HLA-haplotype loss after TCRαβ/CD19-depleted haploidentical HSCT

Shyr, David C.; Zhang, Bing M.; Saini, Gopin; Madani, Nahid D.; Schultz, Liora; Patel, Shabnum; Kristovich, Karen; Fernández-Viña, Marcelo; Bertaina, Alice

doi:10.1038/s41409-020-01081-0

Cited by 9 publications

(4 citation statements)

References 22 publications

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“…Therefore, one of the biological modes of relapse after allo-HCT is the loss of expression of disparate immunodominant HLA alleles via loss of heterozygosity (LOH) or epigenetic down-regulation, which have been demonstrated in haploidentical, mismatched unrelated and matched related settings 6 – 8 . While large genomic aberrations including the loss or the duplication of an entire haplotype or of a single allele have been noted across various studies 6 , 9 – 11 , more granular lesions of the HLA region including microdeletions and point mutations, remain underestimated in allo-HCT. Such lesions, ultimately resulting in phenotypes of immune resistance, have been reported in the context of clonal adaptive recovery in immune-mediated aplastic anemia (AA) or as immune escape drivers in solid tumors, together with up-modulation of negative immune checkpoint regulators 12 – 14 .…”

Section: Introductionmentioning

confidence: 99%

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

et al. 2023

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Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.

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Section: Introductionmentioning

confidence: 99%

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

et al. 2023

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“…Потеря гетерозиготности по генам HLA -проявление геномной нестабильности опухоли, характеризующееся выпадением участка короткого плеча 6-й хромосомы. Среди злокачественных заболеваний крови данный механизм описан при рецидивах острых лейкозов у взрослых и детей после алло-ТГСК [11,18,19]. Потеря донор-специфичного гаплотипа HLA на бластной популяции приводит к необратимой потере экспрессии HLA, невозможности распознавания антигенов опухоли T-клетками и подавлению реакции «трансплантат против лейкемии».…”

Section: обсуждение результатов исследованияunclassified

The prophylaxis of severe hemophilia A with inhibitors in children in the Republic of Belarus: a 12-year experience

Dmitriev,

Volkova,

Aleinikova

et al. 2023

Voprosy gematologii/onkologii i immunopatologii v pediatrii

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The development of inhibitory antibodies against FVIII is the most serious complication associated with the use of FVIII concentrates in hemophilia A patients. There is a need for more research on measures that could reduce the risk of inhibitor formation in previously untreated patients (PUPs) with severe hemophilia A. The purpose of this study was to determine the effectiveness of the prevention of clotting inhibitor development in PUPs (or minimally treated patients) with severe hemophilia A by administering plasma-derived factor VIII concentrate (pdFVIII) at a dose of 25 IU/kg once a week for a year. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). Between 2010 and 2022, 56 boys were newly diagnosed with severe hemophilia A. Twenty-one of them received pdFVIII as on-demand treatment to stop bleeding (Group 1). Thirty-five boys received pdFVIII at a dose of 25 IU/kg body weight once a week during the first 50 weeks of treatment for the prevention of inhibitor development (Group 2). The administration of pdFVIII at a dose of 25 IU/kg once a week in the PUPs (or minimally treated patients) contributed to a decrease in the cumulative incidence of inhibitors to 15.9 ± 7.7% (4 out of the 35 patients who had been treated prophylactically) compared with 43.7 ± 11.8% (8 out of the 21 patients who had received hemostatic therapy to stop bleeding) (log-rank test, p = 0.041). Thus, the administration of pdFVIII concentrate at a dose of 25 IU/kg once a week for the first 50 weeks of treatment lead to a decrease (p = 0.009) in the cumulative incidence of inhibitors against the administered coagulation factor VIII to 15.9 ± 7.7%.

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“…HLA loss may contribute to leukemic escape after allogeneic HCT with a variable frequency, depending on donor type and timing of relapse: studies conducted on patients allografted with T-cell replete haploidentical transplants, showed that AML cells can escape immunologic control through loss of the mismatched HLA in almost one third of cases, although the potent lymphocytolytic action exerted by cyclophosphamide against potent donor alloreactive T-cells clones ( 11 , 12 ). Only recently, HLA loss has been described also in the setting of T-cell depleted haploidentical HCT ( 13 ). Other than haploidentical setting, HLA-loss has been observed in 4-12% with unrelated donors and only sporadically with HLA-matched siblings ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

The prevention of disease relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia

et al. 2022

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Disease relapse represents by far the most frequent cause of hematopoietic cell transplantation (HCT) failure. Patients with acute leukemia suffering relapse after HCT have limited conventional treatment options with little possibility of cure and represent, de facto, suitable candidates for the evaluation of novel cellular and biological-based therapies. Donor lymphocyte infusions (DLI) has been one of the first cellular therapies adopted to treat post HCT relapse of acute leukemia patients and still now, it is widely adopted in preemptive and prophylactic settings, with renewed interest for manipulated cellular products such as NK-DLI. The acquisition of novel biological insights into pathobiology of leukemia relapse are translating into the clinic, with novel combinations of target therapies and novel agents, helping delineate new therapeutical landscapes. Hypomethylating agents alone or in combination with novel drugs demonstrated their efficacy in pre-clinical models and controlled trials. FLT3 inhibitors represent an essential therapeutical instrument incorporated in post-transplant maintenance strategies. The Holy grail of allogeneic transplantation lies in the separation of graft-vs.-host disease from graft vs. tumor effects and after more than five decades, is still the most ambitious goal to reach and many ways to accomplish are on their way.

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HLA-haplotype loss after TCRαβ/CD19-depleted haploidentical HSCT

Cited by 9 publications

References 22 publications

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

The prophylaxis of severe hemophilia A with inhibitors in children in the Republic of Belarus: a 12-year experience

The prevention of disease relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia

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