Primary Myelofibrosis, Secondary Myelofibrosis
Conditions
Brief 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.
Detailed description
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.
Interventions
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic stem cell transplant
DRUGBusulfan
Given IV
DRUGCyclophosphamide
Given IV
DRUGFludarabine Phosphate
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMelphalan
Given IV
DRUGMethotrexate
Given IV
DRUGMycophenolate Mofetil
Given IV or PO
DRUGRuxolitinib
Given PO
DRUGTacrolimus
Given IV or PO
RADIATIONTotal-Body Irradiation
Undergo TBI
PROCEDUREUmbilical Cord Blood Transplantation
Undergo umbilical cord blood transplant
Sponsors
Fred Hutchinson Cancer Center
Incyte Corporation
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2-year Overall Survival (OS) in Patients With Myelofibrosis (MF) Who Receive Treatment With a JAK Inhibitor Followed by an Allogeneic Transplant | 2 years | OS was defined as the time from date of transplantation to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. The 2-year survival probability was estimated using the Kaplan-Meier method and a 2-sided 95% confidence interval (CI). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Acute Graft Versus Host Disease (GVHD) Grade II-IV | Up to 100 days post-transplant | Percentage of Participants with Grade II-IV acute GVHD in the first 100 days post HCT. |
| Percentage of Participants With Chronic Graft Versus Host Disease (GVHD) | 2 years | Max grade of chronic GVHD mild, moderate or severe at any time within the first 2 years following transplant. |
| Percentage of Patients Who Had Relapsed Disease at 1 Year | 1 year | Patients who had evidence of residual disease by molecular, flow cytometric or cytogenetics/FISH were considered relapsed disease. |
| Non-relapse Mortality (NRM) | Day 100 | Patients who died in remission between day of transplant and day 100. |
| Number of Patients Who Experienced Primary Graft Failure/Rejection | Up to 42 days post-transplant | Patients who failed to achieve ANC \> 500 x 3 or chimerism \> 5% by day 42 post-transplant. |
| Number of Patients Who Experienced Secondary Graft Failure/Poor Graft Function | Up to 5 years | Patients who engrafted with an ANC \>500 x 3 or chimerism \> 5% and then became neutropenic with ANC \<500x3 days or chimerism \<5% without evidence of relapse. |
| Percentage of Patients With a Max Grade of Moderate and Severe Chronic GVHD at Any Time Before 2 Years Post Transplant. | 2 years post-HCT | Includes patients who had a max grade of moderate or severe chronic GVHD by the NIH scoring system at any time between day 0 and 2 years post transplant. |
| Percentage of Participants With Acute Graft Versus Host Disease Grade III-IV GVHD | 100 days | Patients who had a max grade of III-IV acute GVHD any time between Day 0 and Day 100. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRachel B. Salit
Fred Hutch/University of Washington Cancer Consortium
Participant flow
Recruitment details
The original accrual goal to reach the primary endpoint was 48 patients. An additional 15 patients were added in order to collect samples for our translational work on GVHD biomarkers (total 63). We stopped our accrual at 61 patients when we opened our current study looking giving Rux in the peri-transplant setting.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Ruxolitinib, Transplant) Patients receive a ruxolitinib for at least 8 weeks and undergo myeloablative or reduced-intensity conditioning followed by transplant and GVHD prophylaxis; see detailed description. | 61 |
| Total | 61 |
Baseline characteristics
| Characteristic | Treatment (Ruxolitinib, Transplant) |
|---|---|
| Age, Continuous | 57 years |
| Conditioning Regimen Intensity High Intensity Myeloablative | 41 Participants |
| Conditioning Regimen Intensity Reduced Intensity Myeloablative | 20 Participants |
| DIPSS (Dynamic International Prognostic Scoring System) for Myelofibrosis High-risk | 2 Participants |
| DIPSS (Dynamic International Prognostic Scoring System) for Myelofibrosis Intermediate 1 risk | 16 Participants |
| DIPSS (Dynamic International Prognostic Scoring System) for Myelofibrosis Intermediate 2 risk | 41 Participants |
| DIPSS (Dynamic International Prognostic Scoring System) for Myelofibrosis Low-risk | 2 Participants |
| Donor Source 1 allele mismatched unrelated | 4 Participants |
| Donor Source Cord Blood | 6 Participants |
| Donor Source HLA-matched sibling | 25 Participants |
| Donor Source Matched unrelated | 26 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Karnofsky Performance Status (KPS) at time of HCT 100 | 10 Participants |
| Karnofsky Performance Status (KPS) at time of HCT 70 | 4 Participants |
| Karnofsky Performance Status (KPS) at time of HCT 80 | 19 Participants |
| Karnofsky Performance Status (KPS) at time of HCT 90 | 28 Participants |
| Primary or Secondary Myelofibrosis Primary MF | 36 Participants |
| Primary or Secondary Myelofibrosis Secondary MF | 25 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 51 Participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 14 / 61 |
| other Total, other adverse events | 61 / 61 |
| serious Total, serious adverse events | 7 / 61 |
Outcome results
Primary
2-year Overall Survival (OS) in Patients With Myelofibrosis (MF) Who Receive Treatment With a JAK Inhibitor Followed by an Allogeneic Transplant
OS was defined as the time from date of transplantation to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. The 2-year survival probability was estimated using the Kaplan-Meier method and a 2-sided 95% confidence interval (CI).
