Safety of Fedratinib As a Maintenance Strategy after Allogeneic Hematopoietic Cell Transplant for Myeloproliferative Neoplasms
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 
Published: December 2024

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 cyclophosphamide based GVHD prophylaxis for 11 (100%) subjects. The median follow-up is 10.7 (range 3.9-26.2) months.
The median time to initiate fedratinib was day +77 (range 62-100) and continued for a median of 151 days (range 31-304). Three subjects were treated at DL1, 3 at DL2, and 5 at DL3. DL3 was identified as the MTD with no DLTs observed at any DL during the 30-day observation window. One subject on DL3 experienced grade 4 cytopenias beyond the DLT window, requiring interruption in therapy but, per protocol, resumed fedratinib at a reduced dose of 300mg daily after resolution of the DLT. Four subjects withdrew from the trial (1 at DL1, 1 at DL2, and 2 at DL3) at a median of 46 days (range: 31-142) due to adverse events that did not meet DLT criteria (hyperkalemia, nausea, and anemia). No therapy related deaths occurred.
One subject on DL1 developed severe chronic GVHD, but there were no other cases of moderate or severe chronic GVHD at any dose level. For all treated subjects, the median OS was not reached and median PFS was 12.4 months, with 2 subjects in DL1 and 1 subject in DL2 experiencing relapse in the first year. OS at 1 year was 100%.
CONCLUSION
In this phase I trial of fedratinib maintenance after allogeneic HCT, fedratinib 400mg daily was safe and identified as the MTD. However, 4 subjects withdrew from the trial prior to completing a full year of maintenance. The phase II expansion cohort is currently enrolling patients at the MTD to confirm safety and evaluate long term efficacy of this maintenance strategy.