil engraftment, and toxicities including febrile neutropenia, diarrhea, mucositis, infection, and intensive care unit transfers.

RESULTS

A total of 222 patients were included, 114 patients in the MEL200 arm and 108 patients in the MEL140 arm. The primary endpoint of one-year PFS had no significant difference, with 103 (90.4%) patients in the MEL200 group compared to 99 (91.7%) patients in the MEL140 group (p=0.732). Similarly, there was no statistically significant difference in the secondary endpoint of one-year OS with 112 (98.3%) patients in the MEL200 group compared to 106 (98.2%) in the MEL140 group (p=0.956). Toxicities were similar; however, grade 3 mucositis was higher in the MEL200 arm.

CONCLUSIONS

Our study found no difference in oneyear PFS or one-year OS when comparing MEL140 to MEL200 with minimal differences in regimen-related toxicities. Although not powered to detect statistical difference, results suggests that dose reduction with MEL140 in patients >65 years does not impact one-year PFS when compared to patients <65 receiving standard MEL200.

BACKGROUND

Multiple myeloma, an incurable plasma cell malignancy, has an average age of diagnosis over 65 years. For transplant-eligible patients, high-dose melphalan 200 mg/m2 (MEL200), followed by autologous stem cell rescue (ASCR) is the standard in consolidation therapy. Most clinical trials evaluating MEL200 with ASCR excluded patients over 65 due to concerns for toxicity and treatment-related mortality, leading to use of reduced dose melphalan 140 mg/m2 (MEL140) in clinical practice for older patients. As this dose has limited studies surrounding its reduction, the purpose of this study was to compare outcomes and toxicities of MEL140 in patients over the age of 65 to MEL200 in patients 65 and under.

METHODS

This single-center institutional review board approved retrospective study was conducted at VA Tennessee Valley Healthcare System. All multiple myeloma patients greater than 18 years of age who received melphalan with ASCR from January 1, 2018, to December 31, 2021, were included. Patients were divided into two arms: age < 65 treated with MEL200 and age >65 treated with MEL140. The primary endpoint was oneyear progression-free survival (PFS). The secondary endpoints were one-year overall survival (OS), treatment related mortality, time to neutrophil engraftment, and toxicities including febrile neutropenia, diarrhea, mucositis, infection, and intensive care unit transfers.

RESULTS

A total of 222 patients were included, 114 patients in the MEL200 arm and 108 patients in the MEL140 arm. The primary endpoint of one-year PFS had no significant difference, with 103 (90.4%) patients in the MEL200 group compared to 99 (91.7%) patients in the MEL140 group (p=0.732). Similarly, there was no statistically significant difference in the secondary endpoint of one-year OS with 112 (98.3%) patients in the MEL200 group compared to 106 (98.2%) in the MEL140 group (p=0.956). Toxicities were similar; however, grade 3 mucositis was higher in the MEL200 arm.

CONCLUSIONS

Our study found no difference in oneyear PFS or one-year OS when comparing MEL140 to MEL200 with minimal differences in regimen-related toxicities. Although not powered to detect statistical difference, results suggests that dose reduction with MEL140 in patients >65 years does not impact one-year PFS when compared to patients <65 receiving standard MEL200.

BACKGROUND

Multiple myeloma, an incurable plasma cell malignancy, has an average age of diagnosis over 65 years. For transplant-eligible patients, high-dose melphalan 200 mg/m2 (MEL200), followed by autologous stem cell rescue (ASCR) is the standard in consolidation therapy. Most clinical trials evaluating MEL200 with ASCR excluded patients over 65 due to concerns for toxicity and treatment-related mortality, leading to use of reduced dose melphalan 140 mg/m2 (MEL140) in clinical practice for older patients. As this dose has limited studies surrounding its reduction, the purpose of this study was to compare outcomes and toxicities of MEL140 in patients over the age of 65 to MEL200 in patients 65 and under.

