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1828 Oral Decitabine/Cedazuridine Is a Tolerable and Effective Ambulatory Regimen for Patients with Advanced Myeloproliferative Neoplasms

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical Practice (Health Services and Quality), MPN, Non-Biological therapies, Clinical Research, Combination therapy, Chronic Myeloid Malignancies, Diseases, real-world evidence, Therapies, Myeloid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Ganesh Sivakumar, MD1*, Shivani Handa, MD2, Andrew Srisuwananukorn, MD3, Douglas Tremblay, MD2, John Mascarenhas, MD4*, Marina Kremyanskaya, MD, PhD2, Yelena Ginzburg, MD2, Xiaoli Wang, MD, PhD2 and Ronald Hoffman, MD4

1Department of Internal Medicine, Icahn School of Medicine/ Mount Sinai Morningside-West, New York, NY
2Division of Hematology & Medical Oncology, Tisch Cancer Institute/ Icahn School of Medicine at Mount Sinai, New York, NY
3Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
4Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY

Background: Treatment options are limited for patients (pts) with advanced myeloproliferative neoplasms (MPNs). Most pts become refractory to JAK2 inhibitor (JAKi) therapy by 3 years with subsequent survival of only 11-16 months.

Sequential treatment with chromatin-modifying agents including decitabine (D) can upregulate CXCR4 expression, correct abnormal trafficking of myelofibrosis (MF) stem cells, and eliminate JAK2V617F+ MF stem and progenitor cells in preclinical models (Wang et al, Cancer Res 2019, Blood 2010). Combination therapy with intravenous D and ruxolitinib (Rux) had a favorable effect on overall survival (OS) in a phase 2 study of MPN-accelerated/blast phase pts (Mascarenhas et al, Blood Adv 2020) and prolonged survival in a cohort of DIPSS-plus high-risk MF pts (Bader et al, Leuk Res 2015). Oral decitabine/cedazuridine (DC), therefore, represents an attractive ambulatory treatment option for pts with advanced MPNs.

Methods: We retrospectively reviewed the electronic health records of pts with advanced high-risk MF (AHR-MF) or MPN- accelerated phase (MPN-AP) seen at our institution that were treated with DC with or without a JAKi from 1/2021–7/2023. MPN-AP was defined by the presence of 10-19% blasts in peripheral blood/ bone marrow. AHR-MF was defined by the presence of 4–9% circulating blasts or 5–9% blasts in the bone marrow, and/or refractoriness to a JAKi.

Results: A total of 14 pts, 7 each with MPN-AP and AHR-MF, respectively received DC therapy (Table 1). Most pts (8/14 or 57%) were older than 75 years. All pts were classified as high risk/very high-risk (MIPPS70 plus v.2). Ten (71%) pts had one or more high molecular risk mutations (ASXL1, EZH2, SRSF2, IDH1/2, U2AF1), with the most prevalent being ASXL1 mutations in 8/14 (57%) pts. Other somatic mutations included NF1, KRAS, NRAS, BRAF, GATA2, STAG2, DNMT3A and TET2 genes. Eight of the 14 pts (57%) had either an unfavorable or very high-risk karyotype (MIPSS70 plus v.2). Thirteen pts had previously failed JAKi therapy. The median number of cycles of DC therapy was 2 (range,1-6) and 4 (range,1-26) for MPN-AP and AHR-MF pts, respectively and 4/7 pts received a concurrent JAKi in each group. Two pts in AHR-MF cohort were successfully bridged to transplant. Two pts in the MPN-AP group discontinued treatment after cycle 1 due to neutropenic sepsis and progression to blast phase, respectively.

Among MPN-AP pts who received ≥ 2 cycles of DC, circulating blasts were reduced to ≤ 5% in 4/5 pts, normalization of thrombocytopenia and improvement in hemoglobin by ≥ 1.5 g/dl each occurred in 3/5 pts (Fig.1). In the AHR-MF cohort, 6/7 pts received ≥ 2 cycles of DC with elimination of circulating blasts in one pt. WBC and platelet count were effectively reduced in 4/4 and 2/2 pts with baseline WBC of >50x 103/uL and platelet count >1000 x 103/uL, respectively. Spleen size reduction was achieved in two pts with combination of DC + Rux who were previously refractory to a JAKi. One pt achieved complete resolution of palpable splenomegaly after 2 cycles of combination therapy.

