Venetoclax Combined with Intensive Chemotherapy As an Induction Chemotherapy in Newly Diagnosed FLT3-ITD Positive AML

Background

The FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is found in approximately 20-25% of newly diagnosed acute myeloid leukemia (AML), which are previously associated with a poor prognosis. The complete response (CR) rate with conventional chemotherapy is around 50-70%. The overall survival (OS) of patients have been improved through the synergistic application of small molecule FIT3 inhibitors (sorafenib, midostaurin, quizartinib, etc) and Allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Nevertheless, no substantial enhancement in the CR rate was observed when compared to traditional chemotherapy. Venetoclax (Ven), an oral Bcl-2 inhibitor, combined with intensive chemotherapy (IC) improved CR rate in de novo AML patients. To date, there has been no reported evidence of the effectiveness of VEN combined with IC for de novo AML with FLT3/ITD.

In this study, we conducted a retrospective analysis of data from 63 newly diagnosed FLT3-ITD positive AML patients who received VEN+IC as inducion chemotherapy. The purpose of this study was to evaluate the efficacy and safety of the regimen in newly diagnosed AML with FLT3/ITD.

Methods

Retrospectively collected and analyzed the clinical data of 63 newly diagnosed AML with FLT3/ITD patients who treated with Ven combined with IC (VEN+DA: ChiCTR2200061524; VEN+HAA: ChiNCT05893472; VEN+HAD) as induction therapy between January, 2022, and June, 2024 in china.

The induction regimen consisted of a 7-day oral administration of VEN, in combination with either DA (DNR 60 mg/m²/day d2–3, and Ara-c 100 mg/m²/q12h d2–7), HAA (HHT 2.5mg/m2/day d3-7, Ara-c 100 mg/m²/day d3-7, and Acla 20mg/day d3-7), or HAD regimen (HHT 2mg/m2/day d2-6, DNR 45 mg/m²/day d 4-5, and Ara-c 100 mg/m²/day d2-6).

After achieving CR or CRi, Allo-HSCT were recommended according to ELN guideline and Chinese guidelines for the diagnosis and treatment of adult AML. Patients who cannot not proceed Allo-HSCT received consolidation and maintenance therapy.

The primary purpose was evaluated the efficacy and safety of VEN combined with IC as induction regimen in patients with de novo FLT3/ITD (+) AML. Secondary purpose was overall survival (OS), event-free survival (EFS), disease-free survival (DFS).

Results

Between January, 2022 and June, 2024, 63 newly diagnosed FLT3-ITD (+) AML patients were enrolled and treated with VEN combined with IC as induction therapy. The median age was 40 years (range, 16-59). The median allelic ratio of FLT3-ITD mutation was 0.53(0.01-14.75). Within this cohort, 28 patients received VEN+DA, 26 patients were treated with VEN+HAA, and 9 patients underwent treatment with VEN+HAD. One patient died during the induction therapy and one patient was not evaluated. The ORR(CR+PR) rate after one cycle of induction was 97.7% (59/61;95% CI 92.3–100%) with CR rate of 91.80% (56/61,95% CI 87.2–99.7%). Moreover, 92.5% (49/53) of the patients achieved CR with undetectable MRD (95% CI 85.1–99.8%). Grade 3 or worse adverse effects included neutropenia (100%), thrombocytopenia (100%), febrile neutropenia (98.4%). The median neutrophil and platelet recovery times were 14(range:5-52) and 14(range:6-63) days, respectively.

Until June,30, 2024, with a median follow-up of 9 (1-25) months, 19.0% of patients underwent allo-HSCT. The median OS, EFS and RFS were not reached. The estimated one-year OS, EFS and RFS were 73% (95% CI: 61.2-84.8%), 59% (95% CI: 45.3-72.7%) and 59% (95% CI: 45.3-72.7%), respectively.

Conclusion

Venetoclax in combination with IC is a highly effective and safe induction therapy for newly diagnosed FLT3-ITD positive AML patients.