ASTX727 delivers superior response rates and associated survival benefit versus hydroxycarbamide/best supportive care in CMML and other MDS/MPN overlap syndromes: First results from the Phase 2 UK multicenter randomized ammo trial
Year: 2025
Type: conference-abstract
Abstract: Background Chronic myelomonocytic leukemia (CMML) and the rarer MDS/MPN overlap syndromes share biological features, poor prognosis (median survival <2y) and few treatment options. Hypomethylating agents (HMA) are approved for CMML but less effective in proliferative disease, for which hydroxycarbamide (HC) remains standard-of-care (SoC). In Europe/UK HMA access is restricted to non-proliferative CMML-2. The phase 3 DACOTA randomized controlled trial (RCT) showed higher response for IV decitabine (DAC) v HC in proliferative CMML, but offset by toxicity for no survival benefit. ASTX727 is an oral fixed-dose combination of DAC 35mg/cedazuridine 100mg, delivering equivalent exposure to IV DAC 20mg/m2 and FDA-approved for MDS/CMML. Methods AMMO (ISRCTN30808508) is a UK phase 2 RCT comparing ASTX727 v HC/BSC in advanced MDS/MPN. Eligibility required Int-2/High risk by CPSS-Mol or other advanced/proliferative features requiring therapy; extending to non-CMML pts with IPSS-R higher-risk/advanced disease. Recruits were randomized (2:1) to ASTX727 (d1-5/28d) for 6 cycles, or BSC including HC (HMA not permitted). Responders could continue ASTX727 until progression. Primary outcome was best overall response rate (ORR) by C6, according to IWG/Savona criteria, analyzed by posterior probability distribution of difference using a Bayesian beta-binomial conjugate model. Secondary outcomes included overall, progression-free and transformation-free survival (OS; PFS; TFS), in a modified intention-to-treat population. Results Between Oct 2022-May 2024 77 pts from 11 centers were recruited, of whom 73 are evaluable for response. Median age was 73y (IQR 67-77). Disease distribution mirrored the epidemiology of MDS/MPN, with the majority (>60%) CMML. Most were higher-risk by CPSS-Mol/IPSS-R; 73% had proliferative disease mandating cytoreduction. Arms were well balanced other than more females (41% v 21%) randomized to ASTX727. Of 49 starting ASTX727, 12 stopped pre-C6 (8 for toxicity); 28 continued beyond C6. Median cycles received was 10 (IQR 5-18). Dose reductions were frequent, applied in (e.g.) 16% and 57% at C2 and C6, respectively. Of 24 on BSC, 75% received HC; 7 discontinued before end of C6 (4 due to progression/death). Best ORR for ASTX727 and HC/BSC was 53.0% (95% CrI 39.3-66.3%) and 30.3% (14.9-49.4%), respectively. Strict CR was achieved by 8.2% and 4.2%. Sampling posterior distribution models median ORR difference was 22.5% (95% HDI 0.1-44%) in favor of ASTX727. Total 227 CTCAE G3+ AEs were reported (in 48 pts): 208 (39 pts) on ASTX727 v 19 (9 pts) on HC/BSC. The only G3+ AEs occurring in ≥5% on either arm were neutropenia (38.8% ASTX727 v 8.3% HC/BSC), thrombocytopenia (30.6% v 8.3%), febrile neutropenia (24.5% v 0), anemia (20.4% v 16.7%) and lung infection (8.2% v 0). No unexpected safety signals were seen. Treatment-related toxicity (defined as any G3+ AE/G1+ SAE considered at least possibly attributable to drug) was experienced by 68% and 17% on ASTX727 and HC/BSC, respectively. The only treatment-attributed death occurred on HC/BSC. With 20mo median follow up, there were 32 deaths (18 on the ASTX727 arm) and 12 progressions (7 on ASTX727) / 4 to AML (1 on ASTX727). All survival measures showed significant advantage for ASTX727. Median PFS was 23.5mo (95% CI 15.8-NR) v 13.9mo (9.4-NR) [HR 0.44, 95% CI 0.22-0.86; p=0.017]. Median TFS was 23.5mo (18.4-NR) v 13.9mo (9.9-NR) [HR 0.40, 0.2-0.8; p=0.01]. At 12mo est survival probability was 0.831 (0.73-0.945) for ASXT727 v 0.724 (0.556-0.941) for HC/BSC. Median OS was 23.5mo (18.4-NR) v 16.9mo (13.9-NR) [HR 0.42, 0.21-0.86; p=0.017]. Survival benefits remained significant in CMML subgroup analyses. Multivariable Cox regression found no survival differences by other stratified variables. Conclusion ASTX727 displayed marked benefit compared with HC/BSC for advanced MDS/MPN. Rapid recruitment (6mo early) and high retention showcases feasibility/appetite for RCTs in this challenging group. Extending access beyond CMML AMMO also showcases HMA efficacy across related biological entities. The 53% ORR is in keeping with that expected for HMA monotherapy and almost double that for HC/BSC. Toxicity was higher, but acceptable and in line with prior ASTX727 trials. Crucially this did not negate its efficacy advantage, translating into significantly longer PFS, TFS and OS: the first randomized survival benefit demonstrated in MDS/MPN for ~30y and supporting ASTX727 as a new SoC for advanced MDS/MPN.
Source: Blood
Authors: Daniel Wiseman, Jak Laight, Rebecca Boucher, Chhaya Sankhalpara, Rebecca Record, Jennifer Byrne, Onima Chowdhury, Dominic Culligan, Nicholas Cunningham, Srinivasan Narayanan, Rob Sellar, Kiran Batta, Manoj Raghavan, Dr. Emma Searle, Catherine Cargo, Steve Knapper, Austin Kulasekararaj
Institutions: University of Manchester, The Christie Hospital, The Christie NHS Foundation Trust, Cancer Research UK Clinical Trials Unit, University of Birmingham, Nottingham University Hospitals NHS Trust, Churchill Hospital, University of Oxford, MRC Weatherall Institute of Molecular Medicine, Oxford University Hospitals NHS Trust, Aberdeen Royal Infirmary, Belfast City Hospital, University Hospital Southampton NHS Foundation Trust, University College London, Queen Elizabeth Hospital Birmingham, St James's University Hospital, Cardiff University, King's College London, King's College Hospital NHS Foundation Trust, King's College Hospital
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7108449635