Abstracts Clinical Lymphoma, Myeloma & Leukemia September 2023 S376 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. Patients: Median age 71 years, 55% patients ECOG PS of 1, 85% no prior anticancer therapy for CMML, onethird 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 transfusiondependent 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. Keywords: MDS, oral decitabine/cedazuridine, oral, hypomethylating agent, CMML, phase II, phase III MDS-641 Randomized Phase 1‑2 Study to Assess Safety and Efficacy of Low‑Dose (LD) Oral Decitabine/ Cedazuridine (ASTX727) in Lower‑Risk Myelodysplastic Syndromes (LR‑MDS) Patients: Interim Safety Analysis Guillermo Garcia-Manero MD1, Kimo Bachiashvili MD2, Elizabeth A. Griffiths MD3, Amer M. Zeidan MD4, Elie Traer MD5, Lalit Saini MD6, Harshad Amin MD7, Sanjay Mohan MD8, Michael Lubbert MD9, Lori Maness-Harris MD10, James Foran MD11, Dominik Selleslag MD12, Blanca Xicoy MD13, Daniel A. Pollyea MD14, David A. Sallman MD15, Aref Al-Kali MD16, Jesus G. Berdeja MD17, Haifa Al-Ali MD18, Nancy Y. Zhu MD19, Patricia Font Lopez MD20, Guillermo Sanz Santillana MD21, Valeria Santini MD22, Habte Yimer MD23, Larry D. Cripe MD24, Victor Priego MD25, Olatoyosi Odenike MD26, Bert Heyrman MD27, David Valcarcel Ferreiras MD28, Pankit J Vachhni MD2, Winny Chan PhD29, Yuri Sano MD, PhD29, Beloo Mirakhur MD, PhD29, Aram Oganesian PhD29, Harold Keer MD, PhD29, Abdulraheem Yacoub MD30 1The University of Texas MD Anderson Cancer Center, Houston, USA. 2University of Alabama at Birmingham O’Neal Comprehensive Cancer Center, Birmingham, USA. 3Roswell Park Comprehensive Cancer Center, New York, USA. 4Yale University and Yale Cancer Center, New Haven, USA. 5Oregon Health and Science University, Portland, USA. 6London Health Sciences Centre, London, Canada. 7Boca Raton Cancer Research, Boca Raton, USA. 8Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, USA. 9UniversitätKlinikum Freiburg, Hematology, Frieburg, Germany. 10University of Nebraska Medical Center, Omaha, USA. 11Mayo Clinic - Cancer Clinical Research Office, Jacksonville, USA. 12AZ Sint Jan, Dept of Hematology, Bruges, Belgium. 13Institut Català d’Oncologia Badalona Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 14University of Colorado School of Medicine, Division of Hematology, Aurora, USA. 15Moffitt Cancer Center, Tampa, USA. 16Mayo Clinic, Rochester, Rochester, USA. 17Sarah Cannon Research Institute, Nashville, USA. 18Universitätsklinikum Halle, Halle, Germany. 19University of Alberta Hospital - Hematology Research, Edmonton, Canada. 20Hospital General Universitario Gregorio Maranon, Madrid, Spain. 21Hospital Universitario y Politécnico La Fe, Valencia, Spain. 22MDS Unit, Hematology, AOUC, University of Florence, Florence, Italy. 23Texas Oncology - Tyler (USO), Tyler, USA. 24Indiana University Health, Indianapolis, USA. 25Regional Cancer Care, Bethesda, USA. 26University of Chicago, Chicago, USA. 27Zna Middelheim, Antwerp, Belgium. 28Hospital Universitario Vall d Hebron, Barcelona, Spain. 29Astex Pharmaceuticals, Inc., Pleasanton, USA. 30The University of Kansas Cancer Center, Westwood, USA Background: Cedazuridine (CED), a cytidine deaminase (CDA), inhibitor allows oral availability of decitabine (DEC); 5 daily doses of the fixed-dose combination (FDC) of 35 mg DEC/100 mg CED standard dose (SD) provides equivalent exposure to an IV DEC regimen of 20 mg/m2 D1-5 (Garcia-Manero et al, 2020). Attenuated HMA regimens (e.g., 3 days IV DEC) have shown activity in LR-MDS (Jabbour, et al. 2017). Aims: This Phase 1/2 study explores lower dose oral DEC/CED regimens in LR-MDS patients. Methods: Phase 1/2 study in lower-risk-MDS (IPSS low risk and lntermediate-1) subjects requiring treatment. Phase 1: explored 28-day regimens, dose ranges 5-20 mg DEC/100mg CED; duration ranges 5-10 days. Primary endpoints: recommended Phase 2 dose (RP2D) based on safety and dose-limiting toxicity (DLT). Secondary endpoints: clinical activity per 2006 IWG (transfusion independence [TI], LFS, OS). Phase 2: randomized 81 LR-MDS 1:1 to receive Phase 1 RP2D vs 35 mg DEC/100 mg CED (SD) for 3days (SD-3Day) (reflecting attenuated HMA regimen for LRMDS). Similar efficacy and safety endpoints as Phase 1. Results: Phase 1: 47 patients treated with five different DEC/CED regimens. DLT (myelosuppression-associated) increased with higher treatment doses and longer duration. Hematologic improvement (HI) %
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