METHODS

This single-center institutional review board approved retrospective study was conducted at VA Tennessee Valley Healthcare System. All multiple myeloma patients greater than 18 years of age who received melphalan with ASCR from January 1, 2018, to December 31, 2021, were included. Patients were divided into two arms: age < 65 treated with MEL200 and age >65 treated with MEL140. The primary endpoint was oneyear progression-free survival (PFS). The secondary endpoints were one-year overall survival (OS), treatment related mortality, time to neutrophil engraftment, and toxicities including febrile neutropenia, diarrhea, mucositis, infection, and intensive care unit transfers.

RESULTS

A total of 222 patients were included, 114 patients in the MEL200 arm and 108 patients in the MEL140 arm. The primary endpoint of one-year PFS had no significant difference, with 103 (90.4%) patients in the MEL200 group compared to 99 (91.7%) patients in the MEL140 group (p=0.732). Similarly, there was no statistically significant difference in the secondary endpoint of one-year OS with 112 (98.3%) patients in the MEL200 group compared to 106 (98.2%) in the MEL140 group (p=0.956). Toxicities were similar; however, grade 3 mucositis was higher in the MEL200 arm.

CONCLUSIONS

Our study found no difference in oneyear PFS or one-year OS when comparing MEL140 to MEL200 with minimal differences in regimen-related toxicities. Although not powered to detect statistical difference, results suggests that dose reduction with MEL140 in patients >65 years does not impact one-year PFS when compared to patients <65 receiving standard MEL200.

A new interim analysis of a large randomized, phase 3 trial provides more evidence that a combination of ibrutinib and rituximab is a better option for younger patients with untreated chronic lymphocytic leukemia (CLL) than the once-standard combination of fludarabine, cyclophosphamide, and rituximab (FCR).

The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).

“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.

There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.

Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”

The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.

According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.

The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.

From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).

Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.

Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.

However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.

In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”

The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)

As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.

All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.

Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).

Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.” 

Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”

He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.

The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.

A new interim analysis of a large randomized, phase 3 trial provides more evidence that a combination of ibrutinib and rituximab is a better option for younger patients with untreated chronic lymphocytic leukemia (CLL) than the once-standard combination of fludarabine, cyclophosphamide, and rituximab (FCR).

The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).

“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.

There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.

Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”

The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.

According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.

The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.

From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).

Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.

Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.

However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.

In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”

The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)

As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.

All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.

Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).

Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.” 

Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”

He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.

The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.

A new interim analysis of a large randomized, phase 3 trial provides more evidence that a combination of ibrutinib and rituximab is a better option for younger patients with untreated chronic lymphocytic leukemia (CLL) than the once-standard combination of fludarabine, cyclophosphamide, and rituximab (FCR).

The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).

“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.

There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.

Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”

The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.

According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.

The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.

From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).

Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.

Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.

However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.

In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”

The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)

As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.

All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.

Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).

Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.” 

Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”

He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.

The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.

Patients with cancer are at a high risk of venous thromboembolism (VTE)—in fact, it’s one of the leading causes of death in patients who receive systemic therapy for cancer. But as cancer treatment has evolved, have the incidence and risk of VTE changed too?

Researchers from Veterans Affairs Boston Healthcare System in Massachusetts conducted a study with 434,203 veterans to evaluate the pattern of VTE incidence over 16 years, focusing on the types of cancer, treatment, race and ethnicity, and other factors related to cancer-associated thrombosis (CAT).

In contrast with other large population studies, this study found the overall incidence of CAT remained largely stable over time. At 12 months, the incidence was 4.5%, with yearly trends ranging between 4.2% and 4.7%. “As expected,” the researchers say, the subset of patients receiving systemic therapy had a higher incidence of VTE at 12 months (7.7%) than did the overall cohort. The pattern was “particularly pronounced” in gynecologic, testicular, and kidney cancers, where the incidence of VTE was 2 to 3 times higher in the treated cohort compared with the overall cohort. 

Cancer type and diagnosis were the most statistically and clinically significant associations with CAT, with up to a 6-fold difference between cancer subtypes. The patients at the highest risk of VTE were those with pancreatic cancer and acute lymphoblastic leukemia.

