Venetoclax with 5+2 chemo looks effective in older AML patients

 

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

Among 41 patients with a median age of 72 years treated at one of five venetoclax dose levels, the objective response rate for all patients combined was 71%, and the median overall survival was 7.7 months, reported Andrew H. Wei, MD, from Monash University in Melbourne.

“Venetoclax up to 600 mg in combination with a 5 plus 2 intensive chemotherapy approach is indeed feasible, with very reasonable count recovery times not unexpected for intensive chemotherapy,” Dr. Wei said at the annual congress of the European Hematology Association.

“A high response rate was observed, and we had very low levels of TLS [tumor lysis syndrome] – in fact no evidence of clinical TLS – and early mortality was also low,” he added.

Previous studies have shown that venetoclax in combination with hypomethylating agents or low-dose cytarabine has promising efficacy for the treatment of elderly patients with AML who are considered to be not fit enough to withstand the rigors of intensive chemotherapy.

“We know that intensive chemotherapy in older patients delivers a remission rate of approximately 60%, and the French group [Acute Leukemia French Association] have demonstrated that low-dose ambulatory approaches are as good as, if not even superior to, intensive consolidation,” he said.

Additionally, other studies have suggested that attenuated-dose or “5+2” induction chemotherapy in patients aged 65 years or older is associated with a combined complete remission (CR) and CR with incomplete recovery of counts (CRi) rate approaching 60%, Dr. Wei noted.

The investigator-initiated CAVEAT study, conducted at four hospitals in Melbourne, is designed to test whether use of a conservative intensive chemotherapy backbone with 5+2 induction could reduce the risk of severe marrow hypoplasia in elderly treatment-naive patients, and minimize the occurrence of TLS with a venetoclax ramp-up prephase and staggered introduction of chemotherapy.

Patients 65 years and older with de novo, secondary, or therapy-related AML with no prior exposure to induction chemotherapy were enrolled. Patients for whom previous therapy with hydroxyurea, low-dose cytarabine, hypomethylating agents, or nonchemotherapy investigational agents had failed could be included in the study. Also eligible for inclusion were patients 60 years and older with a monosomal AML karyotype.

Prior to induction, there was a 7-day venetoclax prephase with a dose ramp-up to achieve a steady state. The trial contains five dose-escalation cohorts, with venetoclax started at doses of either 50 mg (cohort A), 100 mg (B), 200 mg (C), 400 mg (D), or 600 mg (E).

Also during induction, chemotherapy was staggered and doses were attenuated, beginning with the addition of continuous intravenous infusion of cytarabine 100 mg/m² per day on days 8 through 12 and idarubicin 12 mg/m² IV on days 9 and 10 of each cycle.

For those patients who achieved a remission, there was a venetoclax-free phase after day 14 to allow for hematopoietic recovery. Patients in remission can receive further therapy with four cycles of “continuation,” each of which was 14 days of venetoclax at the cohort-prescribed dose plus bolus cytarabine 100 mg/m² IV on days 8 and 9 and idarubicin 12 mg/m² IV on day 8. After the continuation phase, up to seven cycles of venetoclax monotherapy maintenance can be given.

 

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

 

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

Among 41 patients with a median age of 72 years treated at one of five venetoclax dose levels, the objective response rate for all patients combined was 71%, and the median overall survival was 7.7 months, reported Andrew H. Wei, MD, from Monash University in Melbourne.

“Venetoclax up to 600 mg in combination with a 5 plus 2 intensive chemotherapy approach is indeed feasible, with very reasonable count recovery times not unexpected for intensive chemotherapy,” Dr. Wei said at the annual congress of the European Hematology Association.

“A high response rate was observed, and we had very low levels of TLS [tumor lysis syndrome] – in fact no evidence of clinical TLS – and early mortality was also low,” he added.

Previous studies have shown that venetoclax in combination with hypomethylating agents or low-dose cytarabine has promising efficacy for the treatment of elderly patients with AML who are considered to be not fit enough to withstand the rigors of intensive chemotherapy.

“We know that intensive chemotherapy in older patients delivers a remission rate of approximately 60%, and the French group [Acute Leukemia French Association] have demonstrated that low-dose ambulatory approaches are as good as, if not even superior to, intensive consolidation,” he said.

Additionally, other studies have suggested that attenuated-dose or “5+2” induction chemotherapy in patients aged 65 years or older is associated with a combined complete remission (CR) and CR with incomplete recovery of counts (CRi) rate approaching 60%, Dr. Wei noted.

