For patients with secondary acute myeloid leukemia (sAML) or relapsed/refractory (R/R) acute myeloid leukemia (AML), improved responses were anticipated when adding the B-cell lymphoma 2 inhibitor venetoclax (VEN) to a standard regimen of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) as a result of increased apoptosis priming by the preceding multichemotherapy.
Primary objectives of this study included identifying the maximal tolerated dose of FLAG-IDA in combination with VEN (FLAG-IDA-VEN), detecting any dose-limiting toxicities, and assessing safety and tolerability. Secondary objectives included assessment of the overall response rate (ORR: complete response [CR] + CR with incomplete hematologic recovery [CRi] + CR with partial hematologic recovery [CRh] + morphologic leukemia-free state + partial response), composite CR (CRc: CR + CRh + CRi), overall survival (OS), event-free survival (EFS), duration of response (DOR), and biomarkers predicting response/resistance. The phase 1b (P1b) dose-escalation study was described previously. The phase 2 dose-expansion study included patients with newly diagnosed AML (arm A; P2A), and patients with R/R AML (arm B; P2B).
At data cutoff, 68 patients had completed at least 1 cycle of therapy. The median age was 51 years in the P1b arm, 45 in the P2A arm, and 47 in the P2B arm. Of these patients, 16% of patients had sAML or therapy-related AML. Per the European LeukemiaNet classification, 25% had favorable risk, 26% had intermediate risk, and 49% had adverse risk. The proportion of patients previously receiving allogeneic stem-cell transplantation (allo-SCT) was 50% in P1b and 30% in P2B. The most common reason for study discontinuation was transition to allo-SCT. Grade 3/4 adverse events occurring in ≥10% of patients were febrile neutropenia, bacteremia, and pneumonia (50%, 35%, and 28%, respectively). The ORR was 82%, with 97% of newly diagnosed patients and 72% of R/R patients achieving CRc. Overall, 83% of patients achieved a minimal residual disease–negative status while in CRc (newly diagnosed, 96%; R/R, 69%). CRc was achieved by 90% and 67% of newly diagnosed and R/R AML patients, respectively. After a median follow-up of 12 months, the median OS was not reached (NR) and the EFS was 16 months. Landmark 1-year OS rates were 94% in P2A, 38% in P1b, and 68% in P2B. Median DOR was 6 months in the P1b arm and NR in the P2A and P2B arms. Approximately half (46%) of patients (n = 32) moved on to allo-SCT. Among these patients, the 30- and 60-day post–allo-SCT mortality rates were 0%. Among R/R AML patients receiving allo-SCT, the 1-year OS rate was 87% and the 1-year post–allo-SCT OS was 78%. Relapsed/refractory AML patients with mutations in TP53 experienced inferior outcomes (ORR, 43%; CRc, 43%; n = 7).
In conclusion, the combination of VEN and FLAG-IDA was effective, elicited deep responses, and had an acceptable safety profile across multiple AML subgroups. For adverse-risk newly diagnosed AML and R/R AML patients, this treatment regimen may be an attractive option and as a bridge to allo-SCT.
Reference
Abstract 332. ASH 2020. December 6, 2020. Interim Analysis of the Phase 1b/2 Study of the BCL-2 Inhibitor Venetoclax in Combination with Standard Intensive AML Induction/Consolidation Therapy with FLAG-IDA in Patients with Newly Diagnosed or Relapsed/Refractory AML.