Long-Term Follow up of a Randomized Phase 2 Study of Low-Dose Decitabine Versus Low-Dose Azacitidine in Lower-Risk Myelodysplastic Syndromes
Authors: Montalban-Bravo Guillermo , Jabbour Elias , Class Caleb , Short Nicholas J. , Kanagal-Shamanna Rashmi , Kadia Tapan M. , Borthakur Gautam M. , Pemmaraju Naveen , Sasaki Koji , Estrov Zeev E. , Cortes Jorge E. , Ravandi Farhad , Alvarado Yesid , Komrokji Rami S. , Sekeres Mikkael A. , Steensma David P. , DeZern Amy E. , Roboz Gail J. , Yang Hui , Kantarjian Hagop M. , Garcia-Manero Guillermo 
Published: November 2019

INTRODUCTION: Outcomes of pts with lower-risk MDS is heterogeneous as shown by validated prognostic scales such as the MD Anderson lower risk prognostic scoring system (MDA-LRPSS) (Garcia-Manero, et al, Leukemia, 2008). We have previously shown that use of lower doses of HMA in lower-risk MDS is safe and can be effective (Jabbour, et al, Blood, 2017). Determining long-term benefit of early intervention with HMA in pts with lower-risk MDS is necessary.
METHODS: We report the long-term follow up of a phase 2 study of azacitidine (AZA) or decitabine (DAC) for pts with MDS and chronic myelomonocytic leukemia (CMML) with low or intermediate-1 IPSS risk score. A Bayesian response-adaptive design was used to assign pts to either DAC 20mg/m2 intravenously (i.v.) for 3 days or AZA 75mg/m2 i.v. or subcutaneous for 3 days. Courses were repeated every 4 weeks. Response was evaluated following IWG 2006 criteria. Next-generation sequencing was performed using targeted PCR-based sequencing. Sanger sequencing for SF3B1, SRSF2, U2AF1 and ZRSR2 was performed on a subset of pts. Kaplan-Meier product limit method was used to estimate survival outcomes for each clinical/demographic factor. Univariate Cox proportional hazards regression was used to identify any association with each of the variables and survival outcomes.
RESULTS: A total of 113 pts were treated: 73 with decitabine and 40 with azacitidine. Pt characteristics are shown in Figure 1A. Median age was 70 years (44-88). By the MDA-LRPSS 13 (11%) pts had low risk, 52 (46%) intermediate and 48 high (42%). Identified mutations are detailed in Figure 1B. The median number of cycles was 15 (3-74) and the median number of cycles to best response was 2.2 months (1-19.5 months). Response outcomes are shown in Figure 1C. Overall, DAC-treated pts were more likely to show response than AZA-treated (OS = 2.24, 95% C.I. 0.95-5.35, p = 0.047). Median follow-up is 59 months (95% CI 55.7-62.3). Median overall survival (OS) was 33.4 months with no significant difference based on treatment arm (DAC 38 months vs AZA 31 months, p=0.435). A total of 13 (12%) pts suffered transformation to acute myeloid leukemia (AML). Based on the MDA-LRPSS, pts with intermediate risk had worse survival than low-risk, but this was not statistically significant (HR 2.5, p=0.09). High-risk pts had significantly worse survival than low-risk (HR 3.5, p = 0.017) (Figure 1D). To determine if survival outcomes were improved compared to expected based on the MDA-LRPSS, we compared observed outcomes (continues lines in Figure 1E) to reported outcomes in the original MDA-LRPSS cohort (dashed lines in Figure 1E). Median OS compared favorably with expected outcomes in pts with intermediate and high-risk with no significant differences in patients with low risk category. The number of mutations did not correlate with outcomes but DNMT3A (HR 4.1, p=0.003), TP53 (HR 3.6, p=0.002) and U2AF1 (HR 2.1, p=0.018) mutations correlated with poor OS. U2AF1 mutations correlated with shorter transformation free survival (TFS) (HR 6.3, p=0.002). TP53 mutations correlated with shorter event-free survival and response duration (HR 3.9, p=0.006). On multivariate analysis, age, U2AF1, TP53, and DNMT3A mutations all correlate with poor OS. By univariate analysis there were no differences in OS, TFS, or duration of response by HMA. Mutations had similar effects on OS regardless of HMA used. Pts with SF3B1 mutations had a median OS which was not reached at the time of follow up (Figure 1F). Treatment was overall well-tolerated in both arms with most adverse events being grade 1 or 2.
CONCLUSIONS: Low-doses of HMA in pts with lower-risk MDS are safe and can improve outcomes compared to historical data in pts with intermediate or high risk features by the MDA-LRPSS.
Figure 1

Disclosures
Jabbour: AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. Kadia: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; Amgen: Membership on an entity's Board of Directors or advisory committees, 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; AbbVie: Consultancy, Research Funding. Borthakur:Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Eli Lilly and Co.: Research Funding; Cyclacel: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; Oncoceutics: Research Funding; Oncoceutics, Inc.: Research Funding; Janssen: Research Funding; BMS: Research Funding; Polaris: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; Merck: Research Funding; Arvinas: Research Funding; NKarta: Consultancy; GSK: Research Funding; Incyte: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Cortes:Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Komrokji:JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau; Novartis: Speakers Bureau. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Steensma:Arrowhead: Equity Ownership; Onconova: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Aprea: Research Funding; Astex: Consultancy; Summer Road: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Daiichi-Sankyo: Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Garcia-Manero:Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding.