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

  • STATUS
    Recruiting
  • End date
    Jun 11, 2026
  • participants needed
    63
  • sponsor
    Fred Hutchinson Cancer Research Center
Updated on 11 July 2021
stem cell transplantation
total body irradiation
fludarabine
tacrolimus
mycophenolate mofetil
cyclophosphamide
hla-a
busulfan
myeloproliferative disorder
carbon monoxide
ruxolitinib
melphalan
hemolysis
abnormal cells
secondary myelofibrosis
janus kinase inhibitor

Summary

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.

Description

PRIMARY OBJECTIVE:

I. To optimize the role of allogeneic transplantation for primary and secondary myelofibrosis (MF) in the JAK inhibitor era.

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.

Details
Condition Myelosclerosis with myeloid metaplasia, Secondary Myelofibrosis, Myelofibrosis
Treatment cyclophosphamide, fludarabine phosphate, methotrexate, mycophenolate mofetil, laboratory biomarker analysis, busulfan, melphalan, allogeneic hematopoietic stem cell transplantation, Tacrolimus, Total-Body Irradiation, Ruxolitinib, Umbilical Cord Blood Transplantation, Pacritinib, Momelotinib
Clinical Study IdentifierNCT02251821
SponsorFred Hutchinson Cancer Research Center
Last Modified on11 July 2021

Eligibility

Yes No Not Sure

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
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