Impact of HLA Allele Mismatch at HLA-A, -B, -C, and -DRB1 in Single Cord Blood Transplantation

Yokoyama, Hisayuki; Morishima, Yasuo; Fuji, Shigeo; Uchida, Naoyuki; Takahashi, Satoshi; Onizuka, Makoto; Tanaka, Masatsugu; Ohno, Yuju; Eto, Tetsuya; Ozawa, Yukiyasu; Takada, Satoru; Takanashi, Minoko; Kato, Koji; Kanda, Yoshinobu; Ichinohe, Tatsuo; Atsuta, Yoshiko; Kanda, Junya

doi:10.1016/j.bbmt.2019.11.001

Cited by 38 publications

(32 citation statements)

References 36 publications

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“…The lack of any association between the donor-recipient HLA match and PFS is in contrast to a number of single-and double-unit CBT series 35,36 but not others. 37,38 Importantly, our observation permits conducting dCBT in patients without well HLA-matched units, especially for many patients of mixed or non-European ancestry. 34,39 Additionally, MRD did not adversely impact PFS of leukemia patients supporting a robust CB-mediated graft-versus-leukemia effect as previously reported.…”

Section: Discussionmentioning

confidence: 99%

High progression-free survival after intermediate intensity double unit cord blood transplantation in adults

et al. 2020

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Cord blood transplantation (CBT) after high intensity or nonmyeloablative conditioning has limitations. We investigated cyclosporine-A/mycophenolate mofetil–based intermediate intensity (cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 10 mg/kg, total body irradiation 400 cGy) unmanipulated double-unit CBT (dCBT) with prioritization of unit quality and CD34+ cell dose in graft selection. Ninety adults (median age, 47 years [range, 21-63]; median hematopoietic cell transplantation comorbidity index, 2 [range, 0-8]; 61 [68%] acute leukemia) received double-unit grafts (median CD34+ cell dose, 1.3 × 105/kg per unit [range, 0.2-8.3]; median donor-recipient human leukocyte antigen (HLA) match, 5/8 [range 3-7/8]). The cumulative incidences of sustained CB engraftment, day 180 grade III-IV acute, and 3-year chronic graft-versus-host disease were 99%, 24%, and 7%, respectively. Three-year transplant-related mortality (TRM) and relapse incidences were 15% and 9%, respectively. Three-year overall survival (OS) is 82%, and progression-free survival (PFS) is 76%. Younger age and higher engrafting unit CD34+ cell dose both improved TRM and OS, although neither impacted PFS. Engrafting unit-recipient HLA match was not associated with any outcome with a 3-year PFS of 79% in 39 patients engrafting with 3-4/8 HLA-matched units. In 52 remission acute leukemia patients, there was no association between minimal residual disease (MRD) and 3-year PFS: MRD negative of 88% vs MRD positive of 77% (P = .375). Intermediate intensity dCBT is associated with high PFS. Use of highly HLA mismatched and unmanipulated grafts permits wide application of this therapy, and the low relapse rates support robust graft-versus-leukemia effects even in patients with MRD.

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Section: Discussionmentioning

confidence: 99%

High progression-free survival after intermediate intensity double unit cord blood transplantation in adults

et al. 2020

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“…Although recent data suggest that more comprehensive HLA matching between the patient and the cord blood unit is associated with improved outcomes, 25 , 26 , 37 a major advantage of cord blood transplantation is the less stringent requirement for matching than is needed in unrelated donor transplantation. In this way, both cord blood transplantation and haploidentical transplantation significantly advance the availability of these curative modalities.…”