Most studies have focused only on patients with solid tumors, but these researchers observed novel patterns among patients with hematologic neoplasms. Specifically, a higher incidence of VTE among patients with aggressive vs indolent leukemias and lymphomas. This trend, the researchers say, may be associated in part with catheter-related events.

Furthermore, the type of system treatment was associated with the risk of VTE, the researchers say, although to a lesser extent. Chemotherapy- and immunotherapy-based regimens had the highest risk of VTE, relative to no treatment. Targeted and endocrine therapy also carried a higher risk compared with no treatment but to a lesser degree.

The researchers found significant heterogeneity by race and ethnicity across cancer types. Non-Hispanic Black patients had about 20% higher risk of VTE compared with non-Hispanic White patients. Asian and Pacific Islander patients had about 20% lower risk compared with non-Hispanic White patients.

Male sex was also associated with VTE. However, “interestingly,” the researchers note, neighborhood-level socioeconomic factors and patients’ comorbidities were not associated with CAT but were associated with mortality.

Their results suggest that patient- and treatment-specific factors play a critical role in assessing the risk of CAT, and “ongoing efforts to identify these patterns are of utmost importance for risk stratification and prognostic assessment.”

Patients with cancer are at a high risk of venous thromboembolism (VTE)—in fact, it’s one of the leading causes of death in patients who receive systemic therapy for cancer. But as cancer treatment has evolved, have the incidence and risk of VTE changed too?

Researchers from Veterans Affairs Boston Healthcare System in Massachusetts conducted a study with 434,203 veterans to evaluate the pattern of VTE incidence over 16 years, focusing on the types of cancer, treatment, race and ethnicity, and other factors related to cancer-associated thrombosis (CAT).

In contrast with other large population studies, this study found the overall incidence of CAT remained largely stable over time. At 12 months, the incidence was 4.5%, with yearly trends ranging between 4.2% and 4.7%. “As expected,” the researchers say, the subset of patients receiving systemic therapy had a higher incidence of VTE at 12 months (7.7%) than did the overall cohort. The pattern was “particularly pronounced” in gynecologic, testicular, and kidney cancers, where the incidence of VTE was 2 to 3 times higher in the treated cohort compared with the overall cohort. 

Cancer type and diagnosis were the most statistically and clinically significant associations with CAT, with up to a 6-fold difference between cancer subtypes. The patients at the highest risk of VTE were those with pancreatic cancer and acute lymphoblastic leukemia.

Most studies have focused only on patients with solid tumors, but these researchers observed novel patterns among patients with hematologic neoplasms. Specifically, a higher incidence of VTE among patients with aggressive vs indolent leukemias and lymphomas. This trend, the researchers say, may be associated in part with catheter-related events.

Furthermore, the type of system treatment was associated with the risk of VTE, the researchers say, although to a lesser extent. Chemotherapy- and immunotherapy-based regimens had the highest risk of VTE, relative to no treatment. Targeted and endocrine therapy also carried a higher risk compared with no treatment but to a lesser degree.

The researchers found significant heterogeneity by race and ethnicity across cancer types. Non-Hispanic Black patients had about 20% higher risk of VTE compared with non-Hispanic White patients. Asian and Pacific Islander patients had about 20% lower risk compared with non-Hispanic White patients.

Male sex was also associated with VTE. However, “interestingly,” the researchers note, neighborhood-level socioeconomic factors and patients’ comorbidities were not associated with CAT but were associated with mortality.

Their results suggest that patient- and treatment-specific factors play a critical role in assessing the risk of CAT, and “ongoing efforts to identify these patterns are of utmost importance for risk stratification and prognostic assessment.”

Patients with cancer are at a high risk of venous thromboembolism (VTE)—in fact, it’s one of the leading causes of death in patients who receive systemic therapy for cancer. But as cancer treatment has evolved, have the incidence and risk of VTE changed too?

