Matched Unrelated Donor Hematopoietic Cell Transplantation Following Reduced-Intensity Conditioning for Treatment of Myelofibrosis.
Authors: Snyder David S. , Stein Anthony S. , Pullarkat Vinod , Sahebi Firoozeh , Cohen Sandra , Palmer Joycelynne , Vora Nayan , Nakamura Ryotora , Forman Stephen J. 
Published: April 2020

Abstract
Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for patients (pts) with myelofibrosis (MF). Outcomes utilizing fully myeloablative conditioning regimens have been disappointing in large part due to transplant related mortality in this generally older pt population. Recently, there have been encouraging results reported with reduced intensity conditioning (RIC) regimens followed by allogeneic HCT. Most of the reports have focused on HLA matched siblings as the stem cell donors. We have treated nine patients with MF (7 idiopathic, 1 secondary to essential thrombocythemia, 1 secondary to polycythemia vera) with RIC HCT utilizing matched unrelated donors (MUD) for 7 of the 9 patients, and sibling donors for 2 patients. The median age was 54 yrs (range 46 to 68); 4 female and 5 male. (See Table) The time interval from diagnosis to HCT ranged from 8 to 156 mos (median 41 mos). By the Lille classification, 4 pts were characterized as high risk, 4 as intermediate, and 1 as low risk. All 9 pts had significant splenomegaly, and 5/9 underwent splenectomy prior to HCT. Eight of the nine pts had ≥ 1% blasts in the PB at the time of HCT; 3 pts had abnormal cytogenetics (although none had +8 or 12p-); and 4 pts had constitutional symptoms. Seven of the 9 pts were RBC transfusion dependent. The RIC regimen consisted of fludarabine (Flu) and a single dose of total body irradiation (TBI) for Pt 1, and Flu/melphalan (Mel) for the subsequent 8 pts. G-CSF primed peripheral blood stem cells (PBSC) were used for all patients, except for Pt 6 who received a total of 3 products because of graft failure. The number of CD34+ cells X 106 /kg ranged from 0.97 to 17.1 (median 2.8). Prophylaxis against graft vs. host disease (GVHD) consisted of cyclosporin/mycophenolate +/− methotrexate. Seven pts successfully engrafted WBC with ANC &gt; 500 by a median of day +15 (range 10 to 21). Pt 6 never engrafted WBC, and the nadir for Pt 1 was &gt;500. Five pts achieved platelet engraftment (&gt;25k) from 15 to 594 days (median 32), 3 pts never engrafted platelets (Pts 2,6,7), and the nadir for Pt 1 was &gt;25k. At the time of the latest FISH and/or STR analysis, 8/9 pts were chimeric with 96 to 100% donor cells and/or DNA. All but 1 pt developed acute GVHD that was ≥ grade III in 4/8 pts. Four of 6 evaluable pts had extensive chronic GVHD. Six of the 9 pts are alive at the time of last contact with follow-up for the living pts ranging from 3.4 to 48.5 mos (median 11.8). The 3 deaths were from: septic shock due to primary graft failure on day +125 (Pt 6), sepsis related to severe acute GVHD on day + 51 (Pt 4), and sepsis with secondary graft failure related to severe acute GVHD on day +45 (Pt 2). The probability of overall and disease free survival was 64.8% (30.8 to 88.4%, 95% CI). These results demonstrate that MUD HCT utilizing PBSC can be an effective treatment for older pts with MF.
Treatment Summary
Pt Number Age/Gender Dx Donor Cell Material Regimen GVHD Prophylaxis 1 68/M MF MUD PBSC Flu/TBI CSA/MMF 2 58/F MF MUD PBSC Flu/Mel CSA/MMF 3 54/F MF MUD PBSC Flu/Mel CSA/MMF 4 64/F ET to MF Bro PBSC Flu/Mel CSA/MMF 5 46/M MF MUD PBSC Flu/Mel CSA/MMF/MTX 6 53/M MF MUD #1 BM Flu/Mel CSA/MMF/MTX 6 MUD #1 PBSC Flu/ATG 6 MUD #2 BM Flu/Mel 7 63/M PV to MF MUD PBSC Flu/Mel CSA/MMF/MTX 8 54/M MF Bro PBSC Flu/Mel CSA/MMF 9 63/F MF MUD PBSC Flu/Mel CSA/MMF/MTX