Safety of Fedratinib As a Maintenance Strategy after Allogeneic Hematopoietic Cell Transplant for Myeloproliferative Neoplasms

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.1048-1048
• Main Authors: Elmariah, Hany, Kim, Jongphil, Hornfeck, Eric, Urdiales Kouba, Maria, Khimani, Farhad, Faramand, Rawan, Mirza, Sayeef, Pidala, Joseph A., Kuykendall, Andrew T., Komrokji, Rami S., Padron, Eric, Sallman, David, Walker, Alison R., Lancet, Jeffrey E, Mishra, Asmita, Ochoa-Bayona, Jose L., Perez, Lia, Nieder, Michael, Anasetti, Claudio, Bejanyan, Nelli, Nishihori, Taiga
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-210830

Background While potentially curative for myeloproliferative neoplasms (MPNs), the effectiveness of allogeneic hematopoietic cell transplant (HCT) is limited by post-transplant relapse. Given its efficacy in myelofibrosis (MF), favorable safety profile, and oral route of administration, the JAK2 inhibitor fedratinib may prove effective as a maintenance therapy for MPNs in the post-transplant setting. Additionally, models of JAK2 inhibition argue for potential utility in preventing graft-versus-host disease (GVHD) while preserving the graft-versus-tumor (GVT) effect (Betts. PNAS. 2018). As a JAK2-specific inhibitor, fedratinib may prevent GVHD while still preserving the GVT effect. Thus, maintenance fedratinib is a rational strategy to decrease both relapse and, possibly, GVHD in patients with MPNs following HCT. Methods In this single center phase I trial, patients who underwent allogeneic HCT for a MPN or myelodysplastic syndrome (MDS)/MPN overlap syndrome were treated with fedratinib starting between days +60 to +100 and then continued until 1-year post-transplant. Eligibility required adequate organ function, as well as neutrophil and platelet engraftment. JAK2 mutation was not required for eligibility as fedratinib has shown efficacy in JAK2 negative patients with myelofibrosis. Patients with a history of blast phase/acute myeloid leukemia, or those on glucocorticoids for GVHD were excluded. The trial followed a 3+3 design to determine the maximum tolerated dose (MTD) of fedratinib where dose level (DL) 1 was 200 mg daily, DL2 was 300 mg daily, and DL3 was 400 mg daily. An additional 25 patients will be enrolled in a phase II expansion cohort at the MTD. The dose limiting toxicity (DLT) window was 30 days from initiation of fedratinib where DLTs were defined as Wernicke's encephalopathy, grade 4 cytopenias, or any other grade 3 adverse event attributable to the study drug by CTCAE version 5.0. Secondary endpoints included progression free survival (PFS), overall survival (OS), and chronic GVHD at 1-year post-transplant. Results Eleven subjects are evaluable beyond the DLT monitoring window: 5 with MF, 5 with chronic myelomonocytic leukemia (CMML), and 1 with MDS/MPN overlap-unclassified. JAK2 mutation was detected in 3 subjects prior to transplant. The median age of subjects was 66 (range 40-75) years. Transplant regimens included reduced intensity conditioning for 9 (82%) subjects, matched unrelated donor for 10 (91%) subjects, and post-transplant cyc