Ruxolitinib (RUX), the first approved JAK1/2 inhibitor, has consistently demonstrated the ability to improve clinical outcomes in patients with myelofibrosis (MF). In many patients, RUX treatment must be modified or suspended due to low tolerability and/or continued disease progression. These patients generally have poor prognosis. The primary therapy for this subset of patients is allogeneic hematopoietic stem-cell transplantation (allo-SCT) and terminating RUX therapy for allo-SCT worsens symptoms (rebound effect). As a result, patients remain on RUX therapy administered during and after allo-SCT in an “off-label” manner; the safety of this regimen has not been evaluated.
An interim analysis of an ongoing phase 2 study investigating RUX in patients (n = 26) with primary or secondary MF who receive RUX before, during, and 1 year after allo-SCT with 7/8 or 8/8 (88%) human leukocyte antigen─matched peripheral blood stem-cell grafts was performed. Median age was 66 years (range, 46-75 years) and most patients were male (65%). Most patients were previously treated with RUX (54%) and had intermediate-2 or high risk per the Dynamic International Prognostic Scoring System (92%) at the time of transplant. In addition, patients were positive for MF-associated somatic mutations in JAK2 (58%), CALR (12%), MPL (12%), and ASXL1 (35%) genes. Next-generation sequencing was obtained before and 100 days after allo-SCT. In all but 1 patient, mutations were not detected by next-generation sequencing at day 100. Each patient was subjected to a reduced-intensity conditioning regimen with fludarabine (30 mg/m2/day × 5 days) and melphalan (100 mg/m2 or 140 mg/m2 × 1).
The primary end points include 1-year rates of freedom from graft-versus-host disease (GVHD) and GVHD relapse-free survival (GRFS). There was no observation of grade 4 acute GVHD and only 1 case of grade 3 acute GVHD. There was no severe chronic GVHD and only 1 patient developed moderate chronic GVHD, with cumulative incidence of all chronic GVHD (14%) and moderate-severe chronic GVHD (5%) of 14% and 5%, respectively. Among survivors, the 1-year GRFS rate was 65% with median follow-up of 12 months (range, 3-24 months).
Overall survival, progression-free survival, and cumulative incidence of nonrelapse mortality and disease relapse at 18 months after transplantation were 77%, 71%, 13%, and 17%, respectively. No unexpected toxicities related to RUX therapy were observed. The most common grade 3/4 hematologic adverse events included anemia (n = 4) and thrombocytopenia (n = 3). Grade 3/4 nonhematologic adverse events included infection (n = 2) and hypertriglyceridemia (n = 1). All but 1 patient achieved successful neutrophil engraftment after allo-SCT with median time to engraftment at 15 days (range, 11-38 days) after transplant. Median day 30 donor all-cell chimerism was 100% (range, 95%-100%).
RUX is currently being used to treat steroid-refractory acute and chronic GVHD irrespective of underlying disease. To date, this study demonstrated that RUX administration is safe before, during, and after stem-cell transplant with minimal incidence of severe acute and chronic GVHD.
Source: Hobbs G, Kim HT, Bottoms AJS, et al. A phase II study of ruxolitinib pre-, during- and post-hematopoietic cell transplantation for patients with primary or secondary myelofibrosis. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 169.