Allogeneic Transplantation Following Reduced Intensity Conditioning with Fludarabine and Melphalan In Patients with Advanced Myelofibrosis Is Associated with Unacceptable Rates of Acute Graft-Vs-Host Disease and Non-Relapse Mortality.
Authors: Kochuparambil Samith Thomas , Natrajan Kavita , Jillella Anand P. , Hamadani Sayed Mehdi , Awan Farrukh 
Published: October 2019

Abstract
Abstract 4552
Allogeneic hematopoietic stem cell transplant (HSCT) offers a potentially curative option for patients with primary myelofibrosis (PMF). The evidence for the utility of allogeneic HSCT originates from early reports documenting a graft-versus-myelofibrosis effect. The advent of reduced intensity conditioning (RIC) for patients undergoing allogeneic HSCT has resulted in significant improvements in outcomes primarily due to a reduction in non-relapse mortality (NRM). However, there is considerable variation in the outcomes of PMF patients undergoing RIC HSCT. EBMT has reported impressive 5-yr progression free (PFS) and overall survival (OS) of 51% and 67% with fludarabine, busulfan and anti-thymocyte globulin (ATG) based conditioning regimen. In contrast, a recent UK study reported more dismal outcomes with 3-yr OS of 31% and DFS of 24% when utilizing fludarabine, melphalan and ATG as their conditioning regimen. Similarly poor outcomes have also been reported for matched related donor (MRD) HSCT after the use of fludarabine and melphalan without ATG. We report here our experience of MRD Allogeneic HSCT after RIC in patients with PMF and attempt to identify issues in the management of these patients, and propose several quality improvement initiatives to improve HSCT outcomes in these patients. MRD Allogeneic HSCT with RIC regimen consisting of fludarabine (30mg/m2 day -6 to -3) and melphalan (70mg/m2 day -2 to -1) was performed in 6 patients from 2007–2009. The median age of the patients was 55 years (Range 31–66 years) and all had intermediate or high risk disease per the Lille score. The median time between diagnosis of PMF and HSCT was 5.5 months. Graft-vs-Host disease (GVHD) prophylaxis was with tacrolimus, methotrexate and steroids. 3 patients had Jak2 mutation and 2 had prior therapy with IMiDs. 4 patients had palpable splenomegaly at the time of transplant. The mean CD34+ cell dose was 3.5×106 and the mean CD3+ cell dose was 209.95×106. The median time to neutrophil engraftment was 10 days (Range 10–16) and the median time to platelet engraftment was 24 days (Range 16–42). None of our patients had graft failures or disease relapse. At a median follow up of 2 years, the Kaplan-Meier estimate of OS was 17%. Only one patient is alive after 3-years of follow up. The most common cause of death was severe infection or GVHD. Interestingly all patients developed ≥grade 2 GVHD of the gastrointestinal (GI) tract which was associated with significant morbidity. GI GVHD was also the primary form of GVHD in all our patients with limited involvement of other organ systems. Further analysis of patient characteristics revealed that 2 out of the 3 patients who developed ≥grade 2 oral mucositis after the RIC regimen subsequently developed >grade 2 GI GVHD. Interestingly both patients who had received prior therapy with IMiDs developed ≥grade 3 GI GVHD, however, all our analyses are hypothesis generating and our observations are limited by the small sample size. Our limited, single institution experience indicates a potentially higher risk of GI GVHD with the use of melphalan containing regimens, especially in patients who develop mucositis, don't receive ATG and have had prior treatment with IMiDs. As our quality improvement initiative we have introduced fludarabine and busulfan as the standard RIC regimen for patients with PMF. Further controlled studies are needed to establish the optimum RIC regimen for patients with PMF and the utility of ATG even in patients undergoing a MRD HSCT.

Disclosures:
No relevant conflicts of interest to declare.