Researchers from Veterans Affairs Boston Healthcare System in Massachusetts conducted a study with 434,203 veterans to evaluate the pattern of VTE incidence over 16 years, focusing on the types of cancer, treatment, race and ethnicity, and other factors related to cancer-associated thrombosis (CAT).

In contrast with other large population studies, this study found the overall incidence of CAT remained largely stable over time. At 12 months, the incidence was 4.5%, with yearly trends ranging between 4.2% and 4.7%. “As expected,” the researchers say, the subset of patients receiving systemic therapy had a higher incidence of VTE at 12 months (7.7%) than did the overall cohort. The pattern was “particularly pronounced” in gynecologic, testicular, and kidney cancers, where the incidence of VTE was 2 to 3 times higher in the treated cohort compared with the overall cohort. 

Cancer type and diagnosis were the most statistically and clinically significant associations with CAT, with up to a 6-fold difference between cancer subtypes. The patients at the highest risk of VTE were those with pancreatic cancer and acute lymphoblastic leukemia.

Most studies have focused only on patients with solid tumors, but these researchers observed novel patterns among patients with hematologic neoplasms. Specifically, a higher incidence of VTE among patients with aggressive vs indolent leukemias and lymphomas. This trend, the researchers say, may be associated in part with catheter-related events.

Furthermore, the type of system treatment was associated with the risk of VTE, the researchers say, although to a lesser extent. Chemotherapy- and immunotherapy-based regimens had the highest risk of VTE, relative to no treatment. Targeted and endocrine therapy also carried a higher risk compared with no treatment but to a lesser degree.

The researchers found significant heterogeneity by race and ethnicity across cancer types. Non-Hispanic Black patients had about 20% higher risk of VTE compared with non-Hispanic White patients. Asian and Pacific Islander patients had about 20% lower risk compared with non-Hispanic White patients.

Male sex was also associated with VTE. However, “interestingly,” the researchers note, neighborhood-level socioeconomic factors and patients’ comorbidities were not associated with CAT but were associated with mortality.

Their results suggest that patient- and treatment-specific factors play a critical role in assessing the risk of CAT, and “ongoing efforts to identify these patterns are of utmost importance for risk stratification and prognostic assessment.”

Patients with acute myeloid leukemia (AML) who harbor a mutation strongly associated with a poor prognosis and who have minimal residual disease (MRD+) following hematopoietic cell transplantation (HCT) have a reduced risk of relapse with gilteritinib (Xospata) maintenance therapy, results of the MORPHO trial suggest.

The research was presented at the European Hematology Association Hybrid Congress 2023.

For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.

The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.

However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.

While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”

“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”

Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.

He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”

Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.

“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”

He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”

Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.

He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.

As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.

He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”

This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”

Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”

He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”

“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.

Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”

He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”

“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”

Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.

The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”

They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.

Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.

Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.

He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.

MRD positivity, assessed at a cell count of ≥ 10^-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.

The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.

He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”

The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.

Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).

However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”

He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10^-6. “In our study, 98% of participants had samples pre- and post-[transplant].”

Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).

When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.

Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).

Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.

He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.

“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.

Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”

In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.

The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
 

Patients with acute myeloid leukemia (AML) who harbor a mutation strongly associated with a poor prognosis and who have minimal residual disease (MRD+) following hematopoietic cell transplantation (HCT) have a reduced risk of relapse with gilteritinib (Xospata) maintenance therapy, results of the MORPHO trial suggest.

The research was presented at the European Hematology Association Hybrid Congress 2023.

For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.

The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.

However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.

While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”

“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”

Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.

He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”

Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.

“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”

He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”

Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.

He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.

As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.

He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”

This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”

Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”

He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”

“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.

Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”

He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”

“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”

Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.

The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”

They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.

Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.

Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.

He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.

MRD positivity, assessed at a cell count of ≥ 10^-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.

The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.

He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”

The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.

Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).

However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”

He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10^-6. “In our study, 98% of participants had samples pre- and post-[transplant].”

Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).

When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.

Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).

Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.

He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.

“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.

Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”

In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.

