Abstract To clarify the different characteristics and prognostic factors of cord blood transplantation (CBT) in adult patients with lymphoid neoplasms in Europe and Japan, we conducted a collaborative study. Patients aged 18-75 years receiving their first CBT (Europe: single CBT, n = 192; double CBT, n = 304; Japan: single CBT, n = 1150) in 2000-2017 were analyzed. Fewer patients with Hodgkin lymphoma (Europe vs Japan, 26% vs 5%), and older patients (≥50 years) (39% vs 59%) with a higher refined disease risk index (rDRI) (high-very high: 49% vs 14%) were included in the Japanese registry. High-very high rDRI was associated with inferior overall survival (OS) (vs low rDRI, Europe: hazard ratio [HR], 1.87; P = .001; Japan: HR, 2.34; P < .001) with higher progression/relapse risks. Total body irradiation (TBI)–containing conditioning contributed to superior OS both in Europe (vs TBI–reduced-intensity conditioning [RIC], non-TBI-RIC: HR, 1.93; P < .001; non-TBI–Myeloablative conditioning [MAC]: HR, 1.90; P = .003) and Japan (non–TBI-RIC: HR, 1.71; P < .001; non–TBI-MAC: HR 1.50, P = .007). The impact of HLA mismatches (≥2) on OS differed (Europe: HR, 1.52; P = .007; Japan: HR, 1.18; P = .107). CBT for lymphoid neoplasms, especially in those with high rDRI showed poor outcomes despite all the different characteristics in both registries. TBI should be considered in conditioning regimens to improve these outcomes. The different impacts of HLA mismatches call attention to the fundamental differences among these populations.
Background: Despite a better understanding of the genetic heterogeneity of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), relapse rates remain high and long-term survival is suboptimal. In this context, the association between these malignancies and the human leukocyte antigens (HLA) has been widely studied. The highly polymorphic HLA loci have significance and relevance for disease susceptibility thanks to their peptide-binding grooves-dependent antigen presentation to effector cells. Such processes trigger an algorithm of immune responses based on multiple fine-tuned combinations of amino acid sequence interactions. Thus, the HLA genetic diversity has been a focus of interest in acute leukemia settings as exemplified by studies showing the implication of both HLA class I and II polymorphisms. However, there is scarce data regarding the diversity of peptide-binding pockets per se especially in the context of umbilical cord blood transplantation (UCBT). Aims: To analyze whether variants of HLA-DQB1 and -DRB1 peptide-binding groove pockets 4 and 9 and/or their amino acid positions are associated with the diagnosis of ALL or AML among patients undergoing UCBT. Methods: A retrospective analysis was performed including 849 patients with ALL and AML undergoing an UCBT. Demographics and genotyping data were obtained from the Eurocord database. Pockets and amino acids were imputed from the four-digit HLA genotypes of patients. Easy-HLA was used for haplotype inference when needed. Descriptive statistics were applied. Risk ratios (RRs) and 95% confidence intervals (CI) were estimated by applying log-binomial regression to compare the allelic frequencies between both types of leukemia. Results: ALL and AML were diagnosed in 50.2% and 49.8%, respectively. The median age at UCBT was 8.7 and 17.9 years. Overall, they were mostly pediatric patients (61.8%), males (52%), and in first complete remission (58.7%). From the ten variants analyzed in pocket 9 of the HLA-DQB1 allele, only the variant YYVSY, corresponding to the allele HLA-DQB1*05:02/04, was more frequent in ALL when compared to AML (RR=2.12, 95% CI: 1.30-3.44; p=0.001). Also, within the 21 analyzed pocket 4 variants of the HLA-DRB1 allele, RFDRAY, corresponding to DRB1*16:01/02, was the only variant with a significant higher frequency among ALL patients versus AML patients (RR=3.26, 95% CI: 1.81-5.99; p=0.001). No differences were observed when comparing ALL and AML at either pocket 4 of HLA-DQB1 allele or pocket 9 of HLA-DRB1 allele. Further amino acid analysis revealed that the frequency of serine 57 of the HLA-DQB1 pocket 9 was higher in ALL (RR=2.03, 95% CI: 1.26-3.27; p=0.037). None of the analyzed amino acid positions in HLA-DRB1 pockets was statistically enriched neither in ALL or AML. Summary/Conclusion: Our analyses suggest that specific variants in terms of HLA pockets and amino acids might be unique to ALL. As a result of expressing HLA molecules on their surface, leukemic cells may participate to the disease development and/or to immune evasion. Thus, the immune and genetic expression profile of the leukemic microenvironment has been described as a potential useful biomarker in guiding therapeutic approaches. Interestingly, peptide binding to HLA class II molecules is frequently viewed as a merger of detached anchor residue preferences for pockets 4 and 9. In our study, these associations, at a genotypic level, might be a stepping stone towards analyzing results in acute leukemia after UCBT as there is robust evidence supporting the impact of HLA on important post-transplant outcomes.
