Younger Haploidentical Versus Older Matched Sibling Donors in Acute Lymphoblastic Leukemia: A Study from the ALWP of EBMT

Donor selection is fundamental to the success of allogeneic hematopoietic stem cell transplantation (HSCT). Although matched sibling donors (MSD) are the reference donors, the young age of the donor is a well-established prognostic factor in many studies. With the increasing prevalence and improved management of haploidentical transplantation in acute lymphoblastic leukemia (ALL), it is unknown whether outcomes differ after HSCT with older MSD (oMSD) compared to younger haploidentical donors (yhaploD). Therefore, we performed a retrospective analysis comparing the outcomes of ALL patients, aged 45 years and older, in first complete remission (CR1) who underwent HSCT with younger (<40 years) haploD or older (>50 years) MSD between 2012 and 2022. The major endpoints were to assess overall survival, leukemia-free survival, relapse incidence, non relapse mortality, and graft-versus-host disease-free, relapse-free survival (GRFS). A total of 756 patients were included with a median age of 56.8 years (interquartile range [IQR], 52.1- 61.1). Follow up was longer in the oMSD group compared to the yHaploD group (3.5 years vs 2.1 years, p<0.001). hematopoietic cell transplantation-specific comorbidity Index score, Karnofsky score, gender patient and MRD status at transplantation were similar between the 2 groups. The median age of the donor was 56.3 years (IQR, 52.9-60.9) in the oMSD group versus 29 years (IQR, 22.8-34.6] in the yHaploD group. There was no difference in the intensity of the conditioning regimen between the 2 groups (p=0.4). In univariate analysis, neutrophil engraftment at 30 days was significantly higher in the oMSD group: 98% [95% CI, 96.5-98.9] versus 92% [95%, CI 86.6-95.3] for yHaplo (p<0.001). With a median follow-up of 2 years, NRM was significantly higher and relapse incidence significantly lower in the yHaplo group versus the oMSD group. Survival outcomes at 2 years were distributed as follows for oMSD and yHaplo groups, respectively: overall survival 66.2% (95% CI, 61.8-70.2) versus 65.3% (95% CI, 61.8-70.2), p=0.88; LFS 57.6% (95% CI, 53.2-61.8) versus 62.1% (95% CI, 53.2-69.7), p=0.25; relapse incidence 24.9% (95% CI, 21.2-28.7) versus 11.7% (95% CI, 7-17.8), p=0.001; non-relapse mortality 17.5% (14.3-20.9) versus 26.2% (95% CI 14.3-20.9), p=0.022; GRFS 42.6% (95% CI 38.2-46.9) versus 47.2% ( 95% CI, 38.6-55.4)180-day grade II-IV acute GVHD 24.6% (95% CI, 21.1-28.2) versus 32.1% (95% CI, 24.9-39.4), p=0.06; grade III-IV acute GVHD 8.6% (95% CI, 6.5-11.2) versus 13.2% (95% CI, 8.5-19), p=0.08; chronic GVHD of all grades 43.5% (95% CI, 39-48) versus 39.2% (95% CI, 30.7-47.7), p=0.2; extensive chronic GVHD 22.5% (95% CI, 18.8-26.4) versus 18.2% (95% CI, 11.9-25.6), p=0.15. In multivariate analysis, yHaploD was the only factor associated with lower RI (HR=0.49, 95 %CI, 0.9-2.28, p=0.008). All other outcomes including NRM, LFS, OS, and GRFS did not differ between donor types. Patient age (per 10 years) had a negative impact on LFS (HR=1.25, 95% CI, 1-1.55; p=0.047) and also on OS (HR=1.33, 95% CI, 1.06-1.69, p=0.015). In addition, the use of TBI and a female donor with a male recipient were associated with higher risk of extensive chronic GVHD (HR=1.61, 95% CI, 1.04-2.48, p=0.03 and HR=1.52, 95% CI, 1-2.31, p=0.049; respectively). In our study, yHaploD seems to be a valid option compared to oMSD for patients undergoing HSCT for ALL in CR1. Indeed, yHaploD significantly reduces the risk of relapse and achieves similar survival outcomes compared to oMSD.