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

May 6, 2021
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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*

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

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

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*

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

AML, acute myeloid leukemia; CR, complete remission; iCR, CR with incomplete marrow recovery; PR, partial response.

*adapted from Federico V. et al.2

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*

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

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.

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.

  1. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216-228. DOI: 1016/S1470-2045(18)30010-X
  2. Federico V, D’Argenio M, Matera R, et al. Venetoclax combined with hypomethylating agent (HMA) is safe and effective may be a good bridge to transplant in high-risk acute myeloid leukemia. Oral abstract #OS17-5. 47th Annual Meeting of the EBMT; Mar 14−17, 2021; Virtual.

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