Primary Myelofibrosis, Secondary Myelofibrosis
Conditions
Brief summary
This initial cohort of this phase II trial studied the outcomes of using a JAK inhibitor prior to reduced intensity haploidentical (Haplo) transplantation for the treatment of primary or secondary myelofibrosis (MF). The primary risk of using Haplo HCT in patients with MF is graft failure. In the first cohort, all patients engrafted. There were no instances of graft failure. However, a large number of patients did have graft versus host disease as a complication of their transplant. JAK inhibitors have since been approved for the indication of graft versus host disease treatment. And we are also using them for graft versus host disease prevention in a study of MF patients with sibling and unrelated donors. Therefore, we are opening a new cohort of the current study using the JAK inhibitor prior to, during and after Haplo transplant. Our goal is to decrease graft versus host disease in patients receiving a Haplo MF transplant without increasing the risk of graft failure.
Detailed description
OUTLINE: Cohort 1 is now closed and all patients will be enrolled on Cohort 2. COHORT I: 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 about 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. COHORT II: JAK INHIBITOR THERAPY: Patients receive a JAK inhibitor at least 8 weeks prior to the start of HCT conditioning through day -4 before transplantation. Additionally, patients receive a JAK inhibitor following transplantation beginning day +5 through 9-12 months after transplant. 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 about 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 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.
Interventions
PROCEDUREEchocardiography Test
Undergo ECHO
PROCEDUREMultigated Acquisition Scan
Undergo MUGA
DRUGCyclophosphamide
Given IV
DRUGJAK Inhibitor
Given PO
DRUGFludarabine
Given IV
Given SC
DRUGMelphalan
Given IV
DRUGMycophenolate Mofetil
Given PO
PROCEDUREPeripheral Blood Stem Cell Transplantation
Given IV
DRUGTacrolimus
Given IV and PO
RADIATIONTotal-Body Irradiation
Undergo TBI
PROCEDUREComputed Tomography
Undergo CT
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy and aspiration
PROCEDUREBone Marrow Aspiration
Undergo bone marrow biopsy and aspiration
PROCEDUREBiospecimen Collection
Undergo blood sample collection
Sponsors
Fred Hutchinson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* PART 1: JAK INHIBITOR ADMINISTRATION INCLUSION CRITERIA * Age between 18 and 70 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 (or legally authorized representative). 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 willing to continue until 9-12 months post-transplant as tolerated * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Probability of primary and secondary graft failure | Up to 5 years | Primary graft failure is defined as failure to achieve an absolute neutrophil count of \> 500/ul by 42 days after bone marrow or peripheral blood stem cell transplantation. Secondary graft failure is defined as cytopenias after initial engraftment, with (a) donor chimerism of \< 5% or (b) falling donor chimerism with intervention such as second transplant or donor lymphocyte infusion or (c) patient death due to cytopenias, and fall in donor chimerism, even if chimerism is \> 5%. Exclusion criteria for diagnosis of graft failure are (a) disease relapse, (b) graft-versus-host disease, and (c) other causes of cytopenias such as, viral infection and drug toxicity. |
Secondary
| Measure | Time frame |
|---|---|
| Non-relapse mortality (NRM) | Day 100 |
| NRM | 1 year |
| Overall survival | 1 year |
| Incidence of severe (grade 3 or 4) cytokine release syndrome | Up to 5 years |
| Incidence of grade III-IV acute GVHD | Up to 5 years |
| Incidence of moderate-severe chronic GVHD | Up to 5 years |
| Incidence of relapse | At 1 year |
| Incidence of grade II-IV acute graft versus host disease (GVHD) | Up to 5 years |
Countries
United States
Contacts
Primary ContactRachel B. Salit
Outcome results
None listed