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1.
Matched unrelated donor transplantation versus haploidentical transplantation with post-transplant cyclophosphamide in children with acute myeloid leukemia: a PDWP-EBMT study
Ruggeri, A., Santoro, N., Galimard, J. E., Kalwak, K., Algeri, M., Zubarovskaya, L., Czyzewski, K., Skorobogatova, E., Sedlacek, P., Besley, C., et al
Haematologica. 2024
Abstract
In children with acute myeloid leukemia (AML) who lack an HLA identical sibling, the donor can be replaced with an HLA matched unrelated donor (MUD) or a haploidentical donor (haplo). We compared outcomes of patients <18 years with AML in first and second complete remission (CR1 and CR2) undergoing a hematopoietic stem cell transplantation (HCT) either with a MUD with anti-thymocyte globuline (ATG) (n=420) or a haplo HCT with PT-CY (n=96) after a myeloablative conditioning regimen (MAC) between 2011 and 2021, reported to EBMT. A matched pair analysis was performed to adjust for differences among groups. The final analysis was performed on 253 MUD and 95 haplo-HCTs. In the matched cohort, median age at HCT was 11.2 and 10 years and median year of HCT was 2017 and 2018, in MUD and haplo- HCT recipients, respectively. The risk of grade III-IV aGvHD was significantly higher in the haplo group (HR=2.33, 95%CI1.18-4.58, p=0.03). No significant differences were found in 2 years overall survival (OS; 78.4%vs71.5%; HR 1.39, 0.84-2.31, p=0.19), leukemia-free-survival (LFS; 72.7%vs69.5%; HR1.22, 0.76-1.95, p=0.41), CI of relapse (RI; 19.3%vs19.5%; HR=1.14, 0.62-2.08, p=0.68) non-relapse-mortality (NRM; 8%vs11%; HR=1.39, 0.66-2.93, p=0.39) and graft versus host free-relapse free survival (GRFS; 60.7%vs54.5%, HR=1.38, 0.95-2.02, p=0.09) after MUD and haplo-HCT respectively. Our study suggests that haplo-HCT with PT-CY is a suitable option to transplant children with AML lacking a matched related donor.
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2.
Recruiting refugees and migrants as potential hematopoietic stem cell donors to serve patients of comparable ethnicities with rare human leucocyte antigen patterns - The BluStar.NRW project in North Western Germany
Heinemann, F. M., Baumgart, C., Binder, C., Börger, V., Fischer, J., Heinold, A., Jiménez Klingberg, C., Lenz, V., Riebschläger, S., Zeiler, T., et al
Transplant immunology. 2024;:101985
Abstract
Currently, approximately 19 million people with a migration background live in Germany. The majority of those descend from regions where the population has a genetically different distribution of HLA antigens when compared to the HLA frequencies usually found in North Western Europe. In case of severe haematological disorders of these individuals, allogeneic stem cell transplantation may be the treatment of choice. However, finding appropriate histocompatible hematopoietic stem cell donors continues to be a major challenge. If no matching sibling donors are available, there are only few suitable donors with a similar genetic background available in international blood stem cell donor registries. The "BluStar.NRW" project aimed to recruit new blood and hematopoietic stem cell donors with a migration background and to noticeably increase the number of suitable donors for patients within this group. Since December 2017, a total number of 9100 blood and stem cell donors with a migration background were recruited and typed for this project. HLA typing for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 was performed by Next Generation Sequencing. We assessed the proportion of rare alleles according to HLA frequency tables, as defined by a frequency of <1:1000. The rare HLA allele frequencies according to HLA frequency tables of the BluStar.NRW cohort were compared with a matched control donor cohort: Rare HLA-A, -B, -C, -DRB1 and -DQB1 alleles occurred three times more frequent than in the control group, but rare HLA-DPB1 alleles occurred more frequently in the control cohort. This difference was highly significant for all HLA alleles (p < 0.0001 for HLA-A, -B, -C, -DRB1, -DPB1; p = 0.0002 for HLA-DQB1). In addition, the distribution of rare alleles differed between the two groups. To date, 29 work-ups were initiated, 12 PBSC, one BM and three DLI were collected so far out of the BluStar.NRW cohort. The apheresis probability is twofold higher (0.18% vs. 0.07%) compared to the control group which clearly shows a serious medical need. However, 13 work-ups were cancelled in the BluStar.NRW donor cohort which represents an almost twice as higher cancellation rate (45% vs. 25%). This single registry analysis with a large sample cohort clearly indicates that hematopoietic stem cell donors with a migration background represent an adequate donor pool to serve patients of comparable ethnicity.
