Peri-Transplant Gecacitinib in Patients With Myelofibrosis Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Prior treatment

• Previous allogeneic hematopoietic stem cell transplantation.
• Requirement for concomitant strong CYP3A4 inhibitors that cannot be appropriately managed through gecacitinib dose adjustment, monitoring, or substitution in accordance with the protocol.
• Other severe organ dysfunction that, in the investigator's judgment, would preclude safe transplantation or administration of the study treatment.
• Previous gecacitinib treatment failure, including inadequate clinical response or persistent disease progression despite adequate treatment, requiring alternative myelofibrosis-directed therapy, as determined by the investigator.

Other illness

• Uncontrolled active infection requiring intensive intravenous antimicrobial treatment or hospitalization. Patients with stable, adequately controlled chronic infections may be considered eligible according to protocol-defined conditions.
• History of severe hypersensitivity to gecacitinib or any of its excipients.
• History of severe unacceptable gecacitinib-related toxicity, or unresolved grade ≥3 gecacitinib-related adverse events at screening.
• Inability to provide informed consent or serious psychiatric, cognitive, social, or behavioral conditions that may substantially impair protocol adherence, completion of follow-up, or safety assessments.
• Inability to take oral study medication, including swallowing difficulties, severe gastrointestinal malabsorption, persistent vomiting, or other conditions likely to significantly impair oral drug absorption.
• Any other condition that, in the investigator's opinion, may substantially increase study-related risks, compromise adherence, or interfere with the interpretation of study results.

Lab values

• Clinically significant uncontrolled infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Patients with controlled chronic infections may be eligible if they meet protocol-defined conditions, including:
  • HBV: appropriate antiviral management without evidence of active hepatitis. HCV: no acute hepatitis or hepatic decompensation, with acceptable liver function.
  • HIV: stable antiretroviral therapy, undetectable HIV viral load, and CD4 count ≥350 cells/μL.
• Significant hepatic impairment, including any of the following:
  • AST, ALT, or alkaline phosphatase ≥3 × the upper limit of normal (ULN). Direct bilirubin \>2.0 mg/dL. Total bilirubin \>1.5 × ULN.
• Renal impairment with creatinine clearance ≤60 mL/min, calculated using the Cockcroft-Gault formula.
• Severe cardiac dysfunction, including New York Heart Association (NYHA) class III-IV heart failure or left ventricular ejection fraction (LVEF) \<40%.

Other

• History or presence of blast-phase myeloproliferative neoplasm at screening, defined as: blast phase: ≥20% blasts in peripheral blood or bone marrow.
• Pregnancy or breastfeeding, or unwillingness to use effective contraception during the required study period.

• Patients aged 18 to 75 years.
• Confirmed diagnosis of primary myelofibrosis (PMF) according to World Health Organization (WHO) diagnostic criteria, or secondary myelofibrosis (SMF), including post-polycythemia vera myelofibrosis (post-PV MF) and post-essential thrombocythemia myelofibrosis (post-ET MF), according to International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria.
• Patients must meet at least one of the following disease risk criteria:
  • Intermediate-2 or high-risk disease according to the Dynamic International Prognostic Scoring System Plus (DIPSS-plus).
  • Intermediate-1 risk disease according to DIPSS-plus with at least one of the following adverse features:
  • Red blood cell transfusion dependence.
  • Unfavorable cytogenetic abnormalities, including trisomy 8 (+8), monosomy 7 or deletion 7q (-7/del(7q)), isochromosome 17q \[i(17q)\], inversion 3 \[inv(3)\] or abnormalities involving 3q21, monosomy 5 or deletion 5q (-5/del(5q)), deletion 12p \[del(12p)\], or 11q23 rearrangements.
  • Platelet count ≤100 × 10\^9/L.
  • High-risk molecular abnormalities associated with adverse prognosis, including ASXL1, EZH2, IDH1, IDH2, SRSF2, U2AF1, or TP53 mutations.
• Patients must have completed transplantation eligibility assessment and be considered suitable candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Either peripheral blood or bone marrow stem cell grafts are permitted. Donor type is not restricted.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
• Estimated life expectancy ≥3 months.
• Ability to understand the study requirements and provide written informed consent.
• Ability to receive oral gecacitinib, including the ability to swallow tablets without clinically significant gastrointestinal absorption impairment.
• No active severe infection at initiation of study treatment. Patients with infections may be eligible after adequate infection control.
• Patients previously receiving gecacitinib for myelofibrosis may be enrolled if they satisfy all eligibility criteria and have no history of treatment failure, severe unacceptable gecacitinib-related toxicity, or unresolved grade ≥3 gecacitinib-related adverse events. A washout period is not required for patients continuing gecacitinib treatment.
• Previous myelofibrosis-directed therapies, other than ongoing gecacitinib, must be discontinued at least 7 days or 5 drug elimination half-lives (whichever is longer) before initiation of study treatment on Day -14. Concomitant administration of other JAK inhibitors with gecacitinib is not permitted. Short-term hydroxyurea bridging therapy may be permitted if discontinued before Day -14 in accordance with the washout requirements.
• Previous splenectomy is permitted.
• Women of childbearing potential must have a negative pregnancy test before enrollment and agree to use effective contraception during the study and for 6 months after the last dose of gecacitinib. Male participants must agree to use effective contraception according to the protocol.