HLA-DPB1 matching in unrelated hematopoietic stem cell transplantation program contributes to a higher incidence of disease relapse

The impact of patient/donor matching for HLA-A, -B, -C, -DRB1 and -DQB1 genes in hematopoietic stem cell transplantation (HSCT) is well-recognized, but typing for additional genes, such as HLA-DPB1, is still controversial. Based on defined T-cell epitope (TCE) groups, all HLA-DPB1 mismatches can be classified as permissive or non-permissive. In this retrospective study we analysed 82 patient-matched unrelated donor (MUD) pairs who underwent HSCT, and explored the impact of HLA-DPB1 matches, permissive and non-permissive mismatches on transplantation outcomes. Patient-MUD pairs matched for HLA-DPB1 alleles in univariate analysis were associated with a significantly higher incidence of disease relapse compared to pairs who were permissive/non-permissive HLA-DPB1 mismatched according to the TCE3 and TCE4 algorithms (P = 0.025 and P = 0.026, respectively), although the significance was lost in multivariate analysis. The analysis did not reveal any significant influence of HLA-DPB1 alleles on overall survival (OS), non-relapse mortality (NRM) or graft-versus-host disease (GvHD) incidence. In conclusion, our study presents evidence that HLA-DPB1 matching influenced the relapse rate in patients after HSCT so the HLA-DPB1 alleles should be implemented in the MUD search algorithm as a transplantation determinant.     

白消安在非亲缘异基因造血干细胞移植预处理中的应用

背景：口服白消安剂型胃肠道吸收不稳定,影响异基因造血干细胞疗效且毒性增加。静脉剂型白消安在国内最近几年用于临床,但在非亲缘异基因移植预处理中应用的相关报道甚少。 目的：探讨静脉剂型白消安在非亲缘异基因造血干细胞移植预处理中应用的疗效并观察其毒副作用。 方法：14例非亲缘异基因干细胞移植采用静脉剂型白消安联合环磷酰胺预处理方案,18例亲缘异基因干细胞移植采用口服白消安联合环磷酰胺预处理方案,观察两组造血重建、植入率等疗效指标及胃肠道反应、口腔黏膜炎、出血性膀胱炎、肝功能损害、移植物抗宿主病等相关毒性指标。 结果与结论：两组患者植入率均为100%。静脉剂型组肝脏毒性、口腔黏膜炎发生率明显低于口服剂型组(14% vs. 67%,7% vs. 55%),差异均有显著性意义(P < 0.01),而胃肠道反应、出血性膀胱炎、造血重建、急性移植物抗宿主病、局限性移植物抗宿主病等方面差异均无显著性意义(P > 0.05)。结果可见静脉剂型白消安应用于非亲缘异基因造血干细胞移植预处理可获得满意疗效,且毒副反应少。     

Frequencies of 10 autosomal minor histocompatibility antigens in Korean population and estimated disparities in unrelated hematopoietic stem cell transplantation

Disparity of minor histocompatibility antigens (mHAs) is known to induce graft-versus-tumor and graft-versus-host disease reactions in stem cell transplantation. Not much information is available on genotypic and phenotypic distributions of the currently identified mHAs, especially in Korean population. Therefore, we report genotype and phenotype frequency analyses of 10 autosomal mHAs in 329 unrelated healthy Koreans using the Sequenom MassARRAY matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) system and polymerase chain reaction-sequence specific primers (PCR-SSP). Estimates of the probability of immunogenic mismatches between donor/recipient pairs were made from observed phenotypic frequencies. HA-1 was the most favorable mHA for clinical application with the highest disparity of 7.0%. Similar results were obtained in ACC-1. The Korean population can benefit the most in a setting of matched major histocompatibility complex (MHC)-restricted mHAs-mismatched unrelated hematopoietic stem cell transplantations with the disparity rate of 27.5% with eight hematopoietic mHAs. This is the first comprehensive report on the genotypic and phenotypic frequency distributions of human mHAs in the Korean population. It can contribute to not only donor selection before transplantation but also therapeutic approaches after transplantation. It is expected that mHA-based immunotherapy will lead to a new treatment modality tailored for patients at high risk of relapse following allogeneic hematopoietic cell transplantation.     