The lack of an human leucocyte antigen (HLA) identical donor is an obstacle preventing a widespread application of haematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD). To increase the number of patients with SCD likely to benefit from HSCT, the possibility of using alternative sources of stem cells has been explored. Despite promising results after alternative donor transplantation,1, 2 such an approach is still hampered by post-transplant complications including relapse and graft-versus-host disease (GVHD) and warrant more extensive efforts to overcome these issues.3-7 The HLA class I cluster consists of three highly polymorphic loci, namely HLA-A, -B, and -C that encode ubiquitously expressed antigen-presenting molecules pivotal for cellular T-cell immune response. Besides the fact that HLA-B is the most polymorphic gene of the human genome, a single nucleotide polymorphism (SNP), i.e. rs1050458C/T at position −21 of exon 1, gives rise to leader peptides with either methionine (M) or threonine (T) at their second residue.8 The HLA-B leader peptides bearing the amino acid M or T differently influence the cell surface expression of the non-classical HLA-E molecules with consequent inhibition or activation of natural killer (NK)- and T-cell subsets, two cellular players involved in relapse.8-12 Studies on human immunodeficiency virus (HIV) control demonstrated that M-HLA-B leader peptide bind more efficiently to HLA-E, as compared to the T variant. Accordingly, individuals with an M-HLA-B leader have higher surface expression of HLA-E with consequently stronger NK group 2 member A (NKG2A)-mediated NK-cell inhibitory properties.10, 12 Moreover, M-HLA-B seemed to be associated with improved NK-cell-mediated leukaemia-free survival and overall survival (OS) in patients with M-HLA-B as compared to T-HLA-B during interleukin 2–based immunotherapy.13 Petersdorf et al.14 reported the role of the HLA-B leader peptide dimorphism in predicting GVHD after HLA-B-mismatched unrelated transplantations. In single HLA-B mismatched HSCTs, the preferred HLA-B mismatched donor is leader-matched and shares a T-HLA-B leader allotype. In umbilical cord blood transplants with one HLA-B mismatch setting, increasing numbers of cord-blood unit M-leader alleles have been associated with an increased risk of relapse. In addition, leader mismatching with an M-leader of the shared HLA-B allele seem to lower non-relapse mortality in comparison to leader-matching and a shared T-leader allele, suggesting that HLA-B leader may play a role in relapse and non-relapse mortality risk after cord blood transplantation.15 Similarly, HLA-A allele-dependent expression levels influence NK-cell subsets inhibitory properties although consistently presenting an M at the second residue of its leader peptide. High HLA-A allele expression results in stronger binding of the derived leader peptide with consequent stronger NKG2A-mediated NK-cell inhibition. High HLA-A expression has also been showed to be associated with high viral load in HIV-infected patients and to have an impact especially in patients having two M-HLA-B leader peptides.9 As such HLA-A and -B characteristics have never been examined in sickle cell transplantation, we imputed, from the classical HLA-B typing, the prevalence of two T-HLA-B leader peptide (TT) and of at least one M-HLA-B leader peptide (MM or MT). We then assessed the potential impact of HLA-B leader peptide dimorphism on HSCT outcomes, by retrospectively analysing HLA data from 714 patients with SCD transplanted in a European Society