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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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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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HLA haploidentical stem cell transplantation from HLA homozygous donors to HLA heterozygous donors may have lower survival rates than haploidentical transplantation from HLA heterozygous donors to HLA heterozygous donors: a retrospective nationwide analysis
Fukunaga, K., Ikegame, K., Nakamae, H., Doki, N., Fukuda, T., Kondo, Y., Ara, T., Eto, T., Mori, Y., Matsuoka, K. I., et al
International journal of hematology. 2024
Abstract
In HLA haploidentical stem cell transplantation, patients and donors usually share one HLA haplotype and have one different HLA haplotype (hetero-to-hetero). However, there are rare cases of transplantation from HLA homozygous donors to heterozygous recipients (homo-to-hetero), resulting in mismatches only in the graft-versus-host direction. We previously reported that homo-to-hetero transplants have a lower survival rate in a mouse model than hetero-to-hetero transplants due to stronger graft-versus-host disease (GVHD) but inferior graft-versus-leukemia effect. To examine whether homo-to-hetero transplant effects also occur in humans, we retrospectively compared the results of 59 homo-to-hetero and 4,539 hetero-to-hetero cases in the Japanese transplant registry data. The results showed no statistical difference between the homo-to-hetero and hetero-to-hetero groups in the cumulative incidences of neutrophil engraftment (83.1% vs 89.0%), acute GVHD II-IV (36.8% vs 38.8%), III-IV (16.8% vs 17.4%), chronic GVHD (32.7% vs 30.7%), relapse (52.9% vs 49.0%), and non-relapse mortality (31.6% vs 28.2%). In contrast, overall survival was significantly lower in the homo-to-hetero group than in the hetero-to-hetero group (12.6% vs 26.2%, p = 0.0308). The inferior effect of homo-to-hetero transplantation on overall survival remained significant in multivariate analyses.
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Allogeneic hematopoietic stem cell transplantation: A single-center experience, 2017 to 2021
da Silva, P. C. L., Muzzi, G. C., Vilela, M. R., Fabreti-Oliveira, R. A.
Transplant immunology. 2024;82:101989
Abstract
INTRODUCTION Hematopoietic stem cell transplantation (HSCT) remains a critical treatment for advanced or high-risk hematological malignancies, posing challenges such as finding suitable donors and managing of graft-versus-host disease (GvHD). This study estimates 3-year overall survival in patients who underwent HSCT at our referral service in the state of Minas Gerais, Brazil. MATERIAL AND METHODS This retrospective observational cohort study involved 41 patients who received HSCT between 2017 and 2021 at the Felício Rocho Hospital. Recipients received HSCT from either haploidentical donor (Haplo), matched unrelated donor (MUD), or HLA-matched sibling donor (MSD). The study evaluated parameters that included 3-year overall survival (OS), treatment-related mortality (TRM), GvHD incidence, post-transplant relapse rate, and engraftment. ANOVA, Kruskal-Wallis, and chi-square tests were used for statistical analysis. Survival curves were calculated using the Kaplan-Meier method and the Log-rank test compared the curves. RESULTS Our study found that the engraftment time differed among groups: Haplo recipients engrafted earlier within a median of 16 days (ranging between 10 and 20 days) than MSD recipients with 18 days (ranging between 11 and 28 days), and MUD recipients with 19 days (ranging between 11 and 24 days; p = 0.019). Mild acute GvHD (grade I-II) was observed in 13 patients, progressing to chronic GvHD in 5 patients. Three-year OS rates were as follows: MSD group - 67.7%, Haplo group - 42.2%, and MUD group - 44.4% (MSD vs Haplo, p = 0.039). Three-year cumulative treatment-related mortality (TRM) rates were 17.8% for MSD group, 22.9% for Haplo group, and 22.1% for MUD group (pairwise comparisons p > 0.05). Infection-related mortality was reported in eight patients, while relapse rates at 3 years were similar across MSD, Haplo, and MUD groups (p = 0.891). Donor age influenced OS rates, showing better outcomes with donors under 45 years old, and significant differences were found in pairwise comparisons (p = 0.015). CONCLUSION Donor type and donor age significantly impacted HSCT outcomes in our analysis, thus emphasizing the importance of rigorous donor selection in risk stratification and suggesting potential benefits for younger donors.
