Ruxolitinib For Patients With Primary Or Secondary Myelofibrosis before Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT): A Retrospective Study Of The Société Française De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC)
Authors: Lebon Delphine , Rubio Marie T , Legrand Faezeh , Kiladjian Jean-Jacques , Mohty Mohamad , Cahn Jean-Yves , Vincent Laure , Charbonnier Amandine , Raus Nicole , Socié Gérard , Robin Marie 
Published: October 2019

Abstract
Up to now allo-HSCT is the only curative treatment for patients with myelofibrosis (MF) (Ballen, et al, Guardiola, et al 1999, Kroger, et al 2007, Robin, et al 2011). The engraftment rate ranges from 70% to 95% and is influenced by spleen size (delayed in patients with splenomegaly and faster in patients splenectomized prior to allo-HSCT). JAK1/JAK2 inhibitor Ruxolitinib is reported to decrease spleen size and constitutional symptoms. These effects could also be benefit for patients eligible for transplantation, by reducing their splenomegaly and improving their performance status, factors known to impact the results of allo-HSCT. The present study analyzes outcome of patients with MF who have been reported to the SFGM-TC registry.
From 2008 to 2013, 11 patients with primary MF (n=7), MF secondary to PV or ET (n=3) or acute myeloid leukemia secondary to MF (n=1) were treated with Ruxolitinib before allo-HSCT. Median age at allo-HSCT was 54 years (range: 44-66); there were 9 men and 2 women. Nine patients had the JAK2V617F mutation. At Ruxolitinib initiation, median white blood cells were 4.4G/L (3.5–13.7), hemoglobin was 10g/dL (7.5-13.3) and platelets were 99G/L (41-290); all patients had palpable splenomegaly and 8 had constitutional symptoms. Lille score was low in 4, intermediate in 2 and high in 4 patients, respectively. Cytogenetics were favorable in 2, unfavorable in 3 (complex karyotype) and not done or failure in 6 patients, respectively. The median time between diagnosis and treatment with Ruxolitinib was 353 days (16-2687) and median time from diagnosis to allo-HSCT was 433 days (199–2793). Ruxolitinib was progressively tapered in 3 patients (with steroids for 2 of them) and discontinued without tapering in 4 (missing data for 3). Median time between Ruxolitinib withdrawal and allo-HSCT was 10.5 days (4-66). All patients received reduced intensity conditioning regimen based on Fludarabine and a graft-versus-host disease (GVHD) prophylaxis including ciclosporine. Donors were: HLA matched sibling in 4, matched unrelated donor in 3 and mismatched unrelated donor in 4 patients. All but one patients received peripheral stem cell transplantation (one patients received bone marrow).
Before allo-HSCT, 7 patients were in partial response and 4 were stable. After Ruxolitinib treatment, 8 patients had an estimated reduction of spleen size > 25% and 2 underwent splenectomy. There was no progressive disease on therapy and only one patient experienced a grade III-IV hematological toxicity. All patients had neutrophil engraftment (>0.5G/L) in median on day +17 and 10/11 patients had platelet engraftment (> 20G/L) in median on day +21. Chimerism was full donor in 8, mixed in 1 (who relapsed at day 178), and not available in 2 patients, respectively. One patient who was 100% donor chimerism remains pancytopenic and transfused 90 days after allo-HSCT. Three patients experienced grade II and 2 grade IV acute GVHD after a median time of 18 days after allo-HSCT. Acute GVHD was refractory to corticosteroids in 2 patients and was the cause of death in 1 patient. Only 2 patients had chronic GVHD. Median time from Ruxolitinib initiation to last follow-up was 339 days (166 – 1928), 6 (54%) patients were assumed in complete remission (blood cell count normal and 100% donor chimerism) and 9 (80%) were alive. Two patients relapsed on days 77 and 148 and one of them received a second allo-HSCT.
In this retrospective study, Ruxolitinib before allo-HSCT seems to be well tolerated with excellent engraftment rate. A prospective study (JAK-ALLO) is ongoing in France on behalf of SFGM-TC to precisely analyze the role of Ruxolitinib before allo-HSCT.

Disclosures:
Kiladjian: Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees. Mohty:Novartis: Honoraria, Research Support Other. Robin:Novartis: Research Funding.