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3.
Comparing between HLA-matched sibling donor allogenic HSCT and non-sibling matched related donor allogenic HSCT outcome in pediatric patients; single center retrospective study
Essa, M. F., Alghazwani, S., Abujoub, R., Memon, S., Alkaiyat, M., Ardah, H., Alsultan, A.
Pediatric transplantation. 2024;28(1):e14692
Abstract
BACKGROUND Extended family donor search other than siblings may yield an HLA matched donor in communities with high rate of consanguinity. The outcome of patients who are transplanted from non-sibling matched related donors (NS-MRD) including engraftment and graft versus host disease (GVHD) are scarce in comparison with matched sibling donor (MSD). METHODS We retrospectively reviewed the outcome of all our pediatric hematopoietic stem cell transplantation (HSCT) patients who had non-sibling matched related donor and controlled them with matched sibling donor HSCT (based on age, indication of HSCT, conditioning regimen, GVHD prophylaxis, serotherapy, stem cell source and cytomegalovirus status). RESULTS A total of 76 patients were reviewed during study period. Thirty patients (39.5%) in NS-MRD arm and 46 patients in MSD (60.5%) were identified after matching in age, disease, and conditioning regimens. All patients had similar approach including stem cell source and GVHD prophylaxis (CNI + 2nd agent). Out of the NS-MRD group, 18 patients (59%) had one of their parents as a donor and the rest as second degree relatives. Both groups were equally distributed and were homogeneous. Both groups had no statistically significant difference in outcome including engraftment, GVHD and Chimerism tests results. GVHD was seen in (13%) NS-MRD patients compared to (11%) in MSD patients. All patients remain alive with median follow up of 1249 days (431-3525). CONCLUSIONS This study showed no significant difference in allogenic HSCT outcomes between matched sibling donors and non-sibling matched related donors and support using the same management approach in terms of conditioning therapy, GVHD prophylaxis, and serotherapy only if indicated.
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4.
An intermediate-sized donor registry experience: HLA barriers in matching procedures
Grubic, Z., Maskalan, M., Stingl Jankovic, K., Burek Kamenaric, M., Zunec, R.
Hla. 2024;103(1):e15348
Abstract
The data enabling the estimation of the possibility of finding a matched unrelated donor (MUD) within a relatively short time is important for the success of hematopoietic stem cell transplantation (HSCT). In the present study, 738 unrelated Croatian patients in the program of unrelated HSCT were retrospectively analyzed for gender matching, donor origin (national or international), the distribution of HLA alleles and haplotypes, as well as for the probability of finding a 9-10/10 MUD. Almost 70% of the patients in our study group had a 10/10 MUD, while among the patients with a 9/10 MUD, a 1st field resolution level mismatched donor was selected for 55.0% of patients. The majority of pairs were HLA-A mismatched (33.8%). A comparison of HLA allele frequencies between two subgroups of patients revealed significant differences for 13 alleles. However, after p value correction, the difference in frequency remained significant only for four alleles; three HLA alleles (B*08:01, C*07:01, and DRB1*03:01) demonstrated a significantly higher frequency among patients with a 10/10 MUD (Pcorr < 0.0001, Pcorr = 0.0096, and Pcorr < 0.0001, respectively), while the B*35:08 allele was significantly more present among patients with a 9/10 MUD (Pcorr = 0.0328). The comparison of the distribution of HLA haplotypes between patients with a 10/10 MUD and patients with a 9/10 MUD showed significant differences for a number of two-locus and three-locus haplotypes, as well as for one five-locus haplotype (HLA-A*01:01~B*08:01~C*07:01~DRB1*03:01~DQB1*02:01), which was significantly more present in the group of patients with a 10/10 MUD. At least one HLA haplotype from the group of non-frequent HLA haplotypes (positions >1000) was carried by patients with a 9/10 MUD. The data obtained by the present study will contribute to a better estimation of the probability of finding a suitable 9-10/10 MUD for Croatian patients in need of HSCT.