for Blood and Marrow Transplantation (EBMT) centre, between 1988 and 2017, from an HLA-identical sibling (n = 588), an unrelated [n = 67, out of which 32 were HLA matched (10/10), 35 HLA mismatched (8/10 = 5, 9/10 = 30)] or a haploidentical donor (n = 59). Our present study was based on Monacord/EBMT data. Most of the patients were TT (n = 435, 61%), while a minority (39%) was MM or MT (MM n = 36; MT n = 243). AS M-HLA-B leader peptide has stronger NK-cell inhibitory properties10, 12 we compared the main outcomes according to the distribution of recipients’ TT and MM+MT genotypes, assuming that genetic variations modulating NK-cell functions may, at least partly, influence HSCT outcomes. The primary endpoint was 3-year OS, secondary endpoints were 3-year event-free survival (EFS; death, graft failure were considered as events) and 3-year GVHD-free and relapse-free survival (3-year GRFS; Grade 3–4 acute GVHD, extensive chronic GVHD, graft failure, death were considered as events). Probabilities of OS, EFS and GRFS were estimated by the Kaplan–Meier method and reported as percentage and standard error; univariate analysis was performed using the log-rank test. The mean (SE) 3-year OS, 3-year EFS and 3-year GRFS for the entire population (n = 714) were 94·7 (1)%, 89·9 (1)% and 82·6 (2)% respectively. No statistically significant difference for 3-year OS, 3-year EFS and 3-year GRFS was observed between the two genotype-based subpopulations [mean (SE) 94·6 (2)% for ‘MM+MT’ and 94·6 (2)% for ‘TT’, P = 0·976; 90·6 (2)% for ‘MM+MT’ and 89·4 (2)% for ‘TT’, P = 0·419; 82·6 (2)% for ‘MM+MT’ and 82·6 (2)% for ‘TT’, P = 0·819 respectively] (Table I). Further, we defined the HLA-A expression as z-score value, equivalent to one standard deviation change in expression level, and then we analysed ‘MM+MT’ and ‘TT’ patients with either positive or negative z-score in order to evaluate the impact of HLA-A expression on outcomes. Again no significant difference was noted for 3-year OS, 3-year EFS and 3-year GRFS (Table II). MM+MT z-score ≥0 (n = 188) MM+MT z-score <0 (n = 89) TT z-score ≥0 (n = 279) TT z-score <0 (n = 154) In this selected group of transplanted patients with SCD, neither recipient HLA-B leader peptide dimorphism nor HLA-A expression seem to have influenced the outcomes of HSCT. However, a trend for better outcomes for subjects in the MM+MT group (n = 89) with a low expression of HLA-A (negative z-score) was observed. Similarly, Ramsuran et al.,9 albeit in a different clinical context, observed an effect of HLA-A expression of greater magnitude in MM-HLA B individuals. The limitations of our present study are the low number of patients and of clinical events (33 deaths, 5%), likely related to the high proportion of HLA-identical sibling donor HSCTs (82%). Due to this unbalanced population selection, we assessed the effect of patient HLA-B polymorphism on outcomes, but we could not evaluate the impact of patient/donor HLA-B or leader peptide mismatching, unlike previous studies14, 15 as the number of non-identical HLA transplants was too low. Further studies on a larger cohort, favouring HLA-B mismatched patient/donor pairs, are required to confirm our present results and hence provide additional information helping physicians towards the best choice of therapeutic approaches adapted to the risk, with the purpose of lower rejection, GVHD, infections and increase accessibility to HSCT for patients with SCD. This work was supported by the Monaco Government and the “Cordons de Vie” Association, Monaco (President Dr. Fabienne Mourou).
