Myelodysplastic/Myeloproliferative Neoplasm, Primary Myelofibrosis, Secondary Myelofibrosis
Conditions
Brief summary
This phase II trial tests the effect of adding ruxolitinib to standard graft versus host disease (GVHD) prevention in treating older patients with myelofibrosis (MF) or myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes before, during, and after a donor (allogeneic) hematopoietic cell transplant (HCT). Allogeneic HCT is a procedure in which a person receives blood-forming stem cells (cells from which all blood cells develop) from a genetically similar, but not identical donor. Giving chemotherapy, such as cytoxan and busulfan or fludarabine and melphalan, before a donor transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. However, sometimes the transplanted cells from a donor can attack the body's normal cells (called GVHD). Giving standard prevention (prophylaxis) therapies, such as tacrolimus and methotrexate, after the transplant may stop this from happening. Methotrexate, a type of antifolate, is in a class of medications called antimetabolites. Methotrexate stops cells from using folic acid to make deoxyribonucleic acid and may kill cancer cells. Tacrolimus is used to help reduce the risk of rejection by the body of organ and bone marrow transplants. Ruxolitinib, a type of Janus-associated kinase (JAK) inhibitor, blocks a protein called JAK, which may help keep abnormal blood cells or cancer cells from growing. It may also lower the body's immune response and prevent the development of GVHD. Giving ruxolitinib before, during and after allogeneic HCT in addition to standard GVHD prophylaxis may be safe, tolerable and effective in preventing GVHD and improving outcomes in older patients with MF or MDS/MPN overlap syndrome.
Detailed description
OUTLINE: PART 1: Patients receive ruxolitinib or an alternate JAK-inhibitor for at least 8 weeks prior to the start of HCT conditioning. Starting on day -4, patients receive 5 mg of ruxolitinib orally (PO) twice daily (BID) for 12 months then PO once daily (QD) until 18 months. Patients receive high intensity conditioning with cyclophosphamide intravenously (IV) on days -7 and -6 and busulfan IV over 3 hours on days -5 to -2 or reduced intensity conditioning with fludarabine IV over 30 minutes on days -6 to -2 and melphalan IV over 15-30 minutes on days -3 and -2. PART 2: Patients receive stem cells infusion on day 0. Starting on day -3, patients receive tacrolimus IV over 1-2 hours or PO every 12 hours for at least 100 days. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Additionally, patients undergo urine sample collection, echocardiography, chest computed tomography (CT) and pulmonary function testing prior to conditioning and blood sample collection, bone marrow biopsy and aspiration and spleen ultrasound or CT at multiple time points before and after transplant. After completion of study treatment, patients are followed at days 28, 100, 180, and at 9 months, 1 year, 18 months and 2 years.
Interventions
DRUGRuxolitinib
Given PO
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Given infusion
DRUGBusulfan
Given IV
PROCEDUREComputed Tomography
Undergo CT
DRUGCyclophosphamide
Given IV
PROCEDUREEchocardiography Test
Undergo echocardiography
DRUGFludarabine
Given IV
DRUGJAK Inhibitor
Given JAK inhibitor
DRUGMelphalan
Given IV
DRUGMethotrexate
Given IV
DRUGTacrolimus
Given IV or PO
PROCEDUREBiospecimen Collection
Undergo urine and blood sample collection
PROCEDUREBone Marrow Aspiration
Undergo bone marrow biopsy and aspiration
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy and aspiration
Sponsors
Fred Hutchinson Cancer Center
Incyte Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* PART 1 JAK INHIBITOR ADMINISTRATION: Age 18-75 years * Patients \> 75 must be considered an HCT candidate, meet all protocol criteria and have comorbidity score =\< 3 and Karnofsky performance status (KPS) \> or = to 90. Patients. \> 75 who do not meet these criteria may be presented at PCC for consensus exception * PART 1 JAK INHIBITOR ADMINISTRATION: Disease criteria * Diagnosis of primary or secondary MF as defined by the 2022 World Health Organization classification system or the International Consensus Classification for Myeloid and Acute Leukemias * Diagnosis of an MDS/MPN overlap syndrome as defined by the 2022 World Health Organization * PART 1 JAK INHIBITOR ADMINISTRATION: Ability to understand and the willingness to sign a written informed consent document * PART 1 JAK INHIBITOR ADMINISTRATION: Patient must be a potential HCT candidate as assessed by the consenting physician * PART 1 JAK INHIBITOR ADMINISTRATION: Patient must be agreeable to taking a JAK-inhibitor (ruxolitinib preferred) for at least 8 consecutive weeks immediately prior to conditioning and be willing to take ruxolitinib 5mg BID starting from day -4 prior to and continuing until 12 months post-transplant as tolerated followed by a 6-month taper. * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Meeting criteria for Part 1 at time of initiation of JAK-inhibitor, including the ability to understand and willingness to sign a written informed consent. Patients arriving to our institution for HCT and not enrolled in Part 1 may still be enrolled in Part 2 if Part 1 criteria are met. These patients will have Part 1 endpoints transcribed from their medical records * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Received a JAK-inhibitor for at least 8 weeks immediately prior to conditioning and be willing to take Rux from day -4 at the 5mg BID dose until 12 months post-transplant as tolerated followed by a 6 month taper * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Performance