JAK Inhibitor Before Donor Stem Cell Transplant in Treating Patients With Primary or Secondary Myelofibrosis

Study Overview
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Brief Summary
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This phase II trial studies how well giving a JAK inhibitor before a donor stem cell transplant works in treating patients with myelofibrosis that developed without another condition (primary) or evolved from other bone marrow disorders (secondary). JAK inhibitors are a class of drugs that may stop the growth of abnormal cells by blocking an enzyme needed for cell growth. Giving a JAK inhibitor such as ruxolitinib before a donor stem cell transplant may help reduce symptoms of myelofibrosis such as inflammation and enlargement of the spleen, improve the patient's general physical condition, and prevent complications from occurring after the transplant. Infusing healthy stem cells from a donor into the patient may help the patient's bone marrow work normally and make stem cells, red blood cells, white blood cells, and platelets. Giving a JAK inhibitor before a donor stem cell transplant may help improve transplant outcomes in patients with myelofibrosis.

Detailed Description
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OUTLINE: PART 1: Patients receive ruxolitinib orally (PO) twice daily (BID) from at least 8 weeks prior to the start of conditioning through day -4 before transplantation, with a taper schedule reducing the dose every 2-3 days beginning after day -4. PART 2: Patients are assigned to 1 of 2 conditioning regimens at the discretion of the clinical provider and Clinical Coordinators Office (CCO). MYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -8 to -6 (umbilical cord blood transplant recipients only), cyclophosphamide IV on days -7 and -6, and busulfan IV over 3 hours on days -5 to -2. REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and melphalan IV over 15-30 minutes on days -3 and -2. Patients also undergo total-body irradiation (TBI) on day -1 (umbilical cord blood transplant recipients only). TRANSPLANT: Patients undergo allogeneic hematopoietic stem cell transplant or umbilical cord blood transplant on day 0. GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus IV continuously (inpatients) or over 1-2 hours twice daily (BID) (outpatients) or orally (PO) BID on days -1 to +180 (patients receiving related or unrelated stem cells) or days -3 to +180 (patients receiving umbilical cord blood) with taper beginning on day +56 (related donor recipients) or +100 (unrelated donor or umbilical cord blood recipients) in the absence of GVHD. Patients also receive methotrexate IV on days +1, +3, +6, and +11 (related and unrelated donor recipients only) or mycophenolate mofetil IV or PO every 8 hours on days 0 to +40 with taper to day +96 (umbilical cord blood transplant recipients only). After completion of study treatment, patients are followed up at 6 months, 1 year, and then yearly for 4 years.

Official Title
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JAK Inhibitor Prior to Allogeneic Stem Cell Transplant for Patients With Primary and Secondary Myelofibrosis: A Prospective Study

Conditions
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Primary Myelofibrosis, Secondary Myelofibrosis

