Myeloproliferative Neoplasms Clinical Trial
Reduced Intensity Haploidentical Transplantation for the Treatment of Primary or Secondary Myelofibrosis
This phase II trial studies the outcomes of using a JAK inhibitor prior to reduced intensity haploidentical (Haplo) transplantation for the treatment of primary or secondary myelofibrosis (MF). Haplo transplant has been shown to be safe and effective in patients with leukemia and lymphoma who don't have an available sibling donor. The primary risk of using Haplo HCT in patients with MF is graft failure as the graft failure rate has been historically higher with Haplo HCT than with other donor sources and higher with MF patients due to bone marrow fibrosis than in patients with other hematologic malignancies. JAK inhibitors when used in patients with MF may decrease the size of the spleen and decrease inflammation in the bone marrow. Therefore using a JAK inhibitor prior to Haplo transplant has the potential to decrease graft failure in patients with MF. Haplo transplants for patients with MF have been done successfully at multiple institutions in patients not on a study and are currently being covered by Medicare.
JAK INHIBITOR THERAPY: Patients receive a JAK inhibitor at least 8 weeks prior to the start of hematopoietic cell transplantation (HCT) conditioning through day -4 before transplantation.
CONDITIONING: Patients receive melphalan intravenously (IV) over 1 hour on day -5, fludarabine IV over 30-60 minutes on days -5 to -2, and undergo total-body irradiation (TBI) on day -1.
TRANSPLANT: Patients receive peripheral blood stem cell infusion on day 0.
GVHD PROPHYLAXIS: Patients then receive cyclophosphamide IV over 3 hours on days 3-4, tacrolimus IV beginning day 5 then orally (PO) for 6 months, mycophenolate mofetil PO twice daily (BID) or three times daily (TID) beginning day 5 for 6 weeks, and granulocyte colony-stimulating factor (G-CSF) subcutaneously (SC) beginning day 7 until neutrophil recovery is > 1,500/mm^3.
After completion of study treatment, patients are followed up between day 80-100, at 1 year, and then up to 5 years.
PART 1: JAK INHIBITOR ADMINISTRATION INCLUSION CRITERIA
Diagnosis of primary myelofibrosis (PMF) as defined by the 2016 World Health Organization classification system or diagnosis of secondary MF as defined by the International Working Group (IWG) for Myeloproliferative Neoplasms Research and Treatment criteria
Patients meeting the criteria for intermediate-1, intermediate-2 or high-risk disease by the Dynamic International Prognostic Scoring System (DIPSS)-plus scoring system (DIPSS may be used if all data from DIPSS are not available)
Ability to understand and the willingness to sign a written informed consent document (or legally authorized representative)
Patient must be a potential hematopoietic stem cell transplant candidate
PART 2: ALLOGENEIC STEM CELL TRANSPLANT INCLUSION CRITERIA
Meeting criteria for 1st phase as above, at time of initiation of JAK inhibitor, including ability to understand and willingness to sign a written informed consent. Patients arriving to our institution for transplant and not enrolled in Part 1 may still be enrolled in Part 2 if Part 1 criteria met. These patients will have Part 1 endpoints transcribed from medical records
Received JAK inhibitor for at least 8 weeks immediately prior to conditioning and be able to continue until day -4 pre-transplant
Karnofsky performance status score >= 70
Calculated creatinine clearance using the Cockcroft-Gault formula or 24 hour (hr) urine creatinine clearance must be > 60 ml/min
Total serum bilirubin must be < 3 mg/dL unless the elevation is thought to be due to Gilbert's disease or hemolysis
Transaminases must be < 3 x the upper limit of normal
Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension. Patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease will be excluded
Diffusion capacity of the lung for carbon monoxide (DLCO) corrected > 60% normal; may not be on supplemental oxygen
Left ventricular ejection fraction > 40% OR shortening fraction > 26%
Comorbidity Index < 5 at the time of pre-transplant evaluation
DONOR: Patients must be screened prior to transplant for donor-specific anti-HLA antibodies (DSA). Patients with DSA will be reviewed by the principal investigator and considered for desensitization treatment
DONOR: Children are preferred over siblings and parents
DONOR: Younger donors are preferred over older donors
DONOR: ABO matched donors are preferred over minor ABO mismatched and over major ABO mismatch donors
PART 1: JAK INHIBITOR ADMINISTRATION EXCLUSION CRITERIA
Contraindication to receiving a JAK inhibitor including:
Patients who have known hypersensitivity to JAK inhibitors
Clinical or laboratory evidence of significant renal or hepatic impairment including cirrhosis
Active uncontrolled infection
Known human immunodeficiency virus (HIV) positivity
Women who are pregnant or trying to conceive
Caution should be used in patients with platelets < 100 though adjustments in dose can be made to accommodate anyone with platelets > 50
History of prior allogeneic transplant
Leukemic transformation (> 20% blasts)
PART 2: ALLOGENEIC STEM CELL TRANSPLANT EXCLUSION CRITERIA
Uncontrolled viral or bacterial infection at the time of study enrollment
Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval
Known HIV positivity
Pregnant or breastfeeding
Availability of an human leukocyte antigen (HLA)-identical or 1-allele-mismatched related donor or an HLA 10 of 10 matched unrelated donor
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