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Comparative Analysis of Allogeneic Bone Marrow Transplantation Outcomes Between Japanese and Non-Japanese Populations
Yanagisawa, R., Shindo, M., Shinohara, A., Kuwatsuka, Y., Nakase, K., Kimura, F., Shingai, N., Nishida, T., Fukuda, T., Sakurai, M., et al
Transplantation proceedings. 2024
Abstract
BACKGROUND As the Japanese population may have less genetic diversity than other ethnic groups, treatment outcomes may be affected when allogeneic hematopoietic cell transplantation is performed in other races. However, evidence explaining the effect of racial differences is limited. METHODS We used the Japanese National Database to examine the outcomes of first allogeneic bone marrow transplantations (BMTs) performed between Japanese and non-Japanese patients from 1996 to 2021. We performed propensity score matching using sex, age group, underlying disease group, HLA mismatch, conditioning regimen intensity, and BMT implementation age to select Japanese-to-Japanese BMT patients as the controls. RESULTS The numbers of non-Japanese-to-Japanese and Japanese-to-non-Japanese BMT cases included in the analysis were 48 and 75, respectively, and the following outcomes were compared: overall survival, non-relapse mortality, acute graft-vs-host disease (GVHD) ≥ grade II, chronic GVHD, and engraftment of neutrophils and platelets. Most parameters did not differ when comparing BMTs according to ethnicity; only platelet engraftment was delayed in Japanese-to-non-Japanese BMT but not in non-Japanese-to-Japanese BMT. CONCLUSIONS The results of this study suggested that BMT performed in Japanese and non-Japanese patients has little effect on treatment outcomes. The results of this study may be useful for donor selection in Japan, where internationalization has progressed in recent years.
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Genetic Findings of Potential Donor Origin following Hematopoietic Cell Transplantation: Recommendations on Donor Disclosure and Genetic Testing from the World Marrow Donor Association (WMDA): WMDA Guidelines on Genetic Findings of Donor Origin
Pryce, A., Van, E. E., Cody, M., Oakes, J., DeSalvo, A., Bannon, S., Burlton, C., Pawson, R., Fingrut, W., Barriga, F., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
Following hematopoietic cell transplantation, recipients are subjected to extensive genetic testing to monitor the efficacy of the transplant and identify relapsing malignant disease. This testing increasingly includes the use of large gene panels which may lead to incidental identification of genetic and molecular information of potential donor origin. Deciphering whether variants are of donor origin, and if so, whether there are clinical implications for the donor, can prove challenging. In response to queries from donor registries and transplant centers regarding best practice in managing donors when genetic mutations of potential donor origin are identified, the Medical Working Group of the World Marrow Donor Association established an expert group to review available evidence and to develop a framework to aid decision-making. These guidelines aim to provide recommendations on pre-donation consenting, post-donation testing of recipients and informing and managing donors when findings of potential donor origin are identified in recipients post-transplantation. It is recognised that registries will have different access to resources and financing structures. Therefore, where possible, we have made suggestions on how recommendations can be adapted.
PICO Summary
Population
An expert group convened by the Medical Working Group of the World Marrow Donor Association
Intervention
Provide recommendations on pre-donation consenting, post-donation testing of recipients
Comparison
None
Outcome
These guidelines aim to provide recommendations on pre-donation consenting, post-donation testing of recipients and informing and managing donors when findings of potential donor origin are identified in recipients post-transplantation.
