An Exploration of Unrelated Donor Existence for Patients Who Received Haploidentical Hematopoietic Cell Transplants

The number of haploidentical related donor (HRD) hematopoietic cell transplants (HCT) performed in the United States (US) has grown by more than fourfold over the last decade, mainly due to the use of post-transplant cyclophosphamide (PTCy) based graft versus host disease (GVHD) prophylaxis. This has particularly benefited racially and ethnically diverse patients as most do not have a readily available 8/8 unrelated donor (URD) existing in the various global registries. However, not all patients have a suitable or healthy HRD and many patients have donor specific antibodies directed against mismatched HRD antigens that increase the risk of graft rejection and mortality. Recent reports noted similar and, in certain circumstances (reduced intensity conditioning), superior outcomes using matched (8/8) or minimally mismatched (7/8) URD compared to HRD receiving PTCy prophylaxis. In this analysis, we explored the URD existence on the National Marrow Donor Program (NMDP) Registry at 8/8 or 7/8 for patients receiving recent haploidentical HCT in the US and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

The data extracted for this analysis includes patients who received HRD HCT reported to the CIBMTR from 2013-2020. Any patient who was missing HLA or was not able to impute to high resolution 4 locus typing was excluded. The resulting data consists of 8281 HRD HCT recipients between the ages of 0-87. A search simulation was run on each patient to estimate counts of possible 8/8 and 7/8 matches. This process queries a database of pre-imputed donor HLA genotypes and counts any donor matching at 8/8 and 7/8. For each patient, we also determined the Search Prognosis Score (http://search-prognosis.b12x.org/) for their HLA typing. We found that the growth of HRD HCT over the study period exceeded the likelihood of an 8/8 donor existing on the NMDP registry. In contrast, the existence of a potential 7/8 MMUD has increased at a slope similar to the HRD HCT growth curve (Figure 1).

We then limited our analysis to adult HRD HCT recipients (n=6580). During the study period, 91% of the adult HRD HCT were performed using PTCy-based GVHD prophylaxis. Of these patients, 73% underwent a search through the NMDP registry. Consistent with previous data, the search prognosis for patients undergoing a search varied by race/ethnicity. White patients had a 22% likelihood of a good search prognosis (>90% likelihood of an existing 8/8 URD) versus 1.9-9.1% for other broad race categories. Overall, <16% of HRD HCT recipients had at least one existing 8/8 URD. In contrast, when we analyzed for the existence of a 7/8 URD, 84% had at least one and 64% had five or more 7/8 URD. Existence of a 7/8 URD varied by race/ethnicity ranging from 74.2% for African American (AFA) to 90.6% for non-Hispanic White (NHW) HRD HCT recipients. When considering only younger (≤35 years old) 7/8 URD existence ranged from 47% in AFA to 81.9% for NHW recipients. Overall, from 40 to 79% HRD HCT recipients had five or more potential 7/8 URD available (Table 1).

Next, we looked at practices at the 10 TCs performing the most adult HRD HCT in the US during the study period. We observed a dichotomy among them. Five TCs had at least one 8/8 URD in 20-40% of the simulations in their HRD HCT recipients whereas for the other five TCs, < 8% of the simulations identified an existing 8/8 URD. In contrast, at all but one of the 10 largest HRD HCT TCs, > 80% of the recipient simulations yielded at least one 7/8 URD.

Finally, we analyzed URD existence for patients who underwent HRD HCT based on underlying disease. For the four most common malignant indications for adult HRD HCT (AML, ALL, MDS, NHL), > 83% of the simulations revealed at least one 7/8 URD. For severe aplastic anemia, the most common non-malignant indication, that number was 81.6%.

In conclusion, these data demonstrate that most US patients undergoing HRD HCT are unlikely to have an available 8/8 URD. However, we show the existence of a 7/8 URD (and likely higher with lower match grades) for most candidates for HRD HCT. Further, these data support the feasibility of recent BMT CTN State of the Science Symposium high priority clinical trial concepts including a trial in SAA patients without matched related donors and a trial comparing HRD HCT to 7/8 URD HCT in patients with hematological malignancies (Heslop et al, JTCT 2021).

Devine:Orca Bio: Consultancy, Other: Payment to NMDP for consulting.