A Phase II Trial of Azacitidine (AZA) in Combination with Ruxolitinib (RUX) in Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)
Authors: Guerra Veronica A , Kantarjian Hagop M. , Cortes Jorge E. , Garcia-Manero Guillermo , Masarova Lucia , Pemmaraju Naveen , Jabbour Elias , Kadia Tapan M. , DiNardo Courtney D. , Zhou Lingsha , Pierce Sherry A. , Borthakur Gautam M. , Wierda William G. , Ferrajoli Alessandra , Sasaki Koji , Takahashi Koichi , Naqvi Kiran , Alvarado Yesid , Ohanian Maro N. , Jain Nitin , Bose Prithviraj , Ravandi Farhad , Konopleva Marina Y , Estrov Zeev E. , Verstovsek Srdan , Daver Naval G. 
Published: November 2019

Background: The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs) are Philadelphia negative myeloid neoplasms with overlapping clinicopathological features of both MPNs and MDS. Ruxolitinib (RUX), a JAK 1/2 inhibitor is FDA approved for primary myelofibrosis. The hypomethylating agents, azacitidine (AZA) and decitabine, are approved for MDS. The independent activity of RUX and AZA in patients with MPNs and MDS, respectively, and their non-overlapping toxicity profiles suggest that the combination of these two agents administered sequentially and at lower doses may be tolerable and efficacious in patients with MDS/MPNs. Herein we present updated results from a Phase II trial.
Methods: This is a single-arm Phase II trial of RUX in combination with AZA for patients (pts) with MDS/MPNs. Eligible pts included adults > 18 years with newly diagnosed or previously treated (excluding previous therapy with RUX or AZA) MDS/MPNs with intermediate-1, intermediate-2, or high risk according to the DIPSS criteria for PMF. RUX at 15-20 mg orally twice daily was to be given alone in 28 day cycles for the first 3 cycles. AZA was to be added from cycle 4 onward at 25 mg/m2 days 1-5, and could be gradually up-titrated to 75 mg/m2 days 1-5 over subsequent cycles if clinically indicated. AZA could be initiated prior to cycle 4 in pts with proliferative disease or high bone marrow blasts. The primary objective was to determine the response rate per the 2015 IWG MDS/MPN response criteria. The secondary objective was to determine the safety and tolerability of the combination therapy.
Results: Forty-five pts were enrolled between May 2013 and June 2019. The median age was 68 years; 64% were ≥65 years, 77.7% were int-2 or high risk by DIPPS. Twenty one (46.6%) pts had splenomegaly and 16 (35.5%) pts had EUMNET MF-2 or MF-3. JAK2V617F mutation was present in 16 pts (35.5%). Thirteen pts had pre-therapy BM blasts >5%. The pts. characteristics are in Table 1. Fourty three pts were evaluable for response at the time of this report. AZA was given to 41/45 pts (91.1%), with 26 (63%) pts initiating the AZA before cycle 4 due to increased of bone marrow blast or proliferative disease.
After a median follow-up of 30.8 months (mo), 19 pts are still alive. 24 pts (56%) achieved an objective IWG 2015 response. The median time to IWG response was 1.8 mo (0.4-5.5). A ≥50% palpable spleen length reduction was seen in 64% (9/14) of evaluable pts with a median time to response of 1.0 mo. 8/13 (62%) evaluable pts achieved a BM blast reduction to <5%. Specific responses are listed in Table 2. No significant difference in JAK2 mutation status (p=0.215) or frequency of splenomegaly (p=0.298) was noted between responders and non-responders.
The most common possibly related non-hematological adverse events were grade I-II constipation (22.2%), nausea (15.5%) and pain (15.5%). Significant possibly related hematological AEs included grade III-IV anemia (35.5%), neutropenia (22.2%) and thrombocytopenia (53.3%), these were usually transient and only 2 pts had to discontinue protocol therapy due to cytopenias. All possibly related adverse events are listed in Table 3.
Five pts progressed to AML, with a median time to progression of 13.8 mo. Overall, the median OS was 25.4 mo with 1-year and 3-year OS rates of 86% and 40%. Pts with MDS/MPN-U had a better median OS compared with CMML and aCML (31.8 mo vs. 16 mo vs. 1.5 mo; p=0.009). Figure 1 depicts OS by diagnosis. The 1-year and 3-year OS rates for pts with MDS/MPN-U were 100% and 46%, respectively. The median duration of response was 8.35 mo (range 2.1-14.6 mo).The median OS of 31.8 mo among MDS/MPN-U pts compares favorably to a median OS of 16.1 mo from the previously published historical cohort of MDS/MPN-U patients treated with AZA alone (N = 36) at our institution (DiNardo C et al, Leukemia 2014).
Conclusions: RUX in combination with AZA was safe and effective and may be a therapeutic option to consider, especially in pts with MDS/MPN-U. Transient grade III-IV myelosuppression was frequently seen, but only 2 pts (4.4%) required treatment discontinuation, which is similar to discontinuation rates with single agent RUX in MF in COMFORT studies (8-9%). Overall response rate was 56%. Additionally 63% BM remissions were noted among pts with ≥5% blast at baseline. The clinical trial is still recruiting (NCT01787487) and focussed on enrolling MDS/MPN-U pts.

Disclosures
Kantarjian: BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Astex: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Cortes:Merus: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Immunogen: Consultancy, 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. Pemmaraju:novartis: Consultancy, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; cellectis: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding. 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. DiNardo:syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria. Borthakur:Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; 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; Janssen: Research Funding; AbbVie: Research Funding; Bayer Healthcare AG: Research Funding; GSK: Research Funding. Wierda:GSK/Novartis: Research Funding; Genentech: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Acerta Pharma Inc: Research Funding; AbbVie: Research Funding; Juno Therapeutics: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; Pharmacyclics LLC: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Takahashi:Symbio Pharmaceuticals: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Jain:Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Konopleva:Forty-Seven: Consultancy, Honoraria; Astra Zeneca: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding. Verstovsek:Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding. Daver:Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Agios: Consultancy; Incyte: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Servier: Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Celgene: Consultancy.

OffLabel Disclosure:
Ruxolitinib a JAK1/2 is approved for the treatment of MF and PV HMA decitabine and azacitidine are approved for MDS This trial is combining azacitidine and ruxolitinib in MDS/MPNs