status score * Karnofsky ≥ 70 or \> 90 for patients \> 75 years old * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: HCT-CI Score \< 8; if patient is \> 75 years old HCT-CI \< 3 * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Calculated creatinine clearance using the Cockcroft-Gault formula or 24-hour urine creatinine clearance must be \> 60 ml/min * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Total serum bilirubin must be \< 3mg/dL unless the elevation is thought to be due to Gilbert's disease or hemolysis * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Transaminases must be \< 3 x the upper limit of normal * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: 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 \> 3mg/dL, and symptomatic biliary disease will be excluded * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Diffusion capacity of lung for carbon monoxide (DLCO) corrected \> 60% normal. Patient may not be on oxygen * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Left ventricular ejection fraction \> 40% * DONOR: Human leukocyte antigen (HLA)-matched sibling donor * DONOR: 10 of 10 HLA-matched unrelated donor * DONOR: 9 of 10 allele or antigen mismatched unrelated donor * DONOR: Peripheral blood is preferred over bone marrow * DONOR: Matched unrelated donors may be preferred over siblings if the unrelated donor is \< 30 years and the sibling is \> 60 years. However, sibling donors \< 70 should be preferred over mismatched unrelated donors
Exclusion criteria
* PART 1 JAK INHIBITOR ADMINISTRATION: Contraindication to receiving ruxolitinib including patients who have known hypersensitivity to JAK inhibitors and excipients * PART 1 JAK INHIBITOR ADMINISTRATION: History of prior allogeneic transplant * PART 1 JAK INHIBITOR ADMINISTRATION: Leukemic transformation (\> 20% blasts) * PART 1 JAK INHIBITOR ADMINISTRATION: Uncontrolled viral, bacterial, or fungal infection despite being on therapy * PART 1 JAK INHIBITOR ADMINISTRATION: History of HIV infection * PART 1 JAK INHIBITOR ADMINISTRATION: History of untreated tuberculosis (TB) * PART 1 JAK INHIBITOR ADMINISTRATION: Pregnant or breastfeeding * PART 1 JAK INHIBITOR ADMINISTRATION: Patients with history of myocardial infarction (MI), cerebrovascular accident (CVA) or unprovoked pulmonary embolism (PE)/deep vein thrombosis (DVT) in the past 6 months * PART 1 JAK INHIBITOR ADMINISTRATION: Secondary malignancy in last 5 years with \> 20% risk of relapse * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Contraindication to receiving ruxolitinib including patients who have known hypersensitivity to JAK inhibitors and excipients * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: History of prior allogeneic transplant * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Leukemic transformation (\> 20% blasts) * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Uncontrolled viral or bacterial infection at the time of transplant data review and consent conference * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: History of HIV infection * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: History of untreated TB * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Requiring supplemental oxygen * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Pregnant or breastfeeding * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Secondary malignancy in last 5 years with \> 20% risk of relapse * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Patients with a history of MI, CVA, or unprovoked PE/DVT in the past 6 months * PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Patients without an HLA-identical sibling donor, 10 of 10 HLA-matched or 9 of 10 mismatched unrelated donor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of grade II-IV graft versus host disease (GVHD) requiring systemic immune suppression | Up to day-100 | Will be estimated as a simple proportion, and the upper bound of the one-sided 95% confidence interval for the estimated proportion will be estimated using the Clopper-Pearson method. The exact binomial test will be used to compare the observed probability to the benchmark of 65%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of grade III-IV acute GVHD | Up to day-100 | Will be estimated as simple proportions and informally compared to the results from the historical cohort. |
| Incidence of any-grade chronic GVHD | Up to 1 and 2 years | Will be treated as time-to-event endpoints, with specified point estimates. |
| Incidence of moderate-to-severe chronic GVHD | Up to 1 and 2 years | Will be treated as time-to-event endpoints, with specified point estimates. |
| Non-relapse mortality (NRM) | At day-100 | Will be estimated as simple proportions and informally compared to the results from the historical cohort. |
| NRM | At 1 year | Will be treated as time-to-event endpoints, with specified point estimates. |
| Remission status | At day-100 | Will be estimated as simple proportions and informally compared to the results from the historical cohort. |
| Relapse rate | At 1 and 2 years | Will be treated as time-to-event endpoints, with specified point estimates. |
| Overall survival | Up to 1 year and by end of study, assessed up to 2 years | Will be treated as time-to-event endpoints, with specified point estimates. |
| Incidence of graft failure | Up to day-100 | Will be estimated as simple proportions and informally compared to the results from the historical cohort. |
Countries
United States
Contacts
CONTACTRachel Salit, MD
PRINCIPAL_INVESTIGATORRachel Salit, MD
Fred Hutch/University of Washington Cancer Consortium
Outcome results
None listed