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

Pilot Study of JAK Inhibitor Therapy Followed by Reduced Intensity Haploidentical Transplantation for Patients With 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.

Study Overview

• Status: Recruiting
• Conditions: Primary Myelofibrosis; Secondary Myelofibrosis
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Procedure: Computed Tomography; Procedure: Biospecimen Collection; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Melphalan; Drug: Mycophenolate Mofetil; Drug: Tacrolimus; Radiation: Total-Body Irradiation; Procedure: Echocardiography; Procedure: Multigated Acquisition Scan; Drug: JAK Inhibitor; Biological: Recombinant Granulocyte Colony-Stimulating Factor; Procedure: Peripheral Blood Stem Cell Transplantation; Procedure: Bone Marrow Biopsy; Procedure: Bone Marrow Aspiration

Detailed Description

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 or day -1 and day 0.

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.

All patients undergo magnetic resonance imaging (MRI), computed tomography (CT), bone marrow biopsy and aspiration and blood sample collection throughout the trial. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) on the trial.

After completion of study treatment, patients are followed up between day 80-100, at 1 year, and then up to 5 years.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rachel B. Salit; Phone Number: 206-667-1317; Email: rsalit@fredhutch.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Contact: Rachel B. Salit; Phone Number: 206-667-1317; Email: rsalit@fredhutch.org
      • Principal Investigator: Rachel B. Salit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (JAK inhibitor, conditioning, GVHD prophylaxis); 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 or day -1 and day 0. 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. All patients undergo MRI, CT, bone marrow biopsy and aspiration and blood sample collection throughout the trial. Patients also undergo ECHO or MUGA on the trial.

Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; MR Imaging; Procedure: Computed Tomography; Undergo CT; Other Names: CAT Scan; Computed Axial Tomography; CT SCAN; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Asta B 518; B-518; WR-138719; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Drug: Melphalan; Given IV; Other Names: CB-3025; L-PAM; Alanine Nitrogen Mustard; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; L-sarcolysin; L-Phenylalanine mustard; Drug: Mycophenolate Mofetil; Given PO; Other Names: Cellcept; MMF; Drug: Tacrolimus; Given IV and PO; Other Names: Prograf; Hecoria; FK 506; Fujimycin; Protopic; FK-506; Tacforius; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Total-Body Irradiation Prior to Stem Cell Transplant; Procedure: Echocardiography; Undergo ECHO; Other Names: EC; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; Drug: JAK Inhibitor; Given PO; Other Names: Ruxolitinib; Fedratinib; JAK inhibitors; Janus Kinase Inhibitor; Biological: Recombinant Granulocyte Colony-Stimulating Factor; Given SC; Other Names: rhG-CSF; Recombinant Colony-Stimulating Factor 3; 143011-72-7; Procedure: Peripheral Blood Stem Cell Transplantation; Given IV; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant; peripheral stem cell support; peripheral stem cell transplantation; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy and aspiration; Other Names: Biopsy of Bone Marrow; Procedure: Bone Marrow Aspiration; Undergo bone marrow biopsy and aspiration

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Investigators: Principal Investigator: Rachel B. Salit, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2021
• Primary Completion (Estimated): August 31, 2024
• Study Completion (Estimated): August 31, 2029

Study Registration Dates

• First Submitted: April 28, 2020
• First Submitted That Met QC Criteria: April 28, 2020
• First Posted (Actual): April 30, 2020

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Neoplastic Processes; Primary Myelofibrosis; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Protein Kinase Inhibitors; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Lenograstim; Melphalan; Fludarabine; Tacrolimus; Mycophenolic Acid; Mechlorethamine; Nitrogen Mustard Compounds; Janus Kinase Inhibitors
• Other Study ID Numbers: RG1006957; NCI-2020-02422 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10441 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No