The investigator-initiated CAVEAT study, conducted at four hospitals in Melbourne, is designed to test whether use of a conservative intensive chemotherapy backbone with 5+2 induction could reduce the risk of severe marrow hypoplasia in elderly treatment-naive patients, and minimize the occurrence of TLS with a venetoclax ramp-up prephase and staggered introduction of chemotherapy.

Patients 65 years and older with de novo, secondary, or therapy-related AML with no prior exposure to induction chemotherapy were enrolled. Patients for whom previous therapy with hydroxyurea, low-dose cytarabine, hypomethylating agents, or nonchemotherapy investigational agents had failed could be included in the study. Also eligible for inclusion were patients 60 years and older with a monosomal AML karyotype.

Prior to induction, there was a 7-day venetoclax prephase with a dose ramp-up to achieve a steady state. The trial contains five dose-escalation cohorts, with venetoclax started at doses of either 50 mg (cohort A), 100 mg (B), 200 mg (C), 400 mg (D), or 600 mg (E).

Also during induction, chemotherapy was staggered and doses were attenuated, beginning with the addition of continuous intravenous infusion of cytarabine 100 mg/m² per day on days 8 through 12 and idarubicin 12 mg/m² IV on days 9 and 10 of each cycle.

For those patients who achieved a remission, there was a venetoclax-free phase after day 14 to allow for hematopoietic recovery. Patients in remission can receive further therapy with four cycles of “continuation,” each of which was 14 days of venetoclax at the cohort-prescribed dose plus bolus cytarabine 100 mg/m² IV on days 8 and 9 and idarubicin 12 mg/m² IV on day 8. After the continuation phase, up to seven cycles of venetoclax monotherapy maintenance can be given.

 

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

 

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

Among 41 patients with a median age of 72 years treated at one of five venetoclax dose levels, the objective response rate for all patients combined was 71%, and the median overall survival was 7.7 months, reported Andrew H. Wei, MD, from Monash University in Melbourne.

“Venetoclax up to 600 mg in combination with a 5 plus 2 intensive chemotherapy approach is indeed feasible, with very reasonable count recovery times not unexpected for intensive chemotherapy,” Dr. Wei said at the annual congress of the European Hematology Association.

“A high response rate was observed, and we had very low levels of TLS [tumor lysis syndrome] – in fact no evidence of clinical TLS – and early mortality was also low,” he added.

Previous studies have shown that venetoclax in combination with hypomethylating agents or low-dose cytarabine has promising efficacy for the treatment of elderly patients with AML who are considered to be not fit enough to withstand the rigors of intensive chemotherapy.

“We know that intensive chemotherapy in older patients delivers a remission rate of approximately 60%, and the French group [Acute Leukemia French Association] have demonstrated that low-dose ambulatory approaches are as good as, if not even superior to, intensive consolidation,” he said.

Additionally, other studies have suggested that attenuated-dose or “5+2” induction chemotherapy in patients aged 65 years or older is associated with a combined complete remission (CR) and CR with incomplete recovery of counts (CRi) rate approaching 60%, Dr. Wei noted.

The investigator-initiated CAVEAT study, conducted at four hospitals in Melbourne, is designed to test whether use of a conservative intensive chemotherapy backbone with 5+2 induction could reduce the risk of severe marrow hypoplasia in elderly treatment-naive patients, and minimize the occurrence of TLS with a venetoclax ramp-up prephase and staggered introduction of chemotherapy.

Patients 65 years and older with de novo, secondary, or therapy-related AML with no prior exposure to induction chemotherapy were enrolled. Patients for whom previous therapy with hydroxyurea, low-dose cytarabine, hypomethylating agents, or nonchemotherapy investigational agents had failed could be included in the study. Also eligible for inclusion were patients 60 years and older with a monosomal AML karyotype.

Prior to induction, there was a 7-day venetoclax prephase with a dose ramp-up to achieve a steady state. The trial contains five dose-escalation cohorts, with venetoclax started at doses of either 50 mg (cohort A), 100 mg (B), 200 mg (C), 400 mg (D), or 600 mg (E).

Also during induction, chemotherapy was staggered and doses were attenuated, beginning with the addition of continuous intravenous infusion of cytarabine 100 mg/m² per day on days 8 through 12 and idarubicin 12 mg/m² IV on days 9 and 10 of each cycle.

For those patients who achieved a remission, there was a venetoclax-free phase after day 14 to allow for hematopoietic recovery. Patients in remission can receive further therapy with four cycles of “continuation,” each of which was 14 days of venetoclax at the cohort-prescribed dose plus bolus cytarabine 100 mg/m² IV on days 8 and 9 and idarubicin 12 mg/m² IV on day 8. After the continuation phase, up to seven cycles of venetoclax monotherapy maintenance can be given.

 

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.