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Venetoclax plus Standard Intensive AML Induction/Consolidation with FLAG-IDA in Patients with Newly Diagnosed or Relapsed/Refractory AML

2020 Year in Review - AML

In this post-hoc analysis, data from the BRIGHT AML 1003 study were used to evaluate the potential association of early blood counts with overall survival (OS) or leukemia response among patients receiving glasdegib (GLAS) plus low-dose cytarabine (LDAC) or LDAC alone. Patients with newly diagnosed acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy were randomized to GLAS + LDAC (N = 78) or LDAC alone (N = 38). GLAS was given once daily and LDAC was given on days 1 to 10 of a 28-day cycle. Peripheral blood counts were measured at cycle 2, day 1 (C2D1), approximately 1 month prior to the first bone marrow assessments. OS was compared between GLAS + LDAC and LDAC in subgroups meeting thresholds of absolute neutrophil count (ANC; ≥1000 or 500/µL), hemoglobin (Hb; ≥10 or 9 g/dL), or platelets (≥100,000 or 50,000/µL). Patients were included in this analysis regardless of transfusion status. The data cutoff for this analysis was April 2019.

Among all patients, attaining the aforementioned ANC, Hb, and platelet thresholds at C2D1 was associated with improved median OS (mOS) to a greater extent for patients receiving GLAS + LDAC versus LDAC alone, as follows: ANC 0.5 x 103: 9.0 months versus 4.9 months (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.21-0.76; P = .002), ANC 103: 7.4 months versus 3.8 months (HR, 0.36; 95% CI, 0.16-0.81; P = .005), Hb ≥9: 12.4 months versus 4.9 months (HR, 0.35; 95% CI, 0.17-0.72; P = .002), Hb ≥10: 8.7 months versus 3.0 months (HR, 0.33; 95% CI, 0.12-0.8Standard therapy with the fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) regimen is often used in patients with secondary acute myeloid leukemia (AML) or relapsed/refractory AML. Improved responses were anticipated upon addition of the B-cell lymphoma 2 inhibitor venetoclax (VEN) because of an increase in apoptosis priming by the preceding multichemotherapy.

Primary objectives of this study were to assess safety and tolerability, determine any dose-limiting toxicities, and identify the maximal tolerated dose of FLAG-IDA in combination with VEN (FLAG-IDA-VEN). Secondary objectives were to determine 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, duration of response, and biomarkers predicting response/resistance. The phase 1b (P1b) dose escalation was previously described; the 2 arms in the phase 2 dose expansion were arm A (P2A): newly diagnosed AML, and arm B (P2B): relapsed/refractory AML.

At data cutoff, 68 patients completed ≥1 cycles of therapy. The median age was 51, 45, and 47 years in the P1b, P2A, and P2B arms, respectively. Eighteen percent of patients had secondary AML or therapy-related AML. Favorable, intermediate, and adverse risk per the European LeukemiaNet classification were seen among 25%, 26%, and 49% of patients, respectively. Fifty percent and 30% of P1b and P2B patients, respectively, received prior allogeneic stem-cell transplantation (allo-SCT).

Transition to allo-SCT was the most common reason for study discontinuation. Grade 3/4 adverse events occurring in ≥10% of patients were febrile neutropenia (50%), bacteremia (35%), and pneumonia (28%).

The ORR was 82%, with 97% and 72% of newly diagnosed and relapsed/refractory patients achieving CRc, respectively. Eighty-three percent of patients achieved a minimal residual disease–negative status while also in CRc (newly diagnosed, 96%; relapsed/refractory, 69%). CRc was achieved by 90% of newly diagnosed AML patients and 67% of relapsed/refractory AML patients.

Median OS and event-free survival were not reached and 16 months, respectively, after a median follow-up of 12 months. Landmark 1-year OS rates were 94%, 38%, and 68% in P2A, P1b, and P2B, respectively. Median duration of response was 6 months in P1b patients and not reached in patients in P2A and P2B. Approximately half (46%) of patients (n = 32) were successfully bridged to allo-SCT; the 30- and 60-day post–allo-SCT mortality rate was 0%, while 1-year OS was 87% for relapsed/refractory AML patients bridged to allo-SCT. One-year post–allo-SCT OS was 78% in relapsed/refractory AML patients bridged to allo-SCT. Inferior outcomes were observed for relapsed/refractory patients with mutations in TP53 (ORR, 43%; CRc, 43%; n = 7).

Combined therapy with VEN and FLAG-IDA was effective, elicited deep responses, and had an acceptable safety profile across multiple AML subgroups, thus representing an attractive option for adverse-risk newly diagnosed AML patients and relapsed/refractory AML patients, and as a bridge to allo-SCT.

Lachowiez C, Konopleva M, Kadia TM, et al. 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. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition, December 5-8, 2020. Abstract 332.

7; P = .009), platelets ≥0.5 x 105: 14.9 months versus 4.7 months (HR, 0.22; 95% CI, 0.09-0.50; P <.001), and platelets ≥105: 18.5 months versus 4.3 months (HR, 0.17; 95% CI, 0.06-0.51; P <.001), respectively. Similar OS benefits for GLAS + LDAC compared with LDAC alone were observed among patients who did not meet ANC, Hb, or platelet thresholds at C2D1. Patients with baseline anemia or thrombocytopenia also had improved OS associated with C2D1 recovery of Hb or platelets, with mOS for GLAS + LDAC versus LDAC as follows: Hb ≥9: 9.1 months versus 2.9 months (HR, 0.16; 95% CI, 0.04-0.62; P = .001) or Hb ≥10: 9.1 months versus 2.9 months (HR, 0.27; 95% CI, 0.07-0.95; P = .015); and platelets ≥0.5 x 105: 19.1 months versus 6.4 months (HR, 0.19; 95% CI, 0.04-0.82; P = .007) or platelets ≥105: 19.6 months versus 5.1 months (HR, 0.13; 95% CI, 0.03-0.53; P <.001), respectively. Any degree of response (complete response [CR]/CR with incomplete hematologic recovery/partial response) to GLAS + LDAC correlated with achieving platelet thresholds at C2D1, including recovery in patients with baseline thrombocytopenia. Of the 13 patients in the GLAS + LDAC arm with baseline platelets <0.5 x 105 who achieved C2D1 platelets ≥105, 11 (84.6%) were responders compared with 2 (15.4%) who were nonresponders (P <.0001).

In conclusion, improved OS was associated with attaining various blood count thresholds after 1 cycle of GLAS + LDAC versus LDAC alone in patients with newly diagnosed AML who were not eligible for intensive chemotherapy. In addition, recovery of Hb and platelet thresholds was associated with improved OS among patients with baseline measurements below threshold. Finally, platelet recovery was correlated with response in the GLAS + LDAC group.


Wang ES, Heuser M, Sekeres MA, et al. Effect of Early Blood Counts on Response and Overall Survival Following Glasdegib plus LDAC in Newly Diagnosed AML: Bright AML 1003 Post Hoc Analysis. Presented at: 25th European Hematology Association Congress Virtual; June 11-21, 2020. Abstract EP633.

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