Early Intervention with Hypomethylating Agents in Transfusion-Independent Patients with Myelodysplastic Syndrome

Background: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndrome (MDS), but their role in those with lower-risk MDS has not been well-established. A randomized phase 2 study evaluating low-dose decitabine and low-dose azacitidine in patients with lower-risk MDS showed that treatment with attenuated dose schedules of HMA therapy are both well-tolerated and effective in patients with lower-risk MDS (Jabbour E, Blood 2017). However, their use as early intervention in transfusion-independent patients with lower-risk MDS remains unknown. Consequently, we performed a retrospective analysis of a cohort of transfusion-independent lower-risk MDS patients to evaluate the safety and clinical activity of low-dose HMAs in this patient population. Methods: Fifty-four adult patients with low-risk or intermediate-1-risk disease by the International Prognostic Scoring System (IPSS) and transfusion-independence at baseline treated on clinical trial NCT01720225 from November 2012 to February 2016 were included in the analysis. Patients were treated with either decitabine 20 mg/m2 intravenously (IV) daily for 3 days or azacitidine 75 mg/m2 IV daily for 3 days every 28 days. Dose reductions for grade 3 or 4 toxicities were allowed on the clinical trial, and responding patients were allowed to continue therapy indefinitely. Results: Patient characteristics included a median age of 70 with 38 males (70%) and median bone marrow (BM) blast percentage of 3%. Twelve patients (22%) had low-risk disease and 42 patients (78%) had intermediate-1-risk disease by IPSS, and risk groups by revised IPSS (IPSS-R) included very low-risk in 8 patients (15%), low-risk in 22 patients (41%), intermediate-risk in 12 patients (24%), and high-risk in 11 patients (20%). The most commonly observed mutations were TET2 (26%), RUNX1 (9%), ASXL1 (7%), and TP53 (7%). Thirty-three patients (61%) were treated with decitabine while 21 patients (39%) were treated with azacitidine. Grade 3 or 4 adverse events included pneumonia (4%), syncope (4%), myalgias/joint pains (2%), dizziness (2%), and neutropenia (2%). Otherwise, the most common toxicities were grade 1-2 fatigue (17%), nausea (13%), and constipation (11%). No early mortality was observed during the first 60 days. Of the 54 patients included in the analysis, 50 patients (93%) were evaluable for response based on BM blast percentage and cytopenias. Of the 17 patients with BM blasts > 5%, 11 patients achieved complete remission (CR), 4 patients reached marrow CR, and 2 patients had no response. Of the 33 patients with BM blasts ≤ 5% and at least 1 cytopenia, 13 patients demonstrated hematological improvement, 10 patients exhibited stable disease, 8 patients did not respond, and 2 patients progressed. At a median follow-up of 37 months, the median overall survival was not reached, and the median event-free survival was 24.9 months. Four patients (7%) eventually became transfusion-dependent, and 5 patients (9%) ultimately transformed to acute myeloid leukemia (AML). Conclusions: Overall, attenuated doses of decitabine and azacitidine were safe and tolerated in patients with transfusion-independent lower-risk MDS. Higher rates and longer durations of response with improved survival and lower rates of AML transformation were observed. Though patients with lower-risk MDS who are transfusion-independent have traditionally undergone surveillance, early intervention with low-dose HMAs may be beneficial in these patients. Prospective studies, such as with clinical trial NCT02269280, are warranted. Disclosures Jabbour: Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Ravandi: Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Kadia: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Borthakur: FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xbiotech USA: Research Funding; NKarta: Consultancy; AbbVie: Research Funding; Janssen: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Eli Lilly and Co.: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Incyte: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Bayer Healthcare AG: Research Funding; GSK: Research Funding. Short: AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. Cortes: Astellas Pharma: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Merus: Consultancy, Honoraria, Research Funding. Alvarado: Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kantarjian: Astex: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Takeda: Honoraria; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Ariad: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding. Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.