Oral Decitabine/Cedazuridine Is an Effective Ambulatory Therapy for Patients With Myelofibrosis Refractory to JAK2 Inhibitor Therapy

Patients with myelofibrosis (MF) who are refractory to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers have dismal prognosis. We studied a novel ambulatory regimen of decitabine-cedazuridine (DEC-C) + /- JAKi therapy in patients with high-risk MF who were refractory to prior JAKi or MPN-accelerated phase. We demonstrate the therapeutic benefit of this strategy as evidenced by reduction or stabilization of blast cell counts, decrease in splenomegaly or successful bridge to stem-cell transplant. Myelosuppression is a common adverse event but treatment length reduction from 5 to 3 days of DEC-C/cycle is feasible and reduces toxicity without comprising the efficacy. Background: Outcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. Methods: We conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C + /- JAKi at Mount Sinai Hospital from 2021 to 2024. Results: The cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle. Conclusions: This report demonstrates the feasibilit y, tolerabilit y, and clinical benefit of an exclusively ambulatory regimen for high-r isk, elder ly patients with advanced MF which warrants further evaluation in a prospective clinical trial.