Immunogenomics of unrelated hematopoietic cell transplantation

The MHC on human chromosome 6p21 encodes the HLA genes that govern histocompatibility in transplantation. Selection of potential unrelated volunteer donors for hematopoietic cell transplantation has required an understanding of the role of HLA gene products in mediating graft-versus-host and host-versus-graft alloreactions that give rise to the 'transplantation barrier'. Recent advances in the immunogenomics of the MHC in unrelated hematopoietic cell transplantation have been made through systemic examination of the alleles and antigens of large populations of racially and ethnically diverse transplant donors and recipients. The importance of non-HLA MHC-resident genetic variation in clinical outcome is increasingly being recognized. These data show that clinical outcome following transplantation is shaped by the combined effects of many genes within the MHC and their sequence polymorphisms.     

Ethical issues of unrelated hematopoietic stem cell transplantation in adult thalassemia patients

Background  

Beta thalassemia major is a severe inherited form of hemolytic anemia that results from ineffective erythropoiesis. Allogenic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative therapy. Unfortunately, the subgroup of adult thalassemia patients with hepatomegaly, portal fibrosis and a history of irregular iron chelation have an elevated risk for transplantation-related mortality that is currently estimated to be about 29 percent.     

无关供者异基因造血干细胞移植治疗骨髓增生异常综合征9例患者临床分析

目的探讨无关供者异基因造血干细胞移植(UD-HSCT)治疗骨髓增生异常综合征(MDS)的疗效和可行性。方法MDS患者9例,其中男性6例,女性3例;年龄7～46岁,中位年龄30岁。其中难治性贫血(RA)1例,难治性血细胞减少伴有多系发育异常(RCMD)2例,难治性贫血伴有原始细胞过多-2(RAEB-2)5例,MDS进展为急性髓系白血病(MDS-AML)1例。接受UD-HSCT治疗的MDS患者中外周血造血干细胞移植(PBSCT)8例,骨髓移植(BMT)1例。供受者HLA高分辨配型10/10位点相合4例、9/10位点相合4例、7/10位点相合1例。预处理方案为BU+CY+Flud+Ara-C+ATG 8例、BU+Mel+Flud+Ara-C+ATG 1例,移植物抗宿主病(GVHD)预防方案为FK506+MTX+MMF 8例、CsA+MTX+MMF 1例。结果9例患者均获得造血重建,中性粒细胞≥0.5×109/L和血小板≥20×109/L的中位时间分别为移植后15(11～20)d和23(8～32)d。6例患者发生急性GVHD(aGVHD),其中Ⅰ度4例,Ⅱ度2例,5例患者发生局限型慢性GVHD(cGVHD)。中位随访20.3(6.4～50.0)个月,1例患者移植后14个月复发死亡,其余8例患者中位随访27.9(6.4～50.0)个月,均无病存活,总体生存率(OS)及无病生存率(DFS)均为85.7%±13.2%。结论UD-HSCT治疗MDS安全有效,在无同胞全合供者时,无关供者也可以作为此类患者有效治疗选择。     

Non-myeloablative hematopoietic stem cell transplantation.

Conventional approaches to allogeneic stem cell transplantation have used toxic high-dose conditioning therapy in attempts to eradicate underlying diseases and achieve allogeneic engraftment. Preclinical studies and clinical observations have shown that to achieve engraftment conditioning regimens could be markedly reduced in intensity with reduction in treatment toxicities. The use of potent pre- and postgrafting immunosuppression facilitated stable mixed hematopoietic chimerism in a preclinical canine model. The initial clinical experiences with attenuated conditioning regimens have shown promise as a modality to achieve human stem cell transplantation with an improved safety profile. This may allow offering potentially curative hematopoietic stem cell transplantation (HSCT) to a more representative patient population (older and sicker) who are currently not eligible for such therapy. Obtaining a state of mixed hematopoietic chimerism could prove curative of the disease phenotype of various nonmalignant disturbances of the hematopoietic and immune systems. On the other hand, patients with hematopoietic malignancy will likely require conversion to full donor hematopoeisis by virtue of graft-versus-host (GVH) reactions directed against both recipient hematopoiesis and underlying malignancy. The infusion of additional donor lymphocytes has been proposed by many groups to augment graft versus tumor responses, but most likely more specific strategies will need to be developed to improve efficacy and avoid nonspecific GVH reactions.     

