Single HLA Allele Mismatches Are Well Tolerated in the Recipients of T Cell Depleted Reduced Intensity Conditioned Transplants from Unrelated Donors.
Authors: Shaw Bronwen E. , Russell Nigel H. , Devereux Steve , Emma Das-Gupta , Stephen Mackinnon , Madrigal J.Alejandro , Pagliuca Anthony , Mufti Ghulam J. , Byrne Jenny L. 
Published: April 2020

Recently published data, in the T cell replete unrelated Donors (UD) Haematopoietic Cell Transplantation (HCT) setting, shows a survival detriment due to a single HLA allele mismatch. It is not clear whether this finding can be translated to the T cell depleted setting. We analysed the impact of HLA mismatching (and other donor factors) on outcome and complications in 144 recipients of UD-HCT using reduced intensity conditioning (RIC) regimens.

The transplants were performed for a broad range of malignant haematological diseases. Conditioning regimens consisted of fludarabine, melphalan, campath (80), fludarabine, busulphan, campath (38), fludarabine, BEAM, campath (nine) and other (17). The median patient age was 51 and donor age was 36. Of the donors, 94 donated BM and 50 PBSC; 118 were male and 26 female. The donor was 10/10 allele matched in 95 (66%) cases, in 28 (19%) there was a single allele mismatch and in 21 (15%) cases there was more than one mismatched allele.

The three-year probability of overall survival was 43% (median follow-up: 724 days; range: 91–1651 days). The overall incidence of acute graft versus host disease (GvHD) in this cohort was 41% (55/133), only three patients above grade II. The three-year probability of cGvHD was 62% (including that post DLI) and of relapse was 62%. The TRM was 17% at day100 and 33% at one year.

There was no significant difference between fully HLA matched pairs and those with a single HLA mismatch with regards to overall survival, transplant related mortality (TRM), and acute or chronic GvHD. Conversely, in multiply mismatched grafts, overall survival was significantly worse (p=0.005), and TRM (p=0.005) and chronic GvHD (p=0.025) were significantly increased. Donor age and gender did not have any significant effect on any of these outcomes.

Of evaluable patients, 7/140 (5%) failed to achieve myeloid engraftment. Primary graft failure (PGF) was significantly associated with the use of a mismatched donor, even if only a single mismatch was present (6/47,13% versus 1/93, 1%, p=0.006), as well as: BM versus PBSC (7/91, 8% versus 0%, p=0.045), CML compared to other diagnoses (3/14, 21% versus 4/126, 3%, p=0.022) and a female versus a male donor (4/25, 16% versus 3/115, 3%, p=0.019). In multivariate analysis; CML (HR 0.06, p=0.013), and use of an HLA mismatched (HR 0.05, p=0.028), and/or female donor (HR 0.04, p=0.048), retained significance. As all patient who failed to engraft received BM as the stem cell source, and conversely all HLA mismatched PBSC donations did engraft, it is likely that the combination of risk factors is of importance. Thus, negative effects of a single mismatch on PGF could be abrogated by avoiding a female donor and/or accepting only PBSC in this setting.

In conclusion, in the TCD RIC setting a single HLA mismatch was well tolerated with regards to GvHD, TRM and OS, but was not tolerated with regards to PGF, particularly in certain settings. Although PGF is a serious complication it does appear that this can be overcome by selecting the correct donor and/or donation. This possibility of using a single HLA allele mismatched donor without an overall detrimental effect will increase the number of patients eligible for treatment.