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Low levels of CD26 on certain cellular subtypes of donor harvest is associated with better clinical outcomes post allogeneic stem cell transplantation through regulation of NF-κB pathway and pro-inflammatory cytokines
Kandekar, S., Punatar, S., Khattry, N., Gokarn, A., Jindal, N., Mirgh, S., Chichra, A., Tembhare, P., Rane, P., Gawde, J., et al
International immunopharmacology. 2023;125(Pt A):111054
Abstract
BACKGROUND We had previously reported significant association of immunoectoenzyme CD26 expression on donor harvest with acute Graft-versus-Host-Disease (aGVHD) in allogeneic stem cell transplantation (ASCT) patients. The current study was aimed at analysing CD26 signaling pathway molecules and understanding their impact on immune reconstitution and clinical outcomes post-ASCT. SUBJECTS AND METHODOLOGY The study cohort included 26 transplant donors/patients who underwent reduced intensity (n = 21), myeloablative (n = 4) and non-myeloablative (n = 1) ASCT for hematological malignancies. Donors were matched related donors (n = 19) and haploidentical donors (n = 7). Surface expression of CD26, CD73 and ADA, and various immune cell subtypes were assessed by multicolour-flow cytometry. Soluble CD26 (sCD26) and cytokine levels were measured in plasma samples by ELISA and Multiplex Luminex assay, respectively. Immune cells from healthy individuals were stimulated with phytohemagglutinin (PHA) in the presence or absence of CD26 inhibitor. Effect of CD26 inhibition on NF-κB localization in PHA stimulated cells was analysed by immunofluorescence and confocal microscopy. Pro-inflammatory cytokines from the culture supernatants were detected with Cytometric bead array flow cytometry. Association of all measured markers with clinical outcomes was evaluated using appropriate statistical tests. RESULTS CD26 surface expression on PBSC donor harvest cells showed increased risk of chronic GVHD (cGVHD, p = 0.055). Amongst the various immune cell subtypes, decreased B cells in harvest showed significant association with aGVHD (p = 0.022) whereas increased myeloid dendritic cells and CD3(+)T cells at Day100 in peripheral blood of transplant recipients correlated with cGVHD (p = 0.046) and aGVHD (p = 0.035), respectively. Further, high sCD26 in transplant recipients at Day100 exhibited association with reduced event-free survival (EFS) (p = 0.011). Higher CD26 expression on more & less mature NK cells, naïve & post-switched memory B cells and Treg cells in the donor harvest (p < 0.05) led to lower EFS in transplant recipients. Mechanistically, CD26 inhibitor caused dose-dependent reduction in CD26 enzyme activity and in pro-inflammatory cytokine production in post mitogen-stimulated T cell cultures. CONCLUSION Our study has implicated that lower CD26 expression on immune cell subtypes of the donor stem cell harvest is associated with reduced risk of GVHD and better survival. The underlying mechanism was found to be through NF-κB pathway and pro-inflammatory cytokines. Based on these observations, chemically designed or natural resources-based CD26 inhibitors can be explored further in clinical trials for improving ASCT outcomes.
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Associations of minor histocompatibility antigens with outcomes following allogeneic hematopoietic cell transplantation
Jadi, O., Tang, H., Olsen, K., Vensko, S., Zhu, Q., Wang, Y., Haiman, C. A., Pooler, L., Sheng, X., Brock, G., et al
American journal of hematology. 2023;98(6):940-950
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Abstract
The role of minor histocompatibility antigens (mHAs) in mediating graft versus leukemia and graft versus host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT) is recognized but not well-characterized. By implementing improved methods for mHA prediction in two large patient cohorts, this study aimed to comprehensively explore the role of mHAs in alloHCT by analyzing whether (1) the number of predicted mHAs, or (2) individual mHAs are associated with clinical outcomes. The study population consisted of 2249 donor-recipient pairs treated for acute myeloid leukemia and myelodysplastic syndrome with alloHCT. A Cox proportional hazard model showed that patients with a class I mHA count greater than the population median had an increased hazard of GvHD mortality (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.01, 1.77, p = .046). Competing risk analyses identified the class I mHAs DLRCKYISL (GSTP), WEHGPTSLL (CRISPLD2), and STSPTTNVL (SERPINF2) were associated with increased GVHD mortality (HR = 2.84, 95% CI = 1.52, 5.31, p = .01), decreased leukemia-free survival (LFS) (HR = 1.94, 95% CI = 1.27, 2.95, p = .044), and increased disease-related mortality (DRM) (HR = 2.32, 95% CI = 1.5, 3.6, p = .008), respectively. One class II mHA YQEIAAIPSAGRERQ (TACC2) was associated with increased risk of treatment-related mortality (TRM) (HR = 3.05, 95% CI = 1.75, 5.31, p = .02). WEHGPTSLL and STSPTTNVL were both present within HLA haplotype B*40:01-C*03:04 and showed a positive dose-response relationship with increased all-cause mortality and DRM and decreased LFS, indicating these two mHAs contribute to the risk of mortality in an additive manner. Our study reports the first large-scale investigation of the associations of predicted mHA peptides with clinical outcomes following alloHCT.
