Improved Outcomes of Haploidentical Hematopoietic Stem Cell Transplantation with Younger Donors
Authors: Aljawai Yosra M. , Saliba Rima M. , Chen George , Oran Betul , Fingrut Warren B. , Alousi Amin M. , Bashir Qaiser , Hosing Chitra , Kebriaei Partow , Marin David , Olson Amanda L. , Popat Uday , Qazilbash Muzaffar H. , Ramdial Jeremy , Rondon Gabriela , Smallbone Portia , Srour Samer A. , Champlin Richard E. , Shpall Elizabeth J. 
Published: December 2024

Background:
An increasing number of older patients are undergoing hematopoietic stem cell transplantation (HCT). Optimal donor selection is critical for driving positive outcomes post-HCT. Older patients are more likely to have older siblings as potential donors and recent reports have associated older donor age with worse outcomes. In the absence of a suitable matched donor, haploidentical (haplo) donors may be used. However, haplo HCT has been associated with worse non-relapse mortality (NRM) in older patients. Here, we determined if donor age was associated with outcomes in older patients (≥50 years) undergoing haplo HCT for the treatment of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
Methods:
We conducted a single-center retrospective analysis of patients who underwent haplo HCT with post-transplant cyclophosphamide (PTCy) as graft-vs-host disease (GVHD) prophylaxis from 2009-2023. Primary endpoints were NRM and GVHD, and secondary endpoints were overall survival (OS) and progression-free survival (PFS). Only the first transplant was considered for those who underwent ≥1 HCT.
Results:
A total of 363 consecutive patients met the eligibility criteria. Median age at HCT was 56 years (range 18-76) for recipients and 34 years (12-69) for donors. AML was the most common diagnosis. Most patients (70%) received reduced intensity (RIC) or non-myeloablative (NMA) conditioning, had low-intermediate Disease Risk Index (DRI) (60%), and received bone marrow (BM) grafts (80%). Median Hematopoietic Stem Cell Comorbidity Index (HCT-CI) was 3 (0-10). Median follow-up was 3 years.
In multivariate analysis (MVA) of the entire cohort evaluating predictors of primary outcomes, younger donor age (≤30 years, n=139) was associated with lower 3-year NRM (HR 0.5, 95% CI 0.3-0.9, P&lt;0.01) and older recipient age (≥50 years, n=232) with higher NRM (HR 2.7, 95% CI 1.6-4.6, P&lt;0.001). Young donor age was also associated with significantly lower grade III-IV acute GVHD (aGVHD) (HR 0.1, 95% CI 0.02-0.4, P&lt;0.001). No other factors evaluated were associated with grade III-IV aGVHD. Donor age had no effect on grade II-IV aGVHD (HR 0.9, P=0.7) or chronic GVHD (cGVHD) (HR 0.7, P=0.4) and was not considered in MVA for these outcomes.
We next assessed outcomes of the subset of 232 patients who were &gt;50 years of age according to whether their donor was young (≤30 years, n=74) or old (&gt;30 years, n=158). Median age of the young and old donors was 24 years (range 13-49) and 40 years (31-68), respectively. Median age of patients at HCT was 56 years (50-72) and 63 years (51-76) in the young and old donor groups, respectively. Median follow-up was Children compromised 99% of the young donors and 75% of the old donors. The remaining donors were primarily siblings. AML was the most common diagnosis in both groups. BM was the graft source in the young (76%) and old (80%) donor groups. Fifty-five percent and 60% of patients had low-intermediate DRI in the young and old donor groups, respectively. RIC/NMA was used in 74% and 71% of the young and old donor groups, respectively. Median HCT-CI was 2 and 3 in the young and old donor groups, respectively. At least half of the patients in both groups had HCT-CI ≥3.
In the cohort of older patients, young donor age was associated with lower NRM (HR 0.6, 95% CI 0.4-1.03, P=0.07) and grade III-IV aGVHD (HR 0.2, 95% CI 0.04-0.8, P=0.02). Cumulative incidence of grade III-IV aGVHD at day 180 was 3% with young donors and 14% with old donors. Grade III-IV aGVHD accounted for 5% of 5-year NRM in the young donor group vs. 26% in the old donor group.
MVA for NRM and severe aGVHD were not indicated as none of the remaining risk factors were significant in univariate analysis (UVA).
In MVA, young donor age was associated with superior OS HR 0.3, 95% CI 0.1-0.9, P=0.03) and PFS (HR 0.4, 95% CI 0.1-0.9, P=0.04) in patients with low DRI and HCT-CI ≤2. Patients (n=24) in this subset had a 5-years OS of 76% (95% CI 51-9) and PFS of 74% (95% CI 52-88) . Donor age did not have a significant impact on 5-years OS or PFS in patients with high/very high DRI or patients with low / intermediate DRI with HCT-CI ≥3.
Conclusion:
A younger stem cell donor is associated with superior outcomes in patients undergoing haplo HCT, including a subset of elderly patients who exhibit improved survival outcomes with younger donors. If validated in larger cohorts, our results indicate that in the absence of suitable matched donors, younger haplo donors should be considered.