The Combination of Decitabine Plus Venetoclax Is an Active Salvage Therapy for AML Post HR-MDS Progressed during Treatment with Azacitidine Based Regimens

Background: Higher risk IPSS-R myelodysplastic syndromes (HR-MDS) are characterized by high propensity to transform into acute myeloid leukemia (AML). Azacitidine (AZA) and decitabine (DAC) are standard of care for HR-MDS and overall response rates (ORR) range from 25 to 40% with a median overall survival (OS) of 13-17 months. Responses to hypomethylating agents (HMA) are transient and disease progression almost inevitable. These observations prompted to evaluate the ongoing novel combination therapies with HMAs as backbone. At present, acute myeloid leukemia (AML) post HR MDS treated with HMAs have very scarce therapeutic salvage options. The oral inhibitor of BCL-2 Venetoclax (VEN) has been approved for treatment of de novo AML in combination with either HMAs. Scarce data are available describing possible salvage treatment with DAC+VEN after AZA failure in HR MDS progressed to AML.

Aims and Methods: We evaluated at MDS UNIT, AOU Careggi-University of Florence, 6 consecutive patients with AML post HR MDS. Patients were treated as outpatients with decitabine plus venetoclax after progression during AZA treatment. IPSS-R calculated before starting AZA was high (4 pts) and very high (2 pts). All patients had previously received standard regimen of azacitidine 75 mg/mq s.c. for 5+2 days every 28 days; median number of cycles was 19 (3-49). 3 pts were primary refractory to AZA, 1 obtained CR and 2 stable disease with hematological improvement. All patients received DAC 20 mg/mq i.v. for 5 days and VEN 400 mg/day for 14 days every 28 days.

Results: Median age was 72, all patient were male. At progression, median bone marrow blasts were 25% (range 20-90). Five patients had a normal karyotype and 1 had trisomy of chromosome 8. All patients had at least 1 somatic mutation, with a median of 4 mutated genes (1-8), RUNX1 (2 pts), DNMT3A (3 pts), TET2 (3 pts), ASXL1 (2 pts). None presented IDH1/2 mutation, nor FLT3 ITD or TP53. None of them was eligible for intensive chemotherapy nor hematopoietic stem cell transplant. Median number of cycles of DAC + VEN was 5.5 (2-14), overall response rate was 50% with 2 complete responses and 1 partial response. Median duration of response was 8 months.

Response to DAC+VEN was independent from achievement and duration of response to previous AZA therapy and from mutational status. The most frequent side effect was febrile neutropenia G4 with infection: 3 bacterial pneumonia (2 G3 and 1 G2), 2 esophageal candidiasis (1 G2 e 1 G3) and 1 sepsi (G3) with 4/6 who required hospitalization for severe infections. Median OS from starting DAC+VEN was 21 months: 3 patients died during treatment (1 pt died after 2 cycles, 1 after 3 cycles and 1 after 14 cycles): 1 for bleeding and 3 for infection; 1 pt died 5 months after interruption of treatment for relapse of AML. 2 patients are still in treatment.

Conclusions: Combination of Decitabine plus Venetoclax seems to have a role as salvage therapy in AML post AZA-treated HR MDS. In consideration of the absence of effective treatments, our extremely preliminary data could indicate a feasible option for a subset of patients without actionable mutations permissive of rescue with target therapy.

Sanna:Astra Zeneca: Honoraria, Speakers Bureau; Abbvie: Honoraria, Other: travel, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: travel, Speakers Bureau. Santini:AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.