Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia

This is a randomized, multicenter, open-label Phase 2 clinical trial evaluating the efficacy and safety of pacritinib compared to hydroxyurea in adult participants with advanced proliferative chronic myelomonocytic leukemia (CMML). Approximately 66 participants will be randomized in a 2:1 ratio to receive either pacritinib 200 mg twice daily (n=44) or hydroxyurea (n=22) for up to 48 weeks. Randomization will be stratified based on prior therapy (i.e., prior use of hydroxyurea or hypomethylating agents vs. no prior therapy). The study includes: * A 28-day screening period * A 48-week treatment period * A 30-day post-treatment follow-up * A survival follow-up phase lasting approximately one year after randomization Participants receiving pacritinib who are not deriving benefit by Week 24, as assessed by the treating physician, will discontinue treatment. Participants in the hydroxyurea arm who are not deriving benefit by Week 24-or who experience non-leukemic disease progression-may switch to pacritinib for the remainder of the treatment period, provided they meet predefined "Safe to Switch" criteria. Participants who discontinue study therapy due to toxicity, disease progression, or other protocol-defined criteria will enter survival follow-up to monitor overall survival, event-free survival, leukemic-free survival, and receipt of allogeneic hematopoietic stem cell transplant. Data will be collected at least every three months until death, hematopoietic stem cell transplant, or leukemic transformation. An independent data monitoring committee will oversee safety, with the first review after enrollment of \~18 participants and subsequent reviews approximately every 6 months.