Improved Outcomes Using Tacrolimus/Sirolimus for graft Versus Host Disease prophylaxis with a Reduced Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant for Myelofibrosis
Authors: Snyder David S. , Palmer Joycelynne , Gaal Karl , Stein Anthony Selwyn , Pullarkat Vinod , Vora Nyana , Nakamura Ryotaro , Sahebi Firoozeh , Forman Stephen J 
Published: April 2020

Allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) regimens is a potentially curative treatment for patients (pts) with myelofibrosis (MF), as we (BBMT12:1161,2006) and others have reported. Treatment related mortality (TRM) from Graft vs. Host Disease (GVHD) and other complications has limited the success of this approach. We have recently utilized a combination of tacrolimus(tacro)/sirolimus (siro) +/− methotrexate (MTX) for GVHD prophylaxis in a cohort of 14 consecutive pts with MF treated with RIC HCT at City of Hope in an effort to reduce TRM from GVHD and related complications. In this report, we present results for 23 pts including extended follow up for the previously reported 9 pts who received cyclosporine (CSA)/mycophenolate (MMF) +/− MTX, and the current cohort of 14 pts who received tacro/siro +/− MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. MTX was included for all recipients of matched unrelated donor (MUD) products. The cohort median age was 58 yrs (range 39–69) with 12 females, 11 males. Two of nine CSA/MMF pts developed MF secondary to a prior myeloproliferative disorder and 3/14 tacro/siro pts had secondary MF. The Lille risk score was high for 10 pts, intermediate for 12, and low for 1. The RIC regimen consisted of Fludarabine/melphalan for 23 pts, including all 14 of the tacro/siro pts, and fludarabine/total body irradiation for the first pt in the CSA/MMF cohort. Eight pts received stem cell products from HLA matched siblings (2/9 CSA/MMF pts; 6/14 tacro/siro pts) and 15 from MUDs (7/9 CSA/MMF pts; 8/14 tacro/siro pts). The source of stem cells was GCSF primed peripheral blood for 21 pts, and unprimed bone marrow for 2 pts. The median cell dose was 7.8 × 10^6 CD34 cells/kg. Median follow up for alive patients was 26.7 mos (3.4–97.6). All evaluable pts engrafted with neutrophils (median 16.5 days) and platelets (median 18.0 days). Chimerism studies demonstrated donor engraftment in 94–100% of cells using STR or FISH analysis. JAK 2 kinase mutation analysis was available pre-HCT for 4/14 pts in the tacro/siro cohort. Two of these four pts were positive, and both became JAK2 kinase mutation negative post-HCT. No pt in either cohort relapsed, and none developed veno-occlusive disease or thrombotic microangiopathy. Five pts died- 4 from GVHD +/− infections or multi-organ failure and one from graft failure with sepsis. The estimated 2 yr overall survival (OS) for the CSA/MMF cohort was 66.7 %(confidence intervals 20.4,80.5), and for the tacro/siro cohort it was 92.3% (56.6,98.9) (p=0.0472). The probability of grade III or IV acute GVHD was 60% for the CSA/MMF pts, and 10% for the tacro/siro group (p=0.0102). The 100-day TRM was 33.3% for the CSA/MMF pts and 0 for the tacro/siro group (p=0.0215). Five of the six evaluable pts in the CSA/MMF cohort developed chronic GVHD (4/5 extensive) compared to 9/14 pts (6/9 extensive) in the tacro/siro group. We conclude that the combination of tacro/siro +/− MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to lead to improved OS compared to CSA/MMF +/− MTX, and that this benefit may be due to a significant decrease in the incidence of severe acute GVHD with the use of tacro/siro +/− MTX.