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*

Allo-BMT, allogeneic bone marrow transplant; AML, acute myeloid leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; ELN, European LeukemiaNet; HMA, hypomethylating agent; R/R, relapsed/refractory. *Adapted from Federico V. et al.2
Characteristic	All patients (n = 24)	De novo AML (n = 14, 60%)	R/R AML (n = 10, 40%)
Median age, years	69	71	63
Sex               M, %	58	57	60
ECOG PS, %               0−1               2−4	60 40	65 35	50 50
ELN-2017 cytogenetic risk, %               Intermediate               Adverse	40 60	44 56	20 80
Peripheral blasts, %	30	30	20
Bone marrow blasts, %	55	40	60
Previous treatment, %               HMA               AML-like induction therapy               Allo-BMT	— — —	— — —	30 50 20

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.

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*

AML, acute myeloid leukemia; CR, complete remission; iCR, CR with incomplete marrow recovery; PR, partial response. *adapted from Federico V. et al.2
Response	All patients (n = 24)	De novo AML (n = 14, 60%)	R/R AML (n = 10, 40%)
Median number of cycles delivered	3	3	3
Overall response rate, %               CR               iCR               PR	79 42 21 17	78.5 50 21.5 7	70 30 20 20
No response, %	20	21.5	30
Median time to response, months (range)	1−5	1−5	1−5

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*

CR, complete remission; CTX +3, chemotherapy-treated for 3 days; CTX +5, chemotherapy-treated for 5 days; MMF, mycophenolate mofetil; CSA, cyclosporine A; iCR, CR with incomplete bone marrow recovery; R/R, relapse/refractory; TBF BU2, thiotepa-busulfan-fludarabine for 2 days; TBF BU3, thiotepa-busulfan-fludarabine for 3 days. *Adapted from Federico V. et al.2; †All values are in % except mentioned otherwise.
Characteristic	(%)†
Median Age, years	52
Cytogenetic profile               Intermediate               Adverse	22 78
Status at transplant               CR               iCR	66 34
Donor number               Haploidentical               Match related               Match unrelated	66 12 22
Stem cell source               Peripheral blood stem cells	100
Conditioning regimens               TBF BU2               TBF BU3	22 78
GvHD prophylaxis               CTX +3, CTX +5; MMF               CSA; Metorexate	66 34
GvHD Grade 1−2 Grade 3−4	66 12

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.