Peri-transplant ruxolitinib therapy significantly improves GVHD-free, relapse-free survival rates in transplantation for myelofibrosis Free

Introduction Myelofibrosis (MF) is an advanced haematological malignancy manifested by the presence of splenomegaly, B-symptoms and cytopenias. The only curative approach is allogeneic stem cell transplantation (HSCT) however outcomes are significantly restricted by high rates of graft failure and graft-versus-host-disease (GVHD). Following changes to local conditioning protocols based upon clinical trial data (Ali et al, Blood Advances 2022), we evaluated peri-transplant predictors of long-term success in a uniformly managed cohort.

Methods Consecutive patient records were extracted from a comprehensive single-centre database. Key variables included high resolution HLA-matching for DP permissivity based upon the T-cell-epitope model, peri-transplant ruxolitinib use during conditioning, genetic risk scoring and stem cell dose. Multivariate Cox and Fine-Gray models were used to assess factors influencing overall survival (OS), progression-free survival (PFS), GVHD-free relapse-free survival (GRFS), and cause-specific mortality.

Results 37 patients receiving transplants between 2008-2023 were identified. Median age at transplant was 54 (range 32-71), and 65% were male. 68% (25/37) of patients had primary myelofibrosis and 45% had a JAK2 driver mutation (15/33). Most patients were DIPSS+ intermediate-2 (68%) or high risk (19%). 54% received ruxolitinib pre-transplant (20/37), of whom 35% (7/20) continued ruxolitinib 5mg twice daily during transplant conditioning until engraftment and then ceased treatment.

Most patients (86%) received fludarabine/busulfan-based reduced intensity conditioning, with ATG-based GVHD prophylaxis in all but 3 cases. 12 patients received matched sibling donors, 21 10/10 matched unrelated donors, 3 9/10 HLA-matched and 1 haploidentical transplant. 95% of cases (35/37) achieved day 28 neutrophil engraftment, with 2 cases of primary graft failure. Median time to neutrophil and platelet engraftment was 17 and 28 days respectively. Poor graft function was seen in 33% of patients (12/36), defined as 2-3 cytopenias lasting over 2 weeks after day +28 in the presence of donor chimerism >5%, requiring blood or platelet support or GCSF/EPO. At a median follow-up of 5 years, median survival post-HSCT was 17 months. One-, two-, and three-year OS were 66%, 55% and 52% respectively. GRFS at 1 and 3 years was 24% and 17%, highlighting the high burden of GVHD and relapse.

In multivariate models, a CD34+ stem cell dose >7 x 10^6/kg was associated with a reduced risk of death (HR 0.28, p=0.03), while HCT-CI comorbidity ≥3 was associated with a higher risk of death (HR 4.19, p<0.01), driven by increased non-relapse mortality risk (p=0.04). Combined donor-recipient CMV seropositivity predicted improved OS and PFS compared with other serotypes (HR 0.12 & 0.23, p=0.02 for both). Letermovir prophylaxis had no independent impact.

We then focussed on GRFS as a valuable composite endpoint particularly relevant for myelofibrosis outcomes, encompassing survival without severe grade III-IV acute GVHD, chronic GVHD requiring systemic therapy, relapse or death. No benefit was noted for high resolution HLA-matching for DP permissivity based upon the T-cell-epitope model. Continuation of ruxolitinib during conditioning was the only variable significantly associated with improved GRFS (HR 0.29, p=0.03), with 1-year GRFS of 42.9% vs 15.4% in those stopping ruxolitinib pre-conditioning (p=0.02). No significant interaction was seen for transplant year, engraftment kinetics or infection risk. One-year OS for patients continuing vs ceasing ruxolitinib was 85.7% and 61.5% respectively (p≥0.05).

Conclusions This long-term real world analysis underscores the substantial transplant-related morbidity in myelofibrosis. Major barriers to long-term safety and quality of life include high rates of GVHD, immunosuppression-related morbidity and poor graft function. Crucially, our results demonstrate that peri-transplant ruxolitinib continuation appears to significantly improve composite outcomes such as GRFS without compromising engraftment. These findings support ongoing prospective evaluation of JAK inhibition as part of transplant preparation and emphasise the need for optimised donor selection and graft composition in MF.