Engrafting Unit-Recipient HLA-Allele Mismatch Is Not Associated with an Increased Risk of Transplant-Related Mortality (TRM) or Inferior Progression-Free Survival (PFS) after Double Unit Cord Blood (CB) Transplantation (dCBT) in Adults with Hematologic Malignancies

Abstract

Background The less stringent CB HLA-match requirement extends allograft access. The extent to which HLA-mismatch can adversely affect CBT outcomes & the maximum permitted HLA-mismatch, however, are not established. Methods We analyzed TRM, relapse & PFS after cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI dCBT in adults with hematologic malignancies. Eligible patients (pts) were 1st allograft recipients ≤ 65 years transplanted 1/2014 - 12/2017. TNC & CD34+ dose were typically given priority over HLA-match in unit selection. Results 102 pts [51 (50%) non-European, median 50 years (range 21-65), median 80 kg (range 36-137), 71 acute leukemias & 17 CML/ MPD/ MDS (all ≤ 10% blasts pre-CBT), 14 NHLs] received double unit grafts. The majority of units [181 (89%)] were 4/6 matched. At high resolution the unit-recipient 8-allele HLA-match was a median of 5/8 (range 3-7). The median infused viable CD34+ dose was 1.3\u202f×\u202f105/kg/unit (range 0.2-8.6). 48 (47%) pts also received haplo-identical CD34+ cells as a myeloid bridge. 97% (95%CI 90-99) engrafted with CB. All pts had a dominant unit (1 early death excluded). Day 180 grade II-IV & III-IV aGVHD were 89% (95%CI 81-94) & 23% (95%CI 15-31), respectively. 1-yr cGVHD was 4% (95%CI 1-9). Day 180 TRM was 9% (95%CI 4-15) & 14% (95%CI 8-22) at 2 yrs. 11% (95%CI 6-19) of pts relapsed by 2 yrs. With a median survivor follow-up of 2 yrs 3 months (range 6 - 51), 2-yr OS is 82% (95%CI 75-90) & PFS is 74% (95%CI 66-84). Causes of death were transplant-related in 16 pts [6 aGVHD, 4 infection (2 viral, 1 bacterial, 1 fungal), 4 organ failure, 1 graft failure, 1 unknown] & relapse in 4 pts. By 2-yrs, engrafting unit-recipient HLA-allele match had no association with TRM or PFS ( Figure ). Analysis of the association between recipient/ graft variables & TRM/ relapse/ PFS are shown ( Table ). Pts In multivariate analysis, aaHCT-CI was associated with worse PFS [HR 2.82 (1.28-6.25) if score 4-9 vs 0-3, p\u202f=\u202f0.01]; neither rDRI [HR 1.21 (0.54-2.69) if high-very high vs low-intermediate, p\u202f=\u202f0.64] nor engrafting unit-recipient HLA-match [HR 2.06 (0.89-4.74) if 5-7/8 vs 3-4/8 matched (p\u202f=\u202f0.09] were significant. Conclusions dCBT with mismatched units facilitates allograft access extension & has a high PFS. While further investigation of the CD34+ dose – HLA-mismatch interaction is required, this supports unit selection prioritizing quality & dose in adults to optimize engraftment. Finally, this data supports CBT in younger pts, those with low 0-3 aaHCT-CI, or high rDRI given the high 2-yr PFS in such pts.