The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
 

Patients with acute myeloid leukemia (AML) who harbor a mutation strongly associated with a poor prognosis and who have minimal residual disease (MRD+) following hematopoietic cell transplantation (HCT) have a reduced risk of relapse with gilteritinib (Xospata) maintenance therapy, results of the MORPHO trial suggest.

The research was presented at the European Hematology Association Hybrid Congress 2023.

For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.

The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.

However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.

While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”

“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”

Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.

He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”

Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.

“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”

He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”

Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.

He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.

As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.

He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”

This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”

Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”

He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”

“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.

Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”

He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”

“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”

Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.

The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”

They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.

Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.

Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.

He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.

MRD positivity, assessed at a cell count of ≥ 10^-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.

The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.

He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”

The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.

Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).

However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”

He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10^-6. “In our study, 98% of participants had samples pre- and post-[transplant].”

Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).

When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.

Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).

Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.

He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.

“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.

Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”

In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.

The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
 

Patients with chronic lymphocytic leukemia (CLL) – even those who have multiple comorbidities – experience long-term progression-free survival (PFS) benefits with 1 year of venetoclax plus obinutuzumab versus a chemotherapy-based regimen, a 6-year follow-up analysis from CLL14 showed. The research was presented June 9 at the annual meeting of the European Hematology Association.

Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.

They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.

On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.

The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.

Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.

Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”

Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”

He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.

“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”

Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”

He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.

This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.

He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.

“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.

“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”

Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.

“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”

Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.

The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”

A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.

“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.

He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”

Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.

Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.

One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.

“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.

He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”

Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).

The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.

Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.

Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.

There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.

Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.

“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”

He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.

This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.

That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.

Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”

“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”

The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.

Patients with chronic lymphocytic leukemia (CLL) – even those who have multiple comorbidities – experience long-term progression-free survival (PFS) benefits with 1 year of venetoclax plus obinutuzumab versus a chemotherapy-based regimen, a 6-year follow-up analysis from CLL14 showed. The research was presented June 9 at the annual meeting of the European Hematology Association.

Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.

They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.

On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.

The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.

Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.

Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”

Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”

He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.

“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”

Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”

He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.

This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.

He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.

“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.

“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”

Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.

“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”

Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.

The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”

A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.

“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.

He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”

Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.

Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.

One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.

“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.

He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”

Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).

The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.

Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.

Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.

There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.

Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.

“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”

He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.

This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.

That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.

Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”

“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”

The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.

Patients with chronic lymphocytic leukemia (CLL) – even those who have multiple comorbidities – experience long-term progression-free survival (PFS) benefits with 1 year of venetoclax plus obinutuzumab versus a chemotherapy-based regimen, a 6-year follow-up analysis from CLL14 showed. The research was presented June 9 at the annual meeting of the European Hematology Association.

Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.

They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.

On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.

The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.

Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.

Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”

Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”

He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.

“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”

Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”

He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.

This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.

He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.

“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.

“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”

Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.

“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”

Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.

The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”

A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.

“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.

He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”

Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.

Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.

One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.

“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.

He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”

Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).

The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.

Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.

Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.

There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.

Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.

“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”

He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.

This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.

That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.

Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”

“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”

The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.

The Food and Drug Administration has granted accelerated approval for glofitamab (Columvi) for use in certain types of lymphoma.

The indication is for use in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or with LBCL arising from follicular lymphoma who have received two or more lines of systemic therapy.

The product is a T cell–engaging bispecific antibody developed by Genentech, which has a similar product, mosunetuzumab-axgb (Lunsumio), for the treatment of follicular lymphoma. Lunsumio was approved in December 2022.

These drugs could be considered a first choice in the setting of third-line therapy, suggests an expert writing recently in The New England Journal of Medicine.

Nancy Bartlett, MD, from the Siteman Cancer Center, Washington University in St. Louis, is the author of an editorial that accompanied the publication of results with glofitamab in the pivotal trial that led to its approval.

“Bispecific agents will be an excellent option for the 60% of patients in whom second-line CAR [chimeric antigen receptor] T-cell therapy fails,” she wrote in her editorial.