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Lower overall survival in male patients with advanced disease undergoing allogeneic hematopoietic stem cell transplantation is associated with CYP1B1 Leu432Val polymorphism
Stute, N., Koldehoff, M.
Haematologica. 2023
Abstract
Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic key enzyme involved in estrogen metabolism, steroid synthesis, and pro-carcinogen activation. In a single-center retrospective study, 382 patients who underwent allogeneic HSCT and their donors were genotyped for CYP1B1 (C432G) polymorphism by rt-PCR. 169 patients (44%) were homozygous wild-type (wt) gene CC, 157 (41%) heterozygous CG and 56 (15%) homozygous gene mutated GG. Of interest, mutated CYP1B1 was more common in male (62%) than in female patients (48%) p=.006, unlike in donors. Five-year estimate for overall survival (OS) was 58% ±4 (CC) vs. 48% ±3 (CG and GG), p=.048. Surprisingly, this difference was only evident in males (p=.024): OS 58% ±6 vs. 42% ±4, whereas it was virtually absent in females. Importantly, this difference was only evident in male patients with advanced disease (AD) (n=118, p=.002): OS 44% ±8 (CC) vs. 32% ±6 (CG) vs. 6% ±6 (GG), whereas it was virtually absent in male patients with early disease. Oneyear non-relapse mortality (NRM) in male patients with AD was 8% ±4 (CC) vs. 21% ±5 (CG) vs. 50% ±12 (GG), p=.002. Three-year relapse rate in male patients with AD was 31% ±7 (wt) vs. 42% ±6 (mut), p=.04. Multivariate analysis for OS in male patients with AD revealed CYP1B1 polymorphism as the only prognostic factor: RR 1.78, p=.001. In conclusion, these results suggest that male patients with advanced disease and mutant CYP1B1 polymorphism have a lower OS after allogeneic HSCT due to a higher NRM and a higher relapse rate.
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Clinical Impact of Cryopreservation of Allogeneic Hematopoietic Cell Grafts During the Onset of the COVID-19 Pandemic
Devine, S. M., Bo-Subait, S., Kuxhausen, M., Spellman, S. R., Bupp, C., Ahn, K. W., Stefanski, H. E., Auletta, J. J., Logan, B. R., Shaw, B. E.
Blood advances. 2023
Abstract
At the onset of the COVID-19 pandemic, the National Marrow Donor Program mandated the cryopreservation of hematopoietic cell grafts from volunteer unrelated donors due to numerous patient and donor safety concerns and logistical hurdles. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) outcomes database, we report the impact of cryopreservation on overall survival (OS) and other outcomes within one year following hematopoietic cell transplantation (HCT). We analyzed 1,543 recipients of cryopreserved allografts receiving HCT at US centers during the first 6-months of the pandemic and compared them to 2,499 recipients of fresh allografts during the same 6-month period in 2019. On multivariable regression analysis, we observed no difference in OS (HR, 1.12; 95% CI: 0.98-1.28; P=0.09), non-relapse mortality (HR, 1.01; 95% CI: 0.84-1.22; P=0.89), graft-versus-host disease (GVHD), or GVHD-free, relapse-free survival (HR 1.03; 95% CI 0.93-1.14; P=0.58) in recipients of cryopreserved versus fresh allografts. Disease-free survival (DFS) was lower in the cryopreserved group (HR, 1.18; 95% CI: 1.05-1.33; P=0.006) due to a higher risk of relapse (HR, 1.21; 95% CI: 1.04-1.41; P=0.01). Primary graft failure was higher with cryopreservation (OR 1.48; 95% CI: 1.10-2.00; P=0.01) and the risk of chronic GVHD was lower (HR, 0.65; 95% CI: 0.50-0.84; P=0.001). In conclusion, while there was no negative impact of cryopreservation on OS, relapse was higher and DFS was lower. Fresh grafts are recommended as the pandemic related logistical hurdles resolve. Cryopreservation should be considered an option for patients when fresh grafts are not feasible.