TPS6607 Background: Despite progress in the treatment of myelofibrosis (MF) with multiple approved JAK inhibitors (JAKi), the only curative therapy is allogeneic hematopoietic cell transplantation (HCT). Discontinuation of JAKi's before HCT is challenging as patients experience return of symptoms, moreover, hematopoietic recovery post-HCT is challenging as fibrosis takes many months to resolve. Although we have shown that ruxolitinib can be safely used during and after HCT with excellent survival, low rates of GVHD, and no adverse impact on engraftment (Hobbs et al., JCO Advances 2025), important unmet needs persist: better prevention of GVHD and improved management of post-transplant anemia and residual symptoms. Momelotinib is a JAK1/JAK2, ROCK2 and ACVR1 inhibitor that may help prevent GVHD via JAK1 and ROCK2 inhibition, which play key roles in immune cell function and inflammatory signaling. Moreover, in addition to momelotinib’s efficacy in spleen and symptom control, this agent improves anemia through ACVR1 inhibition. Thus, we aim to conduct a phase Ib study to determine the safety and tolerability of momelotinib in the peri/post-HCT period along with its impact on reducing transfusion needs. Methods: This is a phase Ib, single institution study investigating momelotinib given pre-, during- and for 1-year post-HCT for patients with primary or secondary MF (NCT 07104799). The primary endpoint is 1-year GVHD-free, relapse-free survival (GRFS). Secondary endpoints include overall (OS) and progression free survival (PFS), engraftment, and incidence of acute and chronic GVHD. Patients will be treated with reduced intensity conditioning with fludarabine (30mg/m 2 /d x 5 days) and melphalan (100 or 140mg/m 2 x 1). Patients will receive peripheral blood stem cell grafts from either 7/8 or 8/8 HLA-matched donors. GVHD prophylaxis will consist of standard tacrolimus and methotrexate. We will conduct a 3+3 dose escalation of momelotinib starting on day -7 of HCT through engraftment to test the safety of momelotinib at 100 mg, 150 mg and 200 mg during the peri and early post-HCT period. Once patients achieve engraftment, dose escalation to the approved dose of 200 mg daily will be allowed and continued for one-year post-HCT. We will collect samples for correlative analysis at baseline, day +100 and 1 year post-HCT. This study is the first to test momelotinib use pre-, during- and post-HCT in patients with MF. We have demonstrated that ruxolitinib use during and after-HCT leads to excellent GRFS and OS, however, post-HCT cytopenias remain an issue. Moreover, as more JAKi become available, it is important to evaluate the safety and efficacy of different JAKi during the time of HCT. This trial is open to accrual as of January of 2026. Funding and Product for this study is provided by GSK. Clinical trial information: NCT 07104799 . Clinical trial information: NCT 07104799 .
Hobbs et al. (Thu,) studied this question.