Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia

Inclusion Criteria: * Diagnosis of CMML-1 (5th WHO classification), with \<10% bone marrow blasts on morphology and \<5% peripheral blood blasts. * Proliferative disease, defined as white blood cell count ≥13 × 10⁹/L. * Advanced disease, defined as at least one of the following features during screening: spleen palpable ≥5cm below the lower costal margin in the midclavicular line; TSS ≥20; or platelet count \<100 × 10⁹/L. For participants in whom spleen palpation is not feasible, an ultrasound exam may be performed for assessment of spleen craniocaudal length (length ≥12 cm by ultrasound is considered splenomegaly). * ECOG performance status ≤2. * Adequate organ function: AST and ALT ≤3 × ULN, total bilirubin ≤4 × ULN (≤8 × ULN in participants with Gilbert's syndrome), creatinine clearance \>30 mL/min, absolute neutrophil count ≥0.5 × 10⁹/L, PT and PTT ≤1.5 × ULN. * Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to enrollment and, along with male participants, must agree to use a highly effective method of contraception from the first dose through 90 days after the last dose. Exclusion Criteria: * Active malignancy diagnosed within the past 2 years, except for curatively treated non-invasive cancers (e.g., basal/squamous cell skin cancer, low-risk prostate cancer on stable endocrine therapy with PSA stable ≥3 months). * Allogeneic hematopoietic stem cell transplant within 12 months prior to enrollment, or requiring immunosuppressive therapy within 6 months before enrollment. * Likely to undergo allogeneic hematopoietic stem cell transplant within 6 months, per investigator assessment. * Prior systemic treatment with any JAK inhibitor. * Treatment with hypomethylating agents or cytotoxic chemotherapy (excluding hydroxyurea) within 28 days prior to enrollment. * Participation in another interventional study or use of experimental therapy within 28 days or 5 half-lives, whichever is longer. * Use of hematologic support drugs within 28 days prior to enrollment. Supportive care permitted. * Use of strong CYP3A4 inhibitors or inducers within 14 days or 5 half-lives before enrollment, whichever is shorter. * Use of systemic anticoagulants or antiplatelets (except aspirin ≤100 mg/day) within 14 days prior. Therapeutic anticoagulation allowed if stable for ≥90 days without bleeding events. * CTCAE Grade ≥2 bleeding within 3 months prior to enrollment, unless due to a reversible cause (e.g., trauma, surgery). * QTcF \>450 ms (men) or \>470 ms (women); QTcF up to 480 ms allowed if QRS \>100 ms. QTcF may be repeated if affected by reversible factors. * CTCAE Grade ≥3 cardiac event within 3 months before enrollment. * Symptomatic heart failure with limitations on ordinary activity. * Uncontrolled infection at study entry. * Moderate/severe hepatic impairment (Child-Pugh B or C), or active viral hepatitis: * HBV: Exclude if HBsAg+ or HBV DNA detectable. HBV antiviral therapy allowed if HBV DNA undetectable. * HCV: Allowed if HCV Ab+ but RNA negative. * Uncontrolled HIV or detectable viral load while on antiretrovirals. * Known hypersensitivity to pacritinib or its excipients (microcrystalline cellulose, polyethylene glycol, magnesium stearate).