Likelihood of finding an 8/8 HLA-matched unrelated donor (Donor Search Prognosis) is not associated with survival: Primary results from BMT CTN 1702
Authors: Lee Stephanie J. , Logan Brent R. , Horowitz Mary M. , Westervelt Peter , Hogan William J. , Pidala Joseph A. , Dehn Jason , Hayes-Lattin Brandon , Farhadfar Nosha , Bashey Asad , Grunwald Michael R. , Srour Samer A. , Brunstein Claudio , Symons Heather Jill , Uberti Joseph , Pusic Iskra , Leifer Eric , He Naya , Devine Steven M. , Shaw Bronwen E. , Ciurea Stefan O. 
Published: December 2024

Background: A donor search prognosis score based on HLA type and race/ethnicity can classify patients into 3 groups based on the likelihood of finding an HLA-matched (8/8) unrelated donor (MUD): Very Likely (44% of the population), Likely (41%) and Very Unlikely (15%). Previous studies showed that &gt;90% of Very Likely, 26% of Likely and &lt;10% of Very Unlikely patients used a MUD for their hematopoietic cell transplants (HCT), with the rest using other donor sources (mismatched unrelated donor, cord blood, or haploidentical relative). For some patients, prolonged efforts to identify a MUD might be futile and delay HCT, leading to increased morbidity, greater chance for relapse and disease resistance, and worse HCT outcomes. BMT CTN 1702 (NCT03904134) was the first national study to track the entire donor search identification process. Designed as a biologic assignment study, the goal was to estimate and compare overall survival between two arms: patients who are Very Likely to find a MUD versus those who are Very Unlikely to find a MUD. It tested whether provision of a donor search prognosis score to centers could prevent prolonged futile searches for the Very Unlikely group and improve their transplant rates and outcomes, compared to the Very Likely group.

Methods: Eligible diagnoses included acute leukemia, myelodysplastic syndromes, lymphoma, acquired aplastic anemia and sickle cell disease. Patients could be consented at any time after diagnosis until an unrelated donor search was started. Consented patients became evaluable only after it was determined that no appropriate HLA-identical siblings were available. The primary endpoint was survival time after the patient was declared evaluable, regardless of whether HCT occurred, and was compared between the Very Unlikely and Very Likely groups. The target enrollment was 1732 evaluable patients. Because this was a biologic assignment trial and not a randomized trial, formal comparisons of overall survival between the Very Likely and Very Unlikely groups were done using a covariate-adjusted Cox proportional hazards model. The following covariates were a priori specified for adjustment in the model, according to the statistical analysis plan: sex, age, Karnofsky Performance Score (KPS), race/ethnicity, disease, disease status, and interval from consent to evaluability.

Results: 1751 evaluable patients were enrolled at 47 centers: 44% female, median age 59.4 years (range 0.6-81.3 years), 73% were non-Hispanic White, 10% Hispanic White, 8% Black, 5% Asian/Native Hawaiian/Pacific Islander, 0.5% American Indian/Alaska Native. Among the evaluable patients, 1181 received a HCT, 827 died, and 924 are still alive with or without HCT, with a median of 25 months of follow up (range=6-54 months [mos], inter-quartile range [IQR]=25-34 mos). The distribution was: 958 Very Likely, 517 Less Likely, and 276 Very Unlikely. Individuals in the Very Unlikely group were younger and were less likely to be non-Hispanic White. The unadjusted cumulative incidences of undergoing HCT by 6 mos and 2 years [yrs], in the Very Unlikely group were 51% and 61% vs. 60% and 69% in the Very Likely Group; after adjustment, there was not a significant difference in the likelihood of undergoing HCT (Dehn et al, submitted). There was no difference in median time from evaluability to HCT: 3.4 mos Very Unlikely and 3.3 mos Very Likely. Unadjusted survival rates from the time of evaluability for the Very Unlikely and the Very Likely groups were: 6 mos (85% vs 84%), 1 yr (69% vs. 69%) and 2 yrs (55% vs. 56%). In the multivariate Cox model, there was no significant difference in the risk of death (HR = 1.07 for Very Unlikely vs. Very Likely, 95% confidence interval 0.86-1.33, p=0.56) adjusting for significant clinical covariates: age, KPS, disease status, and time from consent to evaluability were all significantly associated with overall survival. There was no significant center effect and no interaction between donor search prognosis group and clinical covariates.

Conclusion: In this large multicenter BMT CTN study, using the donor selection strategy described, there was no difference in adjusted time to HCT or survival for patients Very Likely versus Very Unlikely to find an 8/8 MUD. These results suggest that patients Very Unlikely to identify a MUD should proceed to HCT using the best available alternative donor rather than delaying HCT to try to identify a MUD.