Ruxolitinib Before, During and After Hematopoietic Cell Transplant in Older Patients With Myelofibrosis and Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Enrolling

Phase 2

Conditions

Secondary Myelofibrosis

Primary Myelofibrosis

Myelodysplastic/Myeloproliferative Neoplasm

Treatments

Procedure: Bone Marrow Aspiration

Drug: Melphalan

Drug: Fludarabine

Drug: JAK Inhibitor

Drug: Tacrolimus

Drug: Busulfan

Procedure: Bone Marrow Biopsy

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Procedure: Echocardiography Test

Drug: Cyclophosphamide

Procedure: Computed Tomography

Procedure: Biospecimen Collection

Drug: Methotrexate

Drug: Ruxolitinib

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT07228624

FHIRB0020989 (Other Identifier)

NCI-2025-07728 (Registry Identifier)

RG1125655

Details and patient eligibility

About

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.

Full 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.

Enrollment

50 estimated patients

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

50 participants in 1 patient group

Treatment (ruxolitinib)

Experimental group

Description:

PART 1: Patients receive ruxolitinib or alternate JAK-inhibitor for at least 8 weeks prior to the start of HCT conditioning. PART 2: Starting on day -4, patients receive ruxolitinib 5mg PO BID for 12 months then PO QD until 18 months. Patients receive high intensity conditioning with cyclophosphamide 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. 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, and pulmonary function testing prior to conditioning and blood sample collection, bone marrow biopsy and aspiration, and spleen ultrasound or CT throughout the study.

Treatment: