Ruxolitinib Prior to Transplant in Patients With Myelofibrosis

Exploring the Potential of Dual Kinase JAK 1/2 Inhibitor Ruxolitinib (INC424) With Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients With Myelofibrosis

The purpose of this study is to find out if giving the study drug Ruxolitinib (INC424) prior to a combination of other chemotherapeutic drugs (Fludarabine and Busulfan) before infusing another person's hematopoietic stem cells (bone marrow transplantation) will be successful in people who have advanced primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF), collectively known as myelofibrosis (MF). MF is a disorder in which bone marrow tissue develops in abnormal sites because the bone marrow itself undergoes fibrosis or scarring. This study plans to evaluate whether adding the drug Ruxolitinib will further aid in reducing pre-transplant spleen size, improve physical performance levels and reduce adverse events (side effects) related to the transplant. Ruxolitinib is a drug that is approved by the FDA for the treatment of patients with advanced forms of myelofibrosis. Using Ruxolitinib prior to stem cell transplantation is experimental.

A two- stage Simon Phase II study will be conducted in each of two groups of patients: related and unrelated donor transplants. In each donor transplant group, the first stage of this design will include 11 patients evaluated for death or graft failure by 100 days post-transplant. In each stratum, we will enroll additional patients (up to 20%) of stratum total to take into account exclusions due to donor failure (such as donor deemed unsuitable for stem cell donation due to medical or other reasons) only. Those patients who have toxicities related to Ruxolitinib and not been able to reach HCT due to these toxicities will be included in the estimation of overall failure rates. Only those patients who are excluded based on donor related issues without any regimen related complications will be excluded from the estimation of failure rates. However, all data on these patients will be reported.

Inclusion Criteria:

• Documented diagnosis of primary myelofibrosis according to WHO criteria or post PV myelofibrosis or post ET myelofibrosis as per IWG-MRT criteria

• Age 18-70 years

• Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) criteria OR Intermediate-1 risk disease with one of the following additional unfavorable features known to impact the survival adversely

  1. Red cell transfusion dependency
  2. Unfavorable Karyotype
  3. Platelet count <100 x 109/l

• Blasts in the PB and BM ≤10% prior to study enrollment

• Availability of a suitable matched related (6/6 or 5/6) or unrelated donor (10/10 or 9/10 antigen or allele matched).

• Able to give informed written consent

• ECOG Performance status of 0-2.

• Life expectancy >3 months

• Off all MF-directed therapy including investigational agents for at least 2 weeks prior to study enrollment and recovered from all toxicities*

• Adequate organ function

  • Adequate renal function - creatinine <1.5 x IULN

  • Adequate hepatic function - AST/ALT <2.5 x IULN, Total Bilirubin <1.5 x IULN

  • Adequate hematopoietic function - Platelet ≥50 x 109/l and ANC ≥1.0 x 109/l

  • LVEF >40% (MUGA or echocardiogram) Normal per Institutional standard

  • Adequate pulmonary function with DLCO >50%

    • A patient who has been on stable dose of Ruxolitinib and has received ruxolitinib ≤6 months prior to the study entry will be considered potentially eligible for the study with the caveat that there is no evidence of loss of response (>5cm increase in spleen size from the nadir).

Exclusion Criteria:

• Any previous JAK2 inhibitor treatment prior to study enrollment, with the exception of Ruxolitinib
• Hypersensitivity to JAK inhibitor
• Clinical or laboratory evidence of cirrhosis
• Prior allogeneic transplant for any hematopoietic disorder
• >20% blast in the PB or BM prior to HCT or had leukemic transformation (>20% blasts in PB or BM any time prior to HCT)
• Syngeneic donor
• Cord Blood transplant
• Active uncontrolled infection
• H/o another malignancy within 5-years of date of HCT except h/o basal cell or squamous cell carcinoma of skin or PV or ET
• Known HIV positive
• Pregnancy at the time of BMT
• Any other concurrent illness which in investigator's opinion puts the patient at excessive risk of treatment related toxicities
• Unable to give informed consent
• Active infection with hepatitis A,B or C virus
• Subjects who require therapy with a strong CYP3A4 inhibitor prior to enrollment to this study