The predominant treatment-related adverse event was neutropenic fever in three pts requiring hospitalization. DC cycle length was reduced from 5 to 3/28 days in 7/14 pts, which reduced the degree of therapy related neutropenia and anemia. Pts remained ambulatory during treatment except for hospitalizations related to neutropenic fever. With a median follow-up of 109 days (range, 28 days – 29 months), median OS has not been reached. Three pts in the MPN-AP cohort progressed to MPN-blast phase (BP), including two pts who only received one cycle of DC. Two pts with MPN-BP died after 28 and 68 days of DC therapy, respectively. None of the AHR-MF pts progressed to MPN-AP/BP. The most durable response was observed in a pt who has received a total of 26 cycles of DC + Rux with stable disease for >2 years and loss of BRAF and KRAS mutations after 9 months of treatment.

Conclusions: DC therapy appears to be a well-tolerated and effective oral ambulatory regimen with clinically meaningful responses in elderly, transplant ineligible pts as well as a bridge to transplant in high-risk pts with advanced MPNs. The ease of outpatient administration significantly reduces pt treatment burdens and positively impacts their quality of life. These data provide a rationale for studying oral decitabine/cedazuridine +/- JAKi in a prospective manner, especially in pts with AHR-MF refractory to JAKi prior to evolution MPN-AP/BP.

Disclosures: Tremblay: GSK: Consultancy; Sierra Oncology: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; CTI Biopharma: Consultancy, Research Funding; Cogent Biosciences: Consultancy; Astellas Pharma: Research Funding; Gilead: Research Funding. Mascarenhas: Bristol Myers Squibb, Celgene, Constellation Pharmaceuticals/MorphoSys, CTI BioPharma, Galecto, Geron, GSK, Incyte Corporation, Karyopharm Therapeutics, Novartis, PharmaEssentia, Prelude Therapeutics, Pfizer, Merck, Roche, AbbVie, Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Bristol Myers Squibb, Celgene, CTI BioPharma, Geron, Incyte Corporation, Novartis, Janssen, Kartos Therapeutics, Merck, PharmaEssentia, Roche: Research Funding; Incyte, Novartis, Roche, Geron, GSK, Celgene/BMS, Kartos, AbbVie, Karyopharm, PharmaEssentia, Galecto, Imago, Sierra Oncology, Pfizer, MorphoSys, CTI Bio: Consultancy; Bristol Myers Squibb, Celgene, CTI BioPharma, Geron, Incyte Corporation, Janssen, Kartos Therapeutics, Merck, Novartis, PharmaEssentia, Roche; Participated in consulting or advisory committees – AbbVie, Bristol Myers Squibb, Celgene, Constellation Pharmac: Research Funding; AbbVie, CTI BioPharma Corp, a Sobi company, Geron, GlaxoSmithKline, Imago, Incyte, Kartos, Kayropharm, MorphoSys, Novartis, Pfizer, PharmaEssentia, Sierra: Consultancy; GSK: Honoraria. Kremyanskaya: Protagonist Therapeutics, Inc.: Consultancy, Research Funding. Ginzburg: Protagonist Therapeutics, Inc.: Consultancy, Research Funding. Hoffman: Karyopharm: Research Funding; Kartos Abbvie: Research Funding; Curis: Research Funding; Dexcel Pharma: Research Funding; Summitomo: Research Funding; Dompe: Patents & Royalties; Silence Therapeutics: Consultancy; TD2: Research Funding; Cellinkos: Consultancy; Protagonist Therapeutics: Consultancy.

OffLabel Disclosure: Oral decitabine-cedazuridine is FDA approved for previously treated and untreated, intermediate-high risk, de novo and secondary MDS and CMML. We report on its off-label use in advanced myeloproliferative neoplasms including MPN-accelerated phase.

*signifies non-member of ASH