Dr. Bartlett suggests that these agents may be preferred over CAR T cells. “If longer follow-up confirms that the majority of complete remissions with bispecific agents are durable, on the basis of the advantages of availability (including in the community setting) and more favorable immediate and late toxic-effect profiles, bispecific agents could be considered as the initial choice. ... CAR T-cell therapy could be held in reserve for patients who do not have a complete response or who have a relapse after a complete response.”
 

Most common form of non-Hodgkin’s lymphoma

DLBCL is the most common form of non-Hodgkin’s lymphoma in the United States, the company noted in a press release. While many people with DLBCL are responsive to treatment, the majority of those who experience relapse or whose condition is refractory to subsequent treatments have poor outcomes.

“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” commented Krish Patel, MD, director of the lymphoma program at the Swedish Cancer Institute in Seattle, who is an investigator on the clinical trial that led to the product’s approval. He said that the results from trials suggest that glofitamab gives patients “a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”

The accelerated approval is based on response rate and durability of response results from the phase 1/2 NP30179 study.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

This trial involved 132 patients with DLBCL who experienced relapse or whose condition was refractory to prior therapies. About one-third of patients (30%) had received prior CAR T-cell therapy. Additionally, for 83% of patients, the condition was refractory to their most recent therapy.

Glofitamab was given to all patients as a fixed course for 8.5 months.

More than half (56%) achieved an overall response, and 43% achieved a complete response. Over two-thirds (68.5%) of those who responded continued to respond for at least 9 months The median duration of response was 1.5 years.

The most common adverse events were cytokine release syndrome (CRS; 70%), which may be serious or life-threatening; musculoskeletal pain (21%); fatigue (20%); and rash (20%). CRS was generally of low grade (52% of patients experienced grade 1 CRS, and 14% experienced grade 2).

Results from the NP30179 trial were published in December 2022.

The complete response rates seen with glofitamab rivals the durable complete response that has been observed with CAR T-cell therapy, Dr. Bartlett noted in the accompanying editorial. “Although these results are promising, it is still too early to estimate the curative potential of glofitamab.”

The Food and Drug Administration has granted accelerated approval for glofitamab (Columvi) for use in certain types of lymphoma.

The indication is for use in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or with LBCL arising from follicular lymphoma who have received two or more lines of systemic therapy.

The product is a T cell–engaging bispecific antibody developed by Genentech, which has a similar product, mosunetuzumab-axgb (Lunsumio), for the treatment of follicular lymphoma. Lunsumio was approved in December 2022.

These drugs could be considered a first choice in the setting of third-line therapy, suggests an expert writing recently in The New England Journal of Medicine.

Nancy Bartlett, MD, from the Siteman Cancer Center, Washington University in St. Louis, is the author of an editorial that accompanied the publication of results with glofitamab in the pivotal trial that led to its approval.

“Bispecific agents will be an excellent option for the 60% of patients in whom second-line CAR [chimeric antigen receptor] T-cell therapy fails,” she wrote in her editorial.

Dr. Bartlett suggests that these agents may be preferred over CAR T cells. “If longer follow-up confirms that the majority of complete remissions with bispecific agents are durable, on the basis of the advantages of availability (including in the community setting) and more favorable immediate and late toxic-effect profiles, bispecific agents could be considered as the initial choice. ... CAR T-cell therapy could be held in reserve for patients who do not have a complete response or who have a relapse after a complete response.”
 

Most common form of non-Hodgkin’s lymphoma

DLBCL is the most common form of non-Hodgkin’s lymphoma in the United States, the company noted in a press release. While many people with DLBCL are responsive to treatment, the majority of those who experience relapse or whose condition is refractory to subsequent treatments have poor outcomes.

“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” commented Krish Patel, MD, director of the lymphoma program at the Swedish Cancer Institute in Seattle, who is an investigator on the clinical trial that led to the product’s approval. He said that the results from trials suggest that glofitamab gives patients “a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”

The accelerated approval is based on response rate and durability of response results from the phase 1/2 NP30179 study.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

This trial involved 132 patients with DLBCL who experienced relapse or whose condition was refractory to prior therapies. About one-third of patients (30%) had received prior CAR T-cell therapy. Additionally, for 83% of patients, the condition was refractory to their most recent therapy.