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5.
Graft CD8 T-cell-based risk system predicts survival in antithymocyte globulin-based myeloablative haploidentical peripheral blood stem cell transplantation
Zhu, P., Yang, L., Wu, Y., Shi, J., Lai, X., Liu, L., Ye, Y., Yu, J., Zhao, Y., Yuan, X., et al
Clinical & translational immunology. 2024;13(1):e1484
Abstract
OBJECTIVE This study investigated the cellular composition of peripheral blood grafts for anti-thymocyte globulin (ATG)-based myeloablative haploidentical haematopoietic stem cell transplantation (haplo-HSCT). METHODS Clinical characteristics were retrospectively evaluated in a training cohort with ATG-based myeloablative haplo-HSCT between January 2016 and February 2020 and confirmed in a validation cohort between March 2020 and June 2021. RESULTS A higher dose of graft CD8(+) T cells (≥ 0.85 × 10(8) kg(-1)) was significantly improved overall survival (OS; hazard ratio [HR], 1.750; P = 0.002) and disease-free survival (DFS; HR, 1.751; P < 0.001) in the training cohort, according to multivariate Cox regression analysis. Higher doses of mononuclear cells (MNCs) demonstrated better OS (HR, 1.517; P = 0.038) and DFS (HR, 1.532; P = 0.027). Older patient age (> 46 years), older donor age (≥ 50 years) and a higher refined disease risk index (rDRI) were also related to OS. A graft CD8(+) T-cell risk system based on graft CD8(+) T-cell dose, donor age and rDRI was constructed using a nomogram model after LASSO Cox regression analysis. It showed acceptable discrimination, with a C-index of 0.62 and 0.63, respectively. Graft CD8(+) T-cell dose was negatively correlated with donor age (P < 0.001) and positively correlated with a higher lymphocyte percentage in the peripheral blood before mobilisation (P < 0.001). CONCLUSION A higher CD8(+) T-cell dose in peripheral blood-derived grafts improves patients' survival with ATG-based myeloablative haplo-HSCT. Younger donors with higher lymphocyte percentages improved patients' survival with an intermediate rDRI risk.
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6.
Prognostic impact of HLA supertype mismatch in single-unit cord blood transplantation
Sugio, T., Uchida, N., Miyawaki, K., Ohno, Y., Eto, T., Mori, Y., Yoshimoto, G., Kikushige, Y., Kunisaki, Y., Mizuno, S., et al
Bone marrow transplantation. 2024
Abstract
The "human leukocyte antigen (HLA) supertype" is a functional classification of HLA alleles, which was defined by structural features and peptide specificities, and has been reportedly associated with the clinical outcomes of viral infections and autoimmune diseases. Although the disparity in each HLA locus was reported to have no clinical significance in single-unit cord blood transplantation (sCBT), the clinical significance of the HLA supertype in sCBT remains unknown. Therefore, we retrospectively analyzed clinical data of 1603 patients who received sCBT in eight institutes in Japan between 2000 and 2017. Each HLA allele was categorized into 19 supertypes, and the prognostic effect of disparities was then assessed. An HLA-B supertype mismatch was identified as a poor prognostic factor (PFS: hazard ratio [HR] = 1.23, p = 0.00044) and was associated with a higher cumulative incidence (CI) of relapse (HR = 1.24, p = 0.013). However, an HLA-B supertype mismatch was not associated with the CI of acute and chronic graft-versus-host-disease. The multivariate analysis for relapse and PFS showed the significance of an HLA-B supertype mismatch independent of allelic mismatches, and other previously reported prognostic factors. HLA-B supertype-matched grafts should be selected in sCBT.
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7.
Reduced human leukocyte antigen mismatching is associated with more favourable outcomes after unrelated donor haematopoietic stem cell transplantation
Valatkaite-Rakstiene, B., Cekauskiene, R., Zvirblis, T., Jakubauskas, A.
International journal of immunogenetics. 2024
Abstract
The patient-donor human leukocyte antigen (HLA) match remains the most important prognostic factor for successful unrelated donor haematopoietic stem cell transplantation (UD-HSCT). This single-centre study comprised 125 adult patients with malignant haematological diseases undergoing their first UD-HSCT. The primary goal of this study was to validate the impact of HLA matching on HSCT outcomes, specifically at the HLA-DPB1 and HLA-DRB3/4/5 loci. A multivariable Cox regression analysis with a backward selection algorithm was employed to assess the associations of selected prognostic factors with outcomes after UD-HSCT. Any HLA locus mismatch was found to be associated with an increased incidence of grade II-IV acute graft versus host disease (aGvHD) at 100 days (p = .031; hazard ratio [HR] 1.935) and 6 months (p = .004; HR 2.284) after HSCT. The results of the following analyses also confirmed the strong impact of HLA-DPB1-only mismatch on the incidence of grade II-IV aGvHD at 100-day (p = .006; HR 2.642) as well as at 6-month (p = .007; HR 2.401) time periods. The HLA-DPB1-only mismatch was also shown to be statistically significantly associated with lower relapse incidence (p = .034; HR 0.333). The impact of the HLA-DRB3/4/5 mismatch on outcomes was inconclusive, though the two and more HLA-DPB1 + DRB3/4/5-only mismatches showed a trend towards worse outcomes than a single mismatch. Based on our findings and those of more comprehensive studies, the extended HLA loci typing of patients and donors is suggested to avoid unexpected HLA mismatches during the UD selection.
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8.
A comparison of long-term outcomes by donor type in the era of post-transplantation cyclophosphamide for aggressive adult T-cell leukemia/lymphoma
Hirose, A., Koh, H., Nakamae, M., Nakashima, Y., Nishimoto, M., Okamura, H., Makuuchi, Y., Kuno, M., Takakuwa, T., Ido, K., et al
Bone marrow transplantation. 2024
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9.
Interleukin-10 GCC/GCC haplotype is associated high risk of acute GVHD in patients undergoing allogeneic HSCT in the southern of Brazil
Farias, M. G., Dos Santos, C. A., Paz, A. A., Daudt, L. E.
Transplant immunology. 2024;:102002
Abstract
INTRODUCTION Hematopoietic Stem Cell Transplant (HSCT) is currently an important curative treatment for many patients with malignant and non-malignant diseases. Graft versus host disease (GVHD) represents a major complication in allogeneic HSCT recipients. Several polymorphisms in cytokine genes have recently been investigated as candidates for risk factors for acute-GVHD (aGVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVE In this study, we analyzed specific interleukin (IL)-10 haplotypes polymorphisms, in a cohort of 99 patients and their respective allo-HSCT donors for aGVHD and risk. RESULTS An association was found between IL-10 promoter haplotype polymorphisms at positions -1082, -819 and - 592 with the occurrence of aGVHD. Patients who have the GCC/GCC haplotype are at increased risk of aGVHD (P = 0.017, HR: 5.42 (95% CI: 1.34-21.84). In the donors group and severity of aGVHD as not found statistical significancy. CONCLUSION The results obtained show the IL-10 GCC/GCC haplotype can be an important biomarker to identify the greatest risk of aGVHD in the patient undergoing HSCT.
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10.
Updated comparable efficacy of cord blood transplantation for chronic myelomonocytic leukaemia: a nationwide study
Kurosawa, S., Shimomura, Y., Ishiyama, K., Fuse, K., Shimazu, Y., Doki, N., Uchida, N., Tanaka, M., Takahashi, S., Sakurai, M., et al
Bone marrow transplantation. 2024
Abstract
Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013-2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1-65.5%) and CBT (46.2%, 95% CI: 33.2-58.1%; P = 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57-1.66], P = 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT.