Post-Transplant High-Dose Cyclophosphamide Overcomes the Detrimental Effect of a Single-Locus HLA Mismatched in Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Ferraz Patricia , Pereira Arturo , Suárez-Lledó María , Gutiérrez-García Gonzalo , Fernández-Avilés Francesc , Rosinol Laura , Solano Teresa , Llobet Noemí , Ramos Carla , Marín Pedro , Urbano-Ispizua Alvaro , Rovira Montserrat , Martinez Carmen 
Published: October 2019

Abstract
Background: Allogeneic hematopoietic stem cell transplantation (alloSCT) from unrelated donors mismatched (MMUD) at a single HLA-A, -B, -C, or -DRB1 locus (7/8) were previously reported to be associated with lower overall survival (OS) and disease-free survival (DFS), higher treatment-related mortality (TRM), and more acute graft-versus-host disease (GVHD) compared to 8/8 matched unrelated (MUD) allografts. Despite these risks, 7/8 MMUD grafts remain a viable option for alloSCT, particularly in patients who lack suitable donors or in those with aggressive hematologic malignancies for whom the risks of disease progression due to delays in identifying optimal donors is offset in part by the benefits of earlier transplantation with a 7/8 MMUD alloHCT. According to the published experience of post-transplant cyclophophamide (PTCy) in the context of haploidentical alloSCT, this GVHD prophylaxis strategy could potentialy overcome the detrimental effect of a single-locus HLA MMUD.
Methods: We retrospectively analyzed 72 consecutive adult patients (median age 53y, range 18-69) who received 7/8 MMUD (n=44) or 8/8 MUD (N=28) alloSCT with PTCy in our institution. Unrelated donor selection was performed according to standard criteria, including high resolution typing for alleles at HLA-A, -B, -Cw, DRB1 and DQB1. For those patients in whom an 8/8 HLA-matched related or unrelated donor was not available, a search was performed based on a single HLA-mismatch.
Results: Acute myeloid or lymphoblastic leukemia accounted for 51% of all hematologic diseases, myelodisplastic syndrome for 17%, chronic lymphoproliferative or myeloproliferative disorders for 28%, and severe aplastic anemia for 4%. Disease Risk Index (DRI) was intermediate in 51%, high 16% and very high 6%. Forty-four percent of patients had a HCT-CI ≥3. All patients, except 6 have received peripheral blood stem cells (PBSC). Fludarabine-based conditioning regimens were used in all patients (fludarabine-busulphan in 61%); of them, myeloablative (MAC) in 34 patients (47%) and RIC in 38 (53%). GVHD prophylaxis consisted on PTCy 50mg/kg IV on days 3 and 4 after transplant followed by one (tacrolimus or mycophenolate mofetil, MMF) (n=62, 86%) or 2 (n=10, 14%) immunossuppresor drugs. All but two patients engrafted and the median time to neutrophil (>500/mL) and platelet (>20,000/mL) recovery were 18 days (range 11-30) and 18 days (10-47), respectively. Thirteen patients (18%) developed an invasive pulmonary Aspergillosis, 20 (27%) had severe bacterial infection, 40 (56%) CMV reactivation, 5 (7%) cytomegalic disease and 3 EBV reactivation. The cumulative incidences of 1-year TRM, 100-days acute grade II-IV, 100-days grade III-IV GHVD, and 1-year moderate-severe chronic GHVD were 19%, 24%, 13%, and 11%, respectively. The cumulative incidence of relapse at 1-year was 16%. After a median follow-up for surviving patients of 12 months (2-60), 2-year OS, DFS, and survival free of moderate/severe chronic GVHD and relapse (cGRFS) were 64%, 61%, and 49%, respectively. Univariate analysis of variables that could influence OS, PFS, and cGRFS, including age, donor/patient sex, comorbidity, DRI, conditioning type, 1 vs. 2 immunosuppressors, and HLA 7/8 vs. 8/8 did not show any statistical differences. At 6 and 12 months after alloSCT, 42% and 73% of patients alive and without relapse were free of immunosuppressor drugs and prednisone.
Conclusions: This study suggests that PTCy after unrelated PBSC alloSCT results in a low incidence of acute and chronic GVHD with encouraging survival outcomes even in the context of 7/8 HLA-mismatched transplant. An immunosuppressive schema of intermediate intensity such as PTCy followed by single-agent tacrolimus may provide an adequate GVHD prophylaxis and could be a good alternative to ATG in both MMUD and MUD transplants. Confirmatory and comparative studies are warranted to examine the effect of this approach on alloSCT outcomes.

Disclosures
Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Martinez:BMS: Research Funding; Takeda: Consultancy.