Glofitamab was given to all patients as a fixed course for 8.5 months.

More than half (56%) achieved an overall response, and 43% achieved a complete response. Over two-thirds (68.5%) of those who responded continued to respond for at least 9 months The median duration of response was 1.5 years.

The most common adverse events were cytokine release syndrome (CRS; 70%), which may be serious or life-threatening; musculoskeletal pain (21%); fatigue (20%); and rash (20%). CRS was generally of low grade (52% of patients experienced grade 1 CRS, and 14% experienced grade 2).

Results from the NP30179 trial were published in December 2022.

The complete response rates seen with glofitamab rivals the durable complete response that has been observed with CAR T-cell therapy, Dr. Bartlett noted in the accompanying editorial. “Although these results are promising, it is still too early to estimate the curative potential of glofitamab.”

The Food and Drug Administration has granted accelerated approval for glofitamab (Columvi) for use in certain types of lymphoma.

The indication is for use in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or with LBCL arising from follicular lymphoma who have received two or more lines of systemic therapy.

The product is a T cell–engaging bispecific antibody developed by Genentech, which has a similar product, mosunetuzumab-axgb (Lunsumio), for the treatment of follicular lymphoma. Lunsumio was approved in December 2022.

These drugs could be considered a first choice in the setting of third-line therapy, suggests an expert writing recently in The New England Journal of Medicine.

Nancy Bartlett, MD, from the Siteman Cancer Center, Washington University in St. Louis, is the author of an editorial that accompanied the publication of results with glofitamab in the pivotal trial that led to its approval.

“Bispecific agents will be an excellent option for the 60% of patients in whom second-line CAR [chimeric antigen receptor] T-cell therapy fails,” she wrote in her editorial.

Dr. Bartlett suggests that these agents may be preferred over CAR T cells. “If longer follow-up confirms that the majority of complete remissions with bispecific agents are durable, on the basis of the advantages of availability (including in the community setting) and more favorable immediate and late toxic-effect profiles, bispecific agents could be considered as the initial choice. ... CAR T-cell therapy could be held in reserve for patients who do not have a complete response or who have a relapse after a complete response.”
 

Most common form of non-Hodgkin’s lymphoma

DLBCL is the most common form of non-Hodgkin’s lymphoma in the United States, the company noted in a press release. While many people with DLBCL are responsive to treatment, the majority of those who experience relapse or whose condition is refractory to subsequent treatments have poor outcomes.

“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” commented Krish Patel, MD, director of the lymphoma program at the Swedish Cancer Institute in Seattle, who is an investigator on the clinical trial that led to the product’s approval. He said that the results from trials suggest that glofitamab gives patients “a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”

The accelerated approval is based on response rate and durability of response results from the phase 1/2 NP30179 study.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

This trial involved 132 patients with DLBCL who experienced relapse or whose condition was refractory to prior therapies. About one-third of patients (30%) had received prior CAR T-cell therapy. Additionally, for 83% of patients, the condition was refractory to their most recent therapy.

Glofitamab was given to all patients as a fixed course for 8.5 months.

More than half (56%) achieved an overall response, and 43% achieved a complete response. Over two-thirds (68.5%) of those who responded continued to respond for at least 9 months The median duration of response was 1.5 years.

The most common adverse events were cytokine release syndrome (CRS; 70%), which may be serious or life-threatening; musculoskeletal pain (21%); fatigue (20%); and rash (20%). CRS was generally of low grade (52% of patients experienced grade 1 CRS, and 14% experienced grade 2).

Results from the NP30179 trial were published in December 2022.

The complete response rates seen with glofitamab rivals the durable complete response that has been observed with CAR T-cell therapy, Dr. Bartlett noted in the accompanying editorial. “Although these results are promising, it is still too early to estimate the curative potential of glofitamab.”