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ruxolitinib, transplant) | 2-year Overall Survival (OS) in Patients With Myelofibrosis (MF) Who Receive Treatment With a JAK Inhibitor Followed by an Allogeneic Transplant | 78.24 percentage of participants |
Secondary
Non-relapse Mortality (NRM)
Patients who died in remission between day of transplant and day 100.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ruxolitinib, transplant) | Non-relapse Mortality (NRM) | 4.92 percent of participants |
Secondary
Non-relapse Mortality (NRM)
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ruxolitinib, transplant) | Non-relapse Mortality (NRM) | 13.26 percent of participants |
Secondary
Number of Patients Who Experienced Primary Graft Failure/Rejection
Patients who failed to achieve ANC \> 500 x 3 or chimerism \> 5% by day 42 post-transplant.
Time frame: Up to 42 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (ruxolitinib, transplant) | Number of Patients Who Experienced Primary Graft Failure/Rejection | 1 Participants |
Secondary
Number of Patients Who Experienced Secondary Graft Failure/Poor Graft Function
Patients who engrafted with an ANC \>500 x 3 or chimerism \> 5% and then became neutropenic with ANC \<500x3 days or chimerism \<5% without evidence of relapse.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (ruxolitinib, transplant) | Number of Patients Who Experienced Secondary Graft Failure/Poor Graft Function | 2 Participants |
Secondary
Percentage of Participants With Acute Graft Versus Host Disease Grade III-IV GVHD
Patients who had a max grade of III-IV acute GVHD any time between Day 0 and Day 100.
Time frame: 100 days
Population: Only 58 of the 61 patients had acute GVHD scoring completed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ruxolitinib, transplant) | Percentage of Participants With Acute Graft Versus Host Disease Grade III-IV GVHD | 17.24 percent of participants |
Secondary
Percentage of Participants With Acute Graft Versus Host Disease (GVHD) Grade II-IV
Percentage of Participants with Grade II-IV acute GVHD in the first 100 days post HCT.
Time frame: Up to 100 days post-transplant
Population: Only 58 of the 61 patients had acute GVHD scoring completed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ruxolitinib, transplant) | Percentage of Participants With Acute Graft Versus Host Disease (GVHD) Grade II-IV | 68.97 percent of participants |
Secondary
Percentage of Participants With Chronic Graft Versus Host Disease (GVHD)
Max grade of chronic GVHD mild, moderate or severe at any time within the first 2 years following transplant.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ruxolitinib, transplant) | Percentage of Participants With Chronic Graft Versus Host Disease (GVHD) | 60.66 percent of participants |
Secondary
Percentage of Patients Who Had Relapsed Disease at 1 Year
Patients who had evidence of residual disease by molecular, flow cytometric or cytogenetics/FISH were considered relapsed disease.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ruxolitinib, transplant) | Percentage of Patients Who Had Relapsed Disease at 1 Year | 8.29 percent of participants |
Secondary
Percentage of Patients With a Max Grade of Moderate and Severe Chronic GVHD at Any Time Before 2 Years Post Transplant.
Includes patients who had a max grade of moderate or severe chronic GVHD by the NIH scoring system at any time between day 0 and 2 years post transplant.
Time frame: 2 years post-HCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (ruxolitinib, transplant) | Percentage of Patients With a Max Grade of Moderate and Severe Chronic GVHD at Any Time Before 2 Years Post Transplant. | 44.26 percent of participants |