2023 SOHO: Efficacy and Safety of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subpopulation from Phase 2 and ASCERTAIN Phase 3 Studies

View Presentation:  Efficacy and Safety of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subpopulation from Phase 2 and ASCERTAIN Phase 3 Studies


Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disease characterized by persistent monocytosis, splenomegaly, and both dysplastic and myeloproliferative changes in the bone marrow. Hypomethylating agents (HMAs) are approved for CMML treatment. ASTX727 (DEC/CED), an orally available fixed dose combination (FDC) of 35 mg decitabine (DEC) and 100 mg cedazuridine (CED), a cytidine deaminase inhibitor, produces comparable PK AUC exposure compared to IV DEC (Garcia-Manero, et al, 2019).

Aims: We present the  combined clinical experience of CMML patients in studies leading to FDA approval of oral DEC/CED (ClinicalTrilas.gov NCT02103478 and NCT03306264, respectively) including genetic profiles.

Methods: 33 CMML candidates for parenteral decitabine with PS 0-2 were enrolled and received standard oral decitabine/cedazuridine (DEC/CED) regimen. Clinical endpoints were best response by International Working Group (IWG) 2006, transfusion independence (TI), transformation-free survival (TFS), overall survival (OS), and safety. Molecular profiling used an NGS panel, including somatic mutations affecting CMML prognosis and response to HMA therapy. Cox-regression analysis on various factors (eg binary mutational status, CR, etc.) was used for analyses of risk-factors for OS.

Results: Patients:  Median age 71 years, 55% patients  ECOG PS of 1, 85% no prior anticancer therapy for CMML, one-third RBC transfusion-dependent at baseline, 70% CMML-1 (2022 WHO classification), 76% MD-CMML. Patients received a median of 10 cycles of therapy (range 2-36).

Efficacy: 7 (21.2%) Complete Responses (CR), 14 (42.4%) marrow CR (mCR), including 5 (15.2%) with hematologic improvement (HI); overall response rate (ORR) [CR + PR+ mCR + HI] 75.8%.  Of those RBC transfusion-dependent at baseline, 63.6% became TI for at least 8 weeks. mTFS was 28.3 months; mOS 35.7 months. Safety: profile was consistent with decitabine; most grade ≥3 events from myelosuppression. Given the advanced age, only 3(9%) went on to transplant. Cox regression analysis only associated post-treatment RBC TI with survival with no observed effect on OS for other baseline or response-related factors; the sensitivity of these analyses is limited by patient number.

Conclusions/Summary: DEC/CED has clinical benefit in CMML patients with a well-tolerated safety profile. TI may be associated with longer survival.