Clinical Outcomes with Hypomethylating Agents in Patients with Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T); A Case Series
Authors: Siddiqui Maria Tariq , Kanagal-Shamanna Rashmi , Naqvi Kiran , Sasaki Koji , Masarova Lucia , Jabbour Elias , Pemmaraju Naveen , Kadia Tapan M. , Ravandi Farhad , Daver Naval , Borthakur Gautam , Pierce Sherry A. , Verstovsek Srdan , Bose Prithviraj , Kantarjian Hagop M. , Garcia-Manero Guillermo , Montalban-Bravo Guillermo 
Published: November 2020

INTRODUCTION: Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN RS-T), formerly called refractory anemia with ring sideroblasts and thrombocytosis (RARS-T), is a disease entity characterized by the presence of anemia, thrombocytosis, bone marrow dysplasia with ring sideroblasts and large atypical megakaryocytes. Given the rarity of MDS/MPN-RS-T, there is little data on the efficacy and clinical outcomes of different therapies in this patient population. Prior case reports and series suggest treatment with erythropoietin-stimulating agents (ESAs) and lenalidomide can be effective in this disease, but there is no data detailing the activity of hypomethylating agents (HMA). The aim of this study is to evaluate the outcomes with HMAs in patients with MDS/MPN-RS-T.
MATERIALS AND METHODS: A retrospective review was conducted of patients presenting to MD Anderson Cancer Center between March 2005 and January 2020 at with the diagnosis of MPS/MPN RS-T per World Health Organization (WHO) criteria and 52 patients were identified. Of the 52 patients, 16 patients had received either decitabine or azacitidine in the course of their disease. Of those, 4 were excluded for either receiving HMAs prior to presentation or proceeding to transplant after only 1 cycle of HMA. The data presented is on the remaining 12 patients. Outcomes evaluated included erythroid response, duration of response, response rate, disease progression, overall survival (OS) and progression free survival (PFS). Disease progression was defined as increasing transfusion dependence, development of myelofibrosis (MF) or transformation to acute myeloid leukemia (AML). Overall survival was defined as time from the date of treatment initiation to the date of last follow-up or censorship date. Progression-free survival was defined as the time from the date of starting treatment to the date of progression of disease.
RESULTS: Twelve patients who received HMAs with WHO defined MDS/MPN RS-T were included. Median age was 66 years (51-77) with 7 males (58%). Patient characteristics are detailed in Table 1. Ten patients (83%) were transfusion dependent at the time of HMA therapy initiation. The median number of prior therapies was 2 (range 0-5). A total of 6 patients had received prior ESAs and 3 had received prior lenalidomide. HMAs were used as 1st line treatment in 2 patients (17%), 2nd line in 2 patients (17%), 3rd line in 3 patients (25%), 4th line in 4 patients (33%), 5th line in 1 patient (8%) and 6th line in 1 patient (8%). Nine patients (75%) received azacitidine (of which 1 was in conjunction with ruxolitinib), 2 patients (17%) received decitabine, and 1 patient (8%) received decitabine and then azacitidine (in combination with an investigational agent). Median duration of treatment was 8.5 months (range 0-53). Response was achieved in 3 patients with an overall response rate (ORR) of 25%. Per 2015 International Working Group (IWG) MDS/MPN overlap syndrome response criteria, 1 patient achieved complete response (CR) and 2 patients reached hematological improvement in the erythrocyte lineage (HI-E). Median duration of response was 7 months (range 4-21). For the remaining 9 patients, 2 remain on HMA therapy with stable disease, 1 died during treatment, 3 developed failure/loss of response and proceeded to allogeneic stem cell transplantation and 3 had disease progression, with a median follow-up time of 38 months; median OS from therapy initiation was 46 months (Figure 1). Disease progression was seen in a total of 5 patients (42%, 2 patients from the responder group), with increased transfusion dependence in 1 patient (8%), worsening cytogenetics in 1 patient (8%), increased bone marrow blast count in 1 patient (8%), development of myelofibrosis after 8 months in 1 patient (8%) after introduction of HMA therapy and transformation to AML in 1 patient (8%) 46 months after initiating HMAs (Table 2).
CONCLUSION: Treatment with HMAs can induce responses in up to 25% of patients, including transfusion independence, even in heavily pre-treated patients with prior exposure to lenalidomide, with a median response duration of 7 months.

Disclosures
Sasaki: Daiichi Sankyo: Consultancy; Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding. Pemmaraju:MustangBio: Honoraria; DAVA Oncology: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Blueprint Medicines: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; Roche Diagnostics: Honoraria; AbbVie: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Incyte Corporation: Honoraria; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding. Kadia:Cyclacel: Research Funding; Amgen: Research Funding; Novartis: Honoraria; Ascentage: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Incyte: Research Funding; JAZZ: Honoraria, Research Funding; Cellenkos: Research Funding; Pulmotec: Research Funding; Genentech: Honoraria, Research Funding; Astra Zeneca: Research Funding; Astellas: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: 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. Borthakur:PTC Therapeutics: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Treadwell Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; BioTherix: Consultancy; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Xbiotech USA: Research Funding; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding. Verstovsek:Genentech: Research Funding; CTI Biopharma Corp: Research Funding; NS Pharma: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; Incyte Corporation: Consultancy, Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding. Bose:Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; NS Pharma: Research Funding; Promedior, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Kantarjian:Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding. Garcia-Manero:Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding.