EHA 2018 | BCL-2 inhibitors in AML

BCL-2 family proteins play a key role in regulating apoptosis via the intrinsic mitochondrial cell death pathway. In acute myeloid leukemia (AML), overexpression of the BCL-2 protein has been shown to be associated with poor outcomes and conferring chemotherapeutic resistance.¹

At the 23^rd Congress of the European Hematology Association (EHA), there was an oral session consisting of two talks on BCL2 inhibitors in AML. In an interview with the AGP, Daniel Pollyea from the University of Colorado School of Medicine, Aurora, CO, noted that “BCL-2 inhibition is a very promising therapeutic target in AML.”

At this session, Courtney DiNardo from The University Texas MD Anderson Cancer Center, Houston, TX, presented data from a dual-stage, non-randomized phase Ib study (NCT02203773), which is assessing the safety and efficacy of venetoclax (VEN), a BCL2 inhibitor, in combination with decitabine (DEC) or azacitidine (AZA) in previously untreated older AML patients who are ineligible for standard induction therapy. The results of this study were originally presented at the 2018 American Society of Oncology (ASCO) Annual Meeting and was reported by the AGP here. In an interview with the AGP, Dr. DiNardo noted that the preliminary data from this phase 1b study suggest that VEN in combination with DEC or AZA demonstrated a tolerable safety profile with deep responses and durable outcomes in elderly patients with AML. ²

Andrew Wei (chair of our Rest of the World steering committee) from Monash University, Melbourne, AU, gave the second talk on BCL2 inhibitors. The speaker presented data from a phase Ib dose escalation study of VEN in combination with intensive chemotherapy in fit elderly AML patients. The primary objective of the study was to evaluate the optimal dose, safety and efficacy of VEN 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).³

At data cut-off date of 11 May 2018, a total of 41 AML 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 VEN pre-phase incorporating dose ramp-up to achieve steady state prior to commencing chemotherapy was administered. Dose escalation of VEN began at 50 mg (n = 8), 100 mg (n = 8), 200 mg (n = 9) and 600 mg (n = 8) 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 VEN 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

  • One 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
  • Grade ≥3 adverse events (≥10% of patients) during induction were thrombocytopenia (100%), neutropenia (100%), febrile neutropenia (70%), neutropenic sepsis (24%) and atrial fibrillation (14%)
  • Maximum tolerated dose: not reached
  • Early mortality rate with 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
• During the venetoclax pre-phase, the median relative bone marrow blast count change was 20% (range -70.5 – +14.5%)

• Efficacy

  • Complete remission (CR) plus CR with incomplete blood count (CRi) rate in all patients: 71%
  • CR/CRi rate in 50 mg VEN cohort: 63%
  • CR/CRi rate in 100 mg VEN cohort: 75%
  • CR/CRi rate in 200 mg VEN cohort: 100%
  • CR/CRi rate in 400 mg VEN cohort: 63%
  • CR/CRi rate in 600 mg VEN cohort: 50%
  • Median OS for all patients: 7.7 months
    • Median OS for patients in CR (n = 12), CRi (n = 12) and patients with no CR/CRi (n = 13) were 12, 7.7 and 6.3 months, respectively; P = 0.0039
    • Patients with no prior therapy (no treatment with HMA/LDAC) had a better survival than patients with prior therapy (HMA/LDAC)

In an interview with the AGP, Dr. Wei summarized his data by stating that VEN up to 600 mg in combination with 5 +2 induction is “tolerable”. Additionally, high response rates were observed with low TLS and early mortality rates.  He further added that the findings of this study “paves a way for introducing venetoclax into intensive chemotherapy combinations for potentially younger patients with AML”.