Impact of Ruxolitinib in Myelofibrosis Allogeneic Stem Cell Transplant Outcome---a Pilot Study

Background: Myelofibrosis (MF) is a clonal stem cell disorder that develops de novo or evolves from a pre-existing myeloproliferative neoplasm such as polycythemia vera or essential thrombocythemia. MF is characterized by dysregulated proliferation of myeloid precursor cells and reactive deposition of connective tissue within the bone marrow, leading to bone marrow fibrosis and eventual failure from ineffective hematopoiesis. Common clinical manifestations include constitutional symptoms such as fatigue, fever, night sweats, weight loss, and hepatosplenomegaly. The clinical course and prognosis of MF is heterogenous, and survival outcomes are largely dependent on risk stratification that incorporates both phenotypic characteristics as well as cytogenetic features. Allogeneic stem cell transplant (alloSCT) is the only available treatment option to cure MF. Ruxolitinib (Rux), a potent JAK1/JAK2 inhibitor, has demonstrated significant effects in improving constitutional symptoms and reducing spleen size in intermediate to high risk patients. Hence, pre-transplant Rux treatment has often been practiced on patients with symptomatic splenomegaly and/or constitutional symptoms. Moreover, there are ongoing studies suggesting improved outcomes in patients treated with Rux before receiving alloSCT. However, the toxicity profile and tolerability profile of Rux treatment in transplant eligible patients remains unclear, especially the impacts of post-transplant Rux maintenance treatment.

Method: We retrospectively analyzed the alloSCT outcomes among MF patients who never received Rux, received Rux before alloSCT, and received Rux before and after alloSCT at Penn State Hershey Cancer Institute between 6/2014 and 6/2017.

Result: This pilot study analyzed 15 patients with mean age of 58.5 years old (range: 49-70) at the time receiving alloSCT. Ten patients were male and 5 patients were female. Those patients' MF scores were ranging from 2 to 3 (WHO Grade) at diagnosis. Five patients had primary MF and 10 had secondary MF. At diagnosis, all patients had constitutional symptoms, 14 of them had splenomegaly (1 had splenectomy before his MF diagnosis). Seven patients received Rux treatment before alloSCT, 4 received Rux before and after alloSCT, and 4 never received Rux. The mean length of time for Rux treatment before alloSCT was 8.3 months (range:5-20); the mean length of time for receiving Rux post alloSCT was 12.5 months (range:3-23). All patients received reduced intensity conditioning (RIC) regimen (14 patients received Fludarabine/Bu2, 1 patient received Fludarabine/Cyclophosphamide). One patient in the Fludarabine/Bu2 group also received total body irradiation (TBI) as part of conditioning regimen. The mean neutrophils engraft days for patients received Rux before alloSCT was 13.6 (range: 12-19), for patients received Rux before and after alloSCT was 13.3 (range: 12-16), and for patients never received Rux was 16 (range:13-18). All patients were transfusion independent at day 30 (D30) with >95% donor chimerism in peripheral blood. Following alloSCT, 4 patients restarted Rux at a mean time of 3.5 months (range: 3-4.5) post alloSCT. CMV viremia was detected in 5 patients before day 100 of alloSCT; in which 3 patients never received Rux. Fungal pneumonia (1 aspergillus) occurred in 3 patients who received Rux before allSCT. Multiple episodes of GVHD (grade II-III) occurred in 4 patients, however 3 of them never exposed to Rux before. One patient treated with Rux before alloSCT experienced liver GVHD (grade I to II) and responded well to steroids and immunosuppression treatment. The mean spleen size reduction in 6 months after alloSCT among patients received Rux before and after alloSCT was 26% (20 to 32%), among patients received Rux before alloSCT only was 18.2% (6 to 40%), and among patients never received Rux was 17.7% (12 to 24%). All patients are alive and in complete remission.

Conclusion:

Patients in this pilot study tolerated well to Rux treatment before and after alloSCT with neither prolonged engraft time nor increased toxicity. Before and after alloSCT Rux management may improve overall outcomes. Further study on large patient population is warranted.