自体造血干细胞移植治疗外周T细胞淋巴瘤

背景：外周T细胞淋巴瘤亚洲地区发病率高,具有侵袭性,预后普遍较差,目前尚无标准治疗策略。 目的：评价自体造血干细胞移植治疗外周T细胞淋巴瘤的疗效及毒副反应。 方法：回顾性分析2003年3月至2014年4月行自体造血干细胞移植治疗外周T细胞淋巴瘤35例,包括结外NK/T细胞淋巴瘤鼻型22例,血管免疫母细胞T细胞淋巴瘤1例,外周T细胞淋巴瘤(非特殊型)8例,间变性大T细胞淋巴瘤 ALK(+)3例,ALK(-)1例;所有病例均按WHO 2001年和WHO 2008年分类进行病理分型,均采用VAEMMC+全射照射预处理方案。 结果与结论：随访中位时间54个月(9-120个月),28例患者(80%)存活,其中无病存活25例(71%),8例(23%)复发,其中7例死亡,1例尚在治疗中。近期毒性主要为骨髓造血受抑,无明显远期并发症。结果表明自体造血干细胞移植治疗外周T细胞淋巴瘤安全有效,早期(第1次完全缓解)行移植疗效佳。 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

Investigation of the impact of HLA-DPB1 matching status in 10/10 HLA matched unrelated hematopoietic stem cell transplantation: results of a French single center study

The impact of HLA-DPB1 mismatches after unrelated hematopoietic stem cell transplantation (HSCT) remains controversial. We retrospectively analyzed the impact of permissive/non-permissive HLA-DPB1 mismatches on the outcome of 141 patients who underwent 10/10 HLA allelic-matched unrelated HSCT. Each pair was classified according to the 3 (TCE3) and 4-group (TCE4) algorithm based on DPB1 alleles immunogenicity. Outcome analysis revealed that TCE3 and TCE4 non-permissive HLA-DPB1 disparities were not associated with worsened overall survival, relapse risk neither risk of acute GvHD. Overall, this single center retrospective study does not confirm the adverse prognostic of non-permissive HLA-DPB1 mismatches.     

Adenoviral infections in hematopoietic stem cell transplantation.

Adenoviruses are lytic DNA viruses that are ubiquitous in human communities. In total, 51 different serotypes with varying tissue tropisms have been identified. Adenovirus infections, although frequent, are rarely fatal in immunocompetent individuals who have potent innate and adaptive immunity. But in immunosuppressed individuals, adenoviruses are a significant cause of morbidity and mortality, with limited treatment options. In particular, pediatric recipients of allogeneic hematopoietic stem cell transplantation frequently develop infections early in the posttransplantation period. Because the endogenous recovery of adenovirus-specific T cells has proven important in controlling infection, we explore the potential of adoptive T-cell immunotherapy as a therapeutic strategy. We discuss the advantages and limitations of T-cell therapy for the prophylaxis and treatment of adenovirus infection posttransplantation.     

Impact of HLA-DPB1 haplotypes on outcome of 10/10 matched unrelated hematopoietic stem cell donor transplants depends on MHC-linked microsatellite polymorphisms

Hematopoietic stem cell transplantation (HSCT) with HLA-A, -B, -C, -DRB1, -DQB1 allele matched (10 of 10) unrelated donors is still associated with a significant rate of posttransplantation complications. In order to disclose additional immunogenetic factors, we analyzed the impact of HLA-DPB1 disparities and major histocompatibility complex (MHC)-resident microsatellite polymorphisms in 246 HLA 10 of 10 matched HSCT patients. First we showed that patients with more frequent/conserved HLA haplotypes had a higher 5-year survival (55% ± 18% versus 39% ± 18%, P = .021). In addition, DPB1 incompatibilities and 3 microsatellite alleles were associated with outcome. In a Cox regression model adjusting for European Blood and Marrow Transplant (EBMT) risk score, T cell depletion, and year of treatment, HSCT with a tumor necrosis factor d (TNFd) 4/d5-positive donor was associated with increased mortality (hazard ratio [HR] = 2.03; confidence interval [CI] 1.25-3.31; P = .004), whereas the D6S510-184 allele was protective (HR = 0.44; CI 0.22-0.87; P = .018). The 2 MHC-linked genetic donor factors, DPB1 mismatch (MM), and TNFd4/d5-positivity, acted in synergy with the EBMT risk score with an always lower survival (HR = 2.97; CI 1.27-6.92; P = .012). These data show that multiple MHC-linked genetic donor factors impact on outcome after unrelated donor HSCT. Their additive and potentially divergent effects could explain previous discrepant results, particularly with respect to the role of HLA-DPB1 disparities. We conclude that HLA-DPB1 typing combined with a simple TNFd microsatellite genotyping assay may significantly help in pretransplantation risk assessment for graft-versus-host disease and mortality, particularly for patients with several potential 10 of 10 matched donors.     

