Reduced Intensity Haploidentical Transplantation for the Treatment of Primary or Secondary Myelofibrosis

Study Overview
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Brief Summary
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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.

Detailed Description
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OUTLINE: 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.

Official Title
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Pilot Study of JAK Inhibitor Therapy Followed by Reduced Intensity Haploidentical Transplantation for Patients With Myelofibrosis

Conditions
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Primary Myelofibrosis, Secondary Myelofibrosis

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: JAK Inhibitor
* Drug: Fludarabine
* Biological: Recombinant Granulocyte Colony-Stimulating Factor
* Drug: Melphalan
* Drug: Mycophenolate Mofetil
* Procedure: Peripheral Blood Stem Cell Transplantation
* Drug: Tacrolimus
* Radiation: Total-Body Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PART 1: JAK INHIBITOR ADMINISTRATION INCLUSION CRITERIA Age > 18 years 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (JAK inhibitor, conditioning, GVHD prophylaxis)<br>JAK INHIBITOR THERAPY: Patients receive a JAK inhibitor at least 8 weeks prior to the start of HCT conditioning through day -4 before transplantation. CONDITIONING: Patients receive melphalan IV over 1 hour on day -5, fludarabine IV over 30-60 minutes on days -5 to -2, and undergo 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 PO for 6 months, mycophenolate mofetil PO BID or TID beginning day 5 for 6 weeks, and G-CSF SC beginning day 7 until neutrophil recovery is > 1,500/mm^3. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: JAK Inhibitor<br>* Given PO<br>* Other names: Fedratinib;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Biological: Recombinant Granulocyte Colony-Stimulating Factor<br>* Given SC<br>* Other names: 143011-72-7;Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Given IV<br>* Other names: peripheral stem cell transplantation;Drug: Tacrolimus<br>* Given IV and PO<br>* Other names: Protopic;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: SCT_TBI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of primary and secondary graft failure |  | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of severe (grade 3 or 4) cytokine release syndrome |  | Up to 3 years | 
| Non-relapse mortality (NRM) |  | Day 100 | 
| NRM |  | 1 year | 
| Overall survival |  | 1 year | 
| Overall survival |  | 3 years | 
| Incidence and severity of acute and chronic graft versus host disease (GVHD) |  | Up to 3 years | 
| Incidence of relapse |  | At 1 year |