Venetoclax with HMA: A bridge to transplant in high-risk acute myeloid leukemia

High-risk acute myeloid leukemia (AML) is characterized by a high frequency of cytogenetic adverse-risk features which results in poor response to chemotherapy by patients.

Antiapoptotic B-cell lymphoma protein 2 (BCL-2) overexpression is associated with survival of AML cells and treatment resistance. In preclinical studies, venetoclax, which is an inhibitor of BCL-2, along with hypomethylating agents (HMAs) such as azacitidine, have been shown to induce cell death in AML-derived cell lines. In a previous study, which included elderly patients with intolerance to intensive chemotherapy, a synergistic treatment of venetoclax with HMA provided promising efficacy and a tolerable safety profile.¹

Recently, at the 47th Annual Meeting of the EBMT, Federico V. et al. reported their single-center study to evaluate efficacy and safety of the combination of venetoclax and HMAs in patients with de novo or relapsed/refractory (R/R) AML.²

Patient demographics and baseline characteristics

In total, 24 patients were selected for the study with a median age of 69 (27−80 years). Table 1 includes details of patient demographics and baseline characteristics. Patients were divided into two groups. Patients in the de novo AML group (n = 14) had adverse cytogenic features and were not eligible for intensive chemotherapy treatment, but there was no incidence of relapse. The second group was the R/R AML group (n = 10), which included patients with incidence of relapse after receiving HMA (n = 3), AML induction therapy (n = 5), and allogeneic bone marrow transplant (n = 2).

Table 1. Patient demographics and baseline characteristics*

Dosing schedule and treatment design

Each patient received a median of three cycles of treatment with a range of 1−19 cycles. Each cycle spanned for 28 days. All patients received venetoclax (100−400 mg) orally, while 20 mg/m² decitabine was administrated intravenously to 15 patients, and 75mg/m² of azacitidine was administered subcutaneously in nine patients. The treatment design and dosing schedule are presented in Figure 1.

Figure 1. Dosing schedule and treatment design for the study*

IV, intravenous; SC, subcutaneous; PO, oral administration.

*Adapted from Federico V. et al.²

Patient responses to the treatment

In the de novo AML cohort, the following aspects were observed: 78.5% of overall response rate, 50% of complete remission (CR), and 21.5% CR with incomplete marrow recovery. Median time to respond in this group was 2 months (Table 2).

In the R/R cohort, overall response rate was observed in 70% of patients, 30% had CR, and 20% of patients had CR with incomplete marrow recovery (Table 2).

Table 2. Response to the treatment*

Toxicity

Grade 3−4 toxicities included anemia (52%), thrombocytopenia (44%), leukopenia (62%), febrile neutropenia (61%), sepsis (32%), nausea (20%), and vomiting (12%). No deaths were observed during induction.

Transplant data

After a median of three cycles (range, 3−4) receiving HMA with venetoclax, nine patients (six with R/R AML, and three with de novo AML) underwent allogeneic stem cell transplantation (allo-SCT) with a mean cell dose of 6.3 × 10⁶ kg. Further details on the characteristics of transplanted patients are summarized in Table 3.

After a median follow-up of 5 months (range, 2−22), 14 (58%) patients survived, 5 (21%) patients are still on therapy and in CR, and 10 (42%) patients had died of progressive disease.

Table 3. Patient characteristics for allo-SCT*

Overall survival: transplanted vs nontransplanted patients

Significant overall survival (OS) improvements were observed for transplanted patients compared with nontransplanted patients; OS was 9.7 months in transplanted patients, and 3.0 months in nontransplanted patients (p = 0.001).

Conclusion

These short-term follow-up results indicate that venetoclax plus HMA can be a well-tolerated and effective combination for high-risk AML patients. Outcomes were particularly favorable in patients who underwent allo-SCT after HMA-venetoclax treatment (9.7 vs 3.0; p = 0.001). Thus, prior treatment of de novo or R/R AML patients who are referred for allo-SCT with HMA-venetoclax, could be a suitable option to attain better survival rates.