Ruxolitinib Pre-, During- and Post-HSCT for Patients With Primary or Secondary Myelofibrosis.

A Phase II Study of Ruxolitinib Pre-, During- and Post-Hematopoietic Stem Cell Transplantation for Patients With Primary or Secondary Myelofibrosis.

This research study is studying a drug called Ruxolitinib as a possible treatment for Myelofibrosis.

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has approved Ruxolitinib as a treatment option for this disease.

This is a multi-center, open-label, phase II study to assess the efficacy and tolerability of ruxolitinib patients with myelofibrosis before, during and after hematopoietic stem cell transplantation (HCT). Eligible patients will take ruxolitinib twice daily on a continuous basis, per its FDA indication before HCT. Patients may be receiving ruxolitinib for any period of time at a dose based on institutional practice prior to enrollment to the study. Prior to enrollment, patients already receiving ruxolitinib will undergo dose-reduction to a dose of 5 mg BID, one week before conditioning begins. Patients not currently receiving ruxolitinib will enroll in the study and initiate ruxolitinib at a dose of 5 mg BID one week before conditioning begins. All patients will remain on ruxolitinib 5 mg BID during conditioning and transplant. Once patients have recovered their blood counts, patients will increase the dose (cytopenias permitting) to 10 mg BID. Patients will remain on ruxolitinib for 1 year after transplant, at which point ruxolitinib will be tapered and discontinued. Dose escalation will be permitted in patients with splenomegaly or myelofibrosis related symptoms.

Ruxolitinib is a medication that blocks certain proteins called tyrosine kinases. Specifically, it blocks tyrosine kinases called JAK2. Many cancers have over active "cell signaling." What this means is that certain functions in the cancer cells never turn off and this makes them grow in an uncontrolled way. Ruxolitinib, shuts down the pathway that depends on the JAK2 tyrosine kinases. The JAK2 pathway is over active in the participant's disease, acute myeloid leukemia. The exact way ruxolitinib does this is not yet clear but it may have to do with its ability to block the JAK2 pathway since this pathway can also lead to inflammation in the body.

Ruxolitinib has also been shown to lower the rates of Graft-Versus-Host-Disease (GVHD), a complication of transplant. GVHD is a disease that occurs when the immune cells in transplanted donor tissue from your HCT attack the participant's own tissues and organs. There are two types of GVHD: acute and chronic. Acute GVHD generally occurs within 1 week to 3 months after your HCT and may affect your skin, intestines, and liver. Chronic GVHD begins later on and may affect the organs prone to acute GVHD complications, as well as the lungs, mucous membranes, or other organs.

There is also evidence that ruxolitinib is associated with reduced instances of enlarged spleen size after HCT. Enlarged spleens play a role in the engraftment rate after HCT, which is the rate at which donated tissue and your own tissue begin reproducing and growing together.

In this research study, the investigators are:

• assessing the efficacy (how well the study drug works) and tolerability of Ruxolitinib before, during, and after HCT.
• examining the rates of GVHD after HCT when ruxolitinib is administered.
• determining whether engraftment rates improve when ruxolitinib is given

Inclusion Criteria:

• Participants must have pathologically confirmed primary myelofibrosis according to WHO criteria or secondary myelofibrosis as defined by the IWG-MRT criteria.

  • Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) criteria (Appendix G) OR
  • Intermediate-1 risk disease with one of the following additional unfavorable features known to impact the survival adversely
  • Red cell transfusion dependency
  • Unfavorable Karyotype
  • Platelet count ≤100 x 10^9/L
  • Presence of a high risk molecular marker associated with worsened overall survival (ASXL1, EZH2, IDH1/2, SRSF2, U2AF1, p53)

• Age 18-75

• Participants must be designated to undergo reduced intensity allogeneic peripheral blood (PB) or bone marrow (BM) hematopoietic stem cell transplantation. Consent will be obtained prior to admission for HCT.

• Participants who will undergo HCT from the following donor types are eligible:

  • 6/6 (HLA-A, B, DR) fully matched related donor
  • 8/8 (HLA-A, B, DR, C) fully matched unrelated donor. Matching in the unrelated setting must be at the allele level

• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

• Life expectancy of greater than 3 months

• Able to give informed consent

• Off all MF-directed therapy at the time of enrollment, with the exception of ruxolitinib, one week or 4 half-lives (effective), whichever is longer, prior to the first dose of study treatment

• No allergy to ruxolitinib in the past

• For patients already receiving ruxolitinib at the time of enrollment, patients should be treated with ruxolitinib for a sufficient time to optimize spleen response or symptoms, at the discretion of the treating provider, prior to enrollment. Patients who have had prior splenectomy are eligible.

Exclusion Criteria:

• Prior history of progressive multifocal leukoencephalopathy (PML)

• Concomitant receipt of St. John's Wort

• Hypersensitivity to any JAK inhibitor, including ruxolitinib, fedratinib, or any other JAK inhibitor

• Prior allogeneic transplant for any hematopoietic disorder

• Had accelerated phase or leukemic transformation (≥10% blasts in PB or BM any time prior to HCT)

• Patients with uncontrolled infection (patients with stable controlled infections such as hepatitis B or HIV patients with undetectable viral load on antiviral treatment would be eligible). Patients who are actively ill and require hospitalization to treat an infection will be excluded.

• History of another malignancy within 5-years of date of enrollment except those who have received definitive treatment. Definitive treatment will be defined as the use of surgery, chemotherapy or radiation for the treatment of a malignancy, which susbsquently has no evidence of disease after 2 years or <10% probably of recurrence after 1 year. In addition, patients with history of the following are eligible:

  • basal cell or squamous cell carcinoma of skin
  • Polycythemia Vera or Essential Thrombocythemia
  • ductal carcinoma in situ (DCIS)
  • superficial bladder cancer
  • prostatic intraepithelial neoplasia (PIN)

• Patients without normal organ function defined as follows:

  • AST (SGOT), ALT (SGPT) and Alkaline Phosphatase ≥ 3 × institutional Upper Limit of Normal (ULN)
  • Direct bilirubin >2.0 mg/dL
  • Calculated creatinine clearance ≤60 mL/min (Cockcroft-Gault formula)
  • Note: patients with CrCl ≤60 mL/min but with normal creatinine (within institutional normal ranges) and no other evidence of inadequate renal function are eligible.

• Have current or a history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF < 40%, as measured by MUGA scan or echocardiogram)

• Pregnancy at the time of enrollment

• Unable to give informed consent

• Have an uncontrolled intercurrent illness including, but not limited to, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Not able to take oral medication