Tissue typing in support of unrelated hematopoietic cell transplantation

The success of unrelated hematopoietic cell transplantation (HCT) for the treatment of hematologic malignancies has closely paralleled development of robust typing methods for comprehensive and precise donor-recipient matching. The application of molecular methods in clinical research has led to a more complete understanding of the immunogenetic barriers involving host-vs-graft (HVG) and graft-vs-host (GVH) reactions. Along with the development of less toxic transplant regimens, advances in the prevention and treatment of graft-vs-host disease (GVHD) and in the supportive care of the transplant recipient, improved HLA matching of potential unrelated donors has led to clinical results that begin to compare favorably with that of HLA-identical sibling transplants.     

Results of unrelated umbilical cord blood hematopoietic stem cell transplant.

The number of umbilical cord blood transplants (UCBT) is increasing worldwide, and the purpose of Eurocord is to evaluate the results and compare the outcome of UCBT with allogeneic bone marrow transplants (BMT). Data have been reported to Eurocord by many transplant centers. Close links have been established with cord blood banks through Netcord. BMT data have been provided by transplant centers and also by the European Blood and Marrow Transplant (EBMT) and International Bone Marrow Transplant Registries (IBMTR). Eurocord has analyzed the outcome of unrelated UCBT from 121 transplant centers and 29 countries. The results have shown that survival with unrelated mismatched UCBT was comparable to that with unrelated BMT. Engraftment with cord blood was delayed, resulting in an increased incidence of early transplant complications. The incidence of acute and chronic graft-versus-host-disease (GVHD) was reduced with cord blood grafts even in HLA mismatched transplants and in adults. In patients with leukemia, the rate of relapse was similar to that after BMT. The overall event-free survival with UCBT was not statistically different when compared to BMT. In conclusion, this large registry study confirms the potential benefit of using umbilical cord blood hematopoietic stem cells for allogeneic transplants.     

The MHC gamma block matching: Impact on unrelated hematopoietic stem cell transplantation outcome

Matching for HLA-A, -B, -C, -DRB1, -DQB1 alleles is the gold standard in hematopoietic stem cell transplantation (HSCT). However, this is often not enough to prevent postransplantational complications. The HLA mismatches (MM) have been associated with higher risk of acute graft versus host disease (GvHD). Gamma block (GB) is located in central HLA region, between HLA-B/C and HLA-DRB/DQB blocks and contains many inflammatory and immune regulatory genes. Single nucleotide polymorphisms (SNPs) within that block can be considered as markers for MHC haplotype matching. Aim of the research was to test whether MM in GB impact the outcome of HSCT in 51 patients transplanted with HLA 10/10 matched unrelated donor. The recipient-donor pairs were typed using PCR SSP kit that detects 25 SNPs within GB. Fifteen out of 51 (29.41%) pairs were GT matched (GT-M) while 36 out of 51 pairs (70.59%) were mismatched (GT-MM). In a univariate analysis, GT-MM was a significant risk factor associated with aGvHD (P = 0.041), although this association was not seen in multivariate analysis. No significant difference in overall survival and relapse occurrence was seen. These results were obtained on a small sample, and it is necessary to further test the possible role of GT matching in unrelated HSCT.     

Host T cells affect donor T cell engraftment and graft-versus-host disease after reduced-intensity hematopoietic stem cell transplantation.

Mixed chimerism in the T cell compartment (MCT) after reduced-intensity stem cell transplantation (RIST) may influence immune repopulation with alloreactive donor T cells. We examined effects of host T cell numbers on donor T cell engraftment and recovery and on acute graft-versus-host disease (aGVHD) in a relatively homogeneous patient population with respect to residual host T cells through quantified immune depletion prior to RIST and to donor T cells by setting the allograft T cell dose of 1x10(5) CD3+ cells/kg. In this setting, 2 patterns of early donor T cell engraftment could be distinguished by day +42: (1) early and complete donor chimerism in the T cell compartment (FDCT) and (2) persistent MCT. FDCT was associated with lower residual host CD8+ T cell counts prior to transplant and aGVHD. With persistent MCT, subsequent development of aGVHD could be predicted by the direction of change in T cell donor chimerism after donor lymphocyte infusion, and no aGVHD occurred until FDCT was established. MCT did not affect recovery of donor T cell counts. These observations suggest that the relative number and alloreactivity of donor and host T cells are more important than the absolute allograft T cell dose in determining donor engraftment and aGVHD after RIST.