ASH 2018 | Venetoclax in combination with chemotherapy in elderly patients with acute myeloid leukemia – CAVEAT study

At the 60^th American Society of Hematology Annual Meeting & Exposition, Chong Chyn Chua from The Alfred Hospital and Monash University, Melbourne, AU, gave a talk on the use of venetoclax in combination with intensive chemotherapy in fit elderly patients with acute myeloid leukemia (AML) .

The speaker presented updated data and molecular correlates of response from a phase Ib dose escalation study of venetoclax in combination with a dose-modified intensive chemotherapy regimen, in fit elderly AML patients who have not received prior induction chemotherapy. The primary objective of the study was to evaluate the optimal dose, safety and efficacy of venetoclax in combination with dose-modified intensive chemotherapy in older patients with AML. The secondary objectives were to evaluate the clinical response rates, overall survival (OS), duration response, time to hematopoietic recovery and rate of tumor lysis syndrome (TLS).

At data cut-off of 13 July 2018, 46 patients (median age = 72 years; range, 63–80) have been enrolled in this study. In order to mitigate the risk of hematologic toxicity and TLS, a 7-day venetoclax pre-phase, incorporating dose ramp-up to achieve steady state prior to commencing chemotherapy, was administered. Dose escalation of VEN began at 50 mg (cohort A), 100 mg (cohort B), 200 mg (cohort C), 400 mg (cohort D) and 600 mg (cohort E) on days 6–7 in combination with 5 +2 induction chemotherapy on days 1–5 (cytarabine [100 mg/m²/d IV on days 1–5] and idarubicin [12 mg/m²/d IV on days 2–3]) for one cycle. Patients who achieved complete remission (CR) were administered a consolidation consisting of venetoclax in combination with 2+1 chemotherapy (cytarabine [100 mg/m²/d IV on days 1–2] and idarubicin [12 mg/m²/d IV on day 1) for up to four cycles.

Key findings:

Safety

• Two hematologic dose-limiting toxicity (grade 4 neutropenia or thrombocytopenia persisting beyond day 42 from day 1 of chemotherapy) occurred in the 600 mg VEN cohort
• Main grade ≥3 non-hematological adverse events during induction were febrile neutropenia (56%), sepsis (32%), rapid atrial fibrillation (15%), diarrhea (12%), nausea (10%) and localized infection (10%)
• Maximum tolerated dose: not reached
• Treatment-related early mortality rate within 42 days: 7%
• Median time to both neutrophil (≥ 0.5x10⁹/L) and platelet (≥ 50x10⁹/L) recovery for patients in CR/CRi during induction was 25 days from day 1 of chemotherapy

Efficacy

• Complete remission (CR) plus CR with incomplete blood count (CRi) rate in all patients: 70%
• CR/CRi rate in patients with de novo AML: 96%
• CR/CRi rate in patients with therapy-related (t-AML)/secondary AML (s-AML): 41%
• CR/CRi rate in patients with t-AML/s-AML with prior hypomethylating agents (HMA): 44%
• CR/CRi rate in patients with t-AML/s-AML with no HMA: 33%
• Median follow-up: 11.6 months
• Median OS for all patients: 7.7 months
• Median OS for patients with de novo AML: 15.4 months
• During the venetoclax pre-phase, 47% (18/38) had ≥ 50% relative reduction in bone marrow blasts

• Molecular data were available for 32 responders
  • 8/8 (100%) response-evaluable NPM1mutant AML achieved CR/CRi
  • 10/11 (91%) response-evaluable IDHmutant AML achieved CR/CRi
  • Lowest responses were observed in TP53 mutant AML

The speakers concluded by stating that “venetoclax up to 600mg in combination with 5+2 induction chemotherapy is tolerable and is associated with a high CR/CRi in patients with de novo AML.

Initial response rates were observed in NPM1 and IDH mutant AML, whereas responses were lower in patients with prior HMA exposure, adverse karyotype, secondary and TP53 mutant AML. Molecular determinants of relapse require further study.”