Section: Discussionmentioning

confidence: 99%

Use of the HLA-B leader to optimize cord blood transplantation

et al. 2020

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Cord-blood transplantation (CBT) can cure life-threatening blood disorders. The HLA-B leader affects the success of unrelated donor transplantation but its role in CBT is unknown. We tested the hypothesis that the HLA-B leader influences CBT outcomes in unrelated single-unit cord-blood transplants performed by Eurocord/European Blood and Marrow Transplant (EBMT) centers between 1990 and 2018 with data reported to Eurocord. Among 4822 transplants, 2178 had one HLA-B mismatch of which 1013 were HLA-A and HLA-DRB1-matched. The leader (M or T) was determined for each HLA-B allele in patients and units to define the genotype. Among single HLA-B-mismatched transplants, the patient/unit mismatched alleles were defined as leader-matched if they encoded the same leader, or leader-mismatched if they encoded different leaders; the leader encoded by the matched (shared) allele was determined. The risks of GVHD, relapse, non-relapse mortality and overall mortality were estimated for various leaderdefined groups using multivariable regression models. Among the 1013 HLA-A, -DRB1- matched transplants with one HLA-B mismatch, increasing numbers of cord-blood unit M-leader alleles was associated with increased risk of relapse (hazard ratio [HR] for each increase in one M-leader allele 1.30, 95% confidence interval [CI] 1.05 to 1.60, P 0.02). Furthermore, leader mismatching together with an M-leader of the shared HLA-B allele lowered non-relapse mortality (HR 0.44, 95% CI 0.23 to 0.81; P 0.009) relative to leader-matching and a shared T-leader allele. The HLA-B leader may inform relapse and non-relapse mortality risk after CBT. Future patients might benefit from the appropriate selection of units that consider the leader.

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“…Moreover, insufficient priming of naïve T cells by dendritic cells due to the delayed engraftment of donor-derived dendritic cells can also increase the susceptibility of viral infections in HLA class I mismatched CBTs 21 – 23 . These hypotheses of insufficient antiviral host defense, composed of poor cytotoxic T cell expansion and naïve T cell priming, are partially supported by the recent findings on the correlation of allele-level HLA mismatches and poorer CBT outcomes 24 – 27 . However, whether viral infections themselves actually increase in patients with allele-level HLA mismatches remains unclear.…”

Section: Introductionmentioning

confidence: 73%

Impact of HLA class I allele-level mismatch on viral infection within 100 days after cord blood transplantation

Iemura

Arai

Kanda

et al. 2020

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Viral infection is more frequently reported in cord blood transplantation (CBT) than in transplantation of other stem cell sources, but its precise mechanism related to antiviral host defenses has not been elucidated yet. To evaluate the effect of human leukocyte antigen (HLA) class I allele-level incompatibility on viral infection in CBT, we conducted a single-center retrospective study. Total 94 patients were included, and viral infections were detected in 32 patients (34%) within 100 days after CBT. HLA-C mismatches in graft-versus-host direction showed a significantly higher incidence of viral infection (hazard ratio (HR), 3.67; p = 0.01), while mismatches in HLA-A, -B, or -DRB1 were not significant. Overall HLA class I mismatch was also a significant risk factor and the predictor of post-CBT viral infection (≥ 3 mismatches, HR 2.38, p = 0.02), probably due to the insufficient cytotoxic T cell recognition and dendritic cell priming. Patients with viral infection had significantly worse overall survival (52.7% vs. 72.1%; p = 0.02), and higher non-relapse mortality (29.3% vs. 9.8%; p = 0.01) at 5 years. Our findings suggest that appropriate graft selection as well as prophylaxis and early intervention for viral infection in such high-risk patients with ≥ 3 HLA class I allele-level mismatches, including HLA-C, may improve CBT outcomes.

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Impact of HLA Allele Mismatch at HLA-A, -B, -C, and -DRB1 in Single Cord Blood Transplantation

Cited by 38 publications

References 36 publications

High progression-free survival after intermediate intensity double unit cord blood transplantation in adults

High progression-free survival after intermediate intensity double unit cord blood transplantation in adults

Use of the HLA-B leader to optimize cord blood transplantation

Impact of HLA class I allele-level mismatch on viral infection within 100 days after cord blood transplantation

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