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Busulfan
* Drug: Cyclophosphamide
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Melphalan
* Drug: Methotrexate
* Drug: Mycophenolate Mofetil
* Drug: Ruxolitinib
* Drug: Tacrolimus
* Radiation: Total-Body Irradiation
* Procedure: Umbilical Cord Blood Transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PART 1: PART 1: Disease criteria Diagnosis of primary MF (PMF) as defined by the 2008 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) or DIPSS-plus scoring system PART 1: Ability to understand and the willingness to sign a written informed consent document PART 1: Patient must be a potential hematopoietic stem cell transplant candidate PART 2: PART 2: 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 PART 2: Received ruxolitinib for at least 8 weeks immediately prior to conditioning and be able to continue until Day -4 pre-transplant PART 2: Performance status score Karnofsky >= 70 PART 2: Calculated creatinine clearance using the Cockcroft-Gault formula or 24 hr urine creatinine clearance must be > 60 ml/min PART 2: Total serum bilirubin must be < 3 mg/dL unless the elevation is thought to be due to Gilbert's disease or hemolysis PART 2: Transaminases must be < 3 x the upper limit of normal PART 2: 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 PART 2: Diffusing capacity of the lung for carbon monoxide (DLCO) corrected > 60% normal May not be on supplemental oxygen PART 2: Left ventricular ejection fraction > 40% OR PART 2: Shortening fraction > 26% PART 2: Comorbidity Index < 5 at the time of pre-transplant evaluation DONOR: DONOR: Human leukocyte antigen (HLA)-matched or 1 antigen mismatched sibling donor DONOR: 10 of 10 HLA-matched or 1 allele mismatched (9 of 10) unrelated donor DONOR: Peripheral blood is preferred over bone marrow for non-umbilical cord blood recipients DONOR: Umbilical cord blood units will be selected according to the following umbilical cord blood graft selection criteria; one or 2 cord blood (CB) units may be used to achieve the required cell dose DONOR: The CB graft(s) must be matched at 4-6 HLA-A, B, DR Beta 1 (DRB1) loci with the recipient and therefore may include 0-2 mismatches at the A or B or DRB1 loci; unit selection will be based on cryopreserved nucleated cell dose and intermediate resolution A, B antigen and DRB1 allele typing for determination of HLA-match; while HLA-C antigen/allele level typing is not considered in the matching criteria, if available, it may be used to optimize unit selection DONOR: Selection of two CB units is allowed to provide sufficient cell dose (see below for algorithm to determine single versus double unit transplant); when multiple units are selected, the following rules apply: The CB unit with the least HLA disparity (with the patient) will be selected first (i.e., selection priority is 6/6 match > 5/6 match > 4/6 match); additional CB units then may be selected to achieve the required cell dose, as outlined below; if a second unit is required, this unit will be the unit that most closely HLA matches the patient and meets minimum size criteria outlined below of at least 1.5 x 10^7 total nucleated cells (TNC)/kg (i.e. a smaller, more closely matched unit will be selected over a larger, less well matched unit as long as minimum criteria are met) If two CB units are used: The total cell dose of the combined units must be at least 3.0 x 10^7 TNC per kilogram recipient weight Each CB unit MUST contain at least 1.5 x 10^7 TNC per kilogram recipient weight Algorithm for determining single versus double unit cord blood transplant: Match grade 6/6: TNC dose >= 2.5 x 10^7/kg Match grade 5/6, 4/6: TNC dose >= 4.0 (+/- 0.5) x 10^7/kg DONOR: General comments: Units will be selected first based on the TNC dose and HLA matching Cluster of differentiation (CD)34+ cell dose will not be used for unit selection unless 2 units of equal HLA-match grade are available; in this case, the unit with the larger CD34+ cell dose (if data available) should be selected A CB unit that is 5/6 mismatched but homozygous at the locus of mismatch should be chosen over a 5/6 unit with bidirectional mismatch even if the latter unit is larger (has more cells); this also applies to 4/6 units; this is only applicable to choosing units within a given match grade Other factors to be considered: Within the same HLA match grade, matching at DR takes preference Cord blood banks located in the United States are preferred Up to 5% of the cord blood product(s), when ready for infusion, may be withheld for research purposes as long as thresholds for infused TNC dose are met; these products will be used to conduct studies involving the kinetics of engraftment and immunobiology of double cord transplantation Exclusion Criteria: PART 1: PART 1: Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology PART 1: Uncontrolled viral, bacterial, or fungal infections at the time of study enrollment PART 1: History of prior allogeneic transplant PART 1: Pregnant or breastfeeding (only if patients have not been started on ruxolitinib [Rux] by their primary oncologist prior to enrollment) PART 2: PART 2: Uncontrolled viral or bacterial infection at the time of study enrollment PART 2: Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval PART 2: History of HIV infection PART 2: Pregnant or breastfeeding PART 2: Patients without an HLA-identical or 1-allele-mismatched related donor or unrelated donor or umbilical cord blood units that meet transplant criteria

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 (ruxolitinib, transplant)<br>Patients receive a ruxolitinib and undergo myeloablative or reduced-intensity conditioning followed by transplant and GVHD prophylaxis; see detailed description. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic hematopoietic stem cell transplant<br>* Other names: HSCT;Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Drug: Mycophenolate Mofetil<br>* Given IV or PO<br>* Other names: MMF;Drug: Ruxolitinib<br>* Given PO<br>* Other names: Jakafi;Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: Protopic;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: SCT_TBI;Procedure: Umbilical Cord Blood Transplantation<br>* Undergo umbilical cord blood transplant<br>* Other names: UCB transplantation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of 2-year survival in patients with myelofibrosis (MF) who receive treatment with a JAK inhibitor followed by an allogeneic transplant | The exact benchmark that will be used for comparison will be determined from the mix of Dynamic International Prognostic Scoring System (DIPSS) categories among those enrolled and treated with JAK on the current trial. From this mix, an expected two-year survival will be created as a weighted average of the data cited above. This weighted average will be used as the benchmark to which the data from the current trial will be compared. | At 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of acute graft versus host disease (GVHD) |  | Up to 70 days post-transplant | 
| Incidence and severity of chronic GVHD |  | Up to 2 years | 
| Incidence of relapse |  | 1 year | 
| Non-relapse mortality (NRM) |  | Day 100 | 
| Non-relapse mortality (NRM) |  | 1 year | 
| Overall incidence of primary graft failure/rejection |  | Up to 5 years | 
| Overall incidence of secondary graft failure/rejection |  | Up to 5 years |