Effect of Donor-Source and Conditioning Regimen on the Outcome of Children with Hemophagocytic Lymphohistiocytosis undergoing Hematopoietic Stem Cell Transplantation: A National Multicenter Retrospective Study

Yarden Greental Ness ¹ Amir A Kuperman ^1,2 Jerry Stein ^3,4 Joanne Yacobovich ^3,4 Ehud Even-Or ⁵ Irina Zaidman ⁵ Aharon Gefen ⁶ Neta Nevo ⁶ Amos Toren ^4,7 Polina Stepensky ⁵ Bella Bielorai ^4,7 Elad Jacoby ^4,7

¹Azrieli Faculty of Medicine, Bar Ilan University, ישראל
²Blood Coagulation Service and Pediatric Hematology Clinic, Galilee Medical Center, ישראל
³Hematology-Oncology Division, Schneider Children's Medical Center of Israel, ישראל
⁴Sackler Faculty of Medicine, Tel Aviv University, ישראל
⁵Department of Bone Marrow Transplantation, Hadassah Medical Center, ישראל
⁶Ruth Rappaport Children’s Hospital, Rambam Medical Center, ישראל
⁷The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, ישראל

Background: Hemophagocytic lymphohistiocytosis (HLH) is an immune dysregulation disorder of impaired lymphocyte cytotoxicity with an estimated incidence of 1:50,000 live-born children. Five-year survival rates are 61%. Allogeneic hematopoietic stem-cell transplantation (HSCT) is currently the only curative option for familial or refractory HLH. Ideally, an HLA-matched donor is required for optimal transplant outcomes. Recent use of alternative-donors – either partial HLA-mismatched, haploidentical (partially-matched family members) or cord-blood units – has increased. Outcomes using alternative-donors and novel reduced-intensity conditioning (RIC) regimens are yet unknown.

Methods: We conducted a national, multi-center, retrospective study of children with HLH undergoing HSCT in 4 pediatric centers in Israel.

Results: Between 2000 and 2018, 48 HSCT procedures were performed in 47 children. Donors were either HLA-matched (n=27), partially-mismatched (n=7), haploidentical (n=9) or cord-blood (n=5). A myelo-ablative (MAC) regimen was used in 27 procedures (44%) and RIC in 21 (56%). The median follow-up time was 4.2 years. Forty-five patients engrafted. The five-year probabilities of overall-survival and event-free survival (EFS) were 84% and 83%, respectively. EFS was lower following RIC compared to MAC (69% vs 95% p=0.03) and with alternative donors compared to HLA-matched (69% vs 93%, p=0.04). The leading mortality cause was transplant-related mortality (TRM).

Conclusions: Results of the national study show superior outcomes of HSCT for HLH in Israel compared to recently published cohorts. Despite the use of safer RIC regimens, TRM remains a major barrier. The results of alternative-donor HSCT, though worse than for HLA-matched transplants, are still superior to previous reports. Further randomized prospective studies are warranted.