Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

Abstract

At present, allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment for patients with myelofibrosis (MF). Unfortunately a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at time of diagnosis. The approval of the first JAK inhibitor, Ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support to assess the drug’s candidacy in the peri-transplant period. The drug’s precise impact on clinical outcome following allo-SCT is currently not known; nor is the drug’s long term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who are undergoing allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54th American Society of Hematology’s meeting in New Orleans, USA, on 6th December 2013 and the European Hematology Association meeting in Milan, Italy on 13th June 2014. This document summarizes the results of these efforts.

Impact of ruxolitinib pretreatment on outcomes after allogeneic stem cell transplantation in patients with myelofibrosis

“…In this study, we review the impact of pre‐ASCT ruxolitinib on the outcome of ASCT in myelofibrosis patients. There have been conflicting reports on the safety and impact of JAK1/2 inhibitor treatment before ASCT . We did not observe any withdrawal syndrome in our cohort.…”

“…There have been conflicting reports on the safety and impact of JAK1/2 inhibitor treatment before ASCT. 12,14,16,18,24 We did not observe any withdrawal syndrome in our cohort. The first prospective study evaluating the use of ruxolitinib prior to ASCT was by multicenter one developed cardiogenic shock, resulting in discontinuation of study enrollment.…”

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors

“…9–13 Theoretically, JAK1/2 inhibitor therapy may help in overcoming some of these barriers. 7,14,15 Its potential benefits in this setting include:(a) reduction in splenomegaly, which may facilitate engraftment, (b) decreasing symptoms due to pro-inflammatory cytokines, (c) improvement in performance status prior to HCT, (d) and a possible beneficial effect on GVHD. 16 However, conflicting data have emerged in the last two years on the safety of JAK1/2 inhibitors prior to HCT.…”

hGATA1 Under the Control of a μLCR/β-Globin Promoter Rescues the Erythroid but Not the Megakaryocytic Phenotype Induced by the Gata1low Mutation in Mice

“…In fact, drugs targeting the driver mutations displayed by the malignant hematopoietic stem clones, such as the JAK1/2 inhibitor ruxolitinib, are greatly effective in ameliorating the clinical manifestation of the disease but it is still unclear whether they are also effective in halting the progression toward its final stage ( Mascarenhas and Hoffman, 2013 ; Tefferi, 2021 ). As of today, with exception of bone marrow transplantation which may be offered to a limited number of patients ( Tamari et al, 2015 ), this disease is still an unmet clinical need. Based on the observation that bone marrow transplantation cures the disease by rescuing both the hematopoietic stem cell and the microenvironmental abnormalities displayed by the patient, the consensus has been reached that treatment of the disease requires the use of drug combinations targeting both abnormalities ( Eran et al, 2019 ; Tefferi, 2021 ).…”