ISSN 1866-8836
Клеточная терапия и трансплантация

PO-10. Incidence and clinical characteristics of relapse with loss of HLA heterozygosity after haplo-HSCT in children with acute lymphoblastic leukemia

Liubov A. Tsvetkova, Aleksey A. Evdokimov, Ildar M. Barkhatov, Olesya V. Paina, Olga S. Epifanovskaya, Elena V. Babenko, Zhemal Z. Rakhmanova, Polina V. Kozhokar, Anna A. Osipova, Аnastasia S. Frolova, Elena V. Semenova, Alexander D. Kulagin, Ludmila S. Zubarovskaya

RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russia


Contact: Dr. Liubov A. Tsvetkova, phone: +7 (921) 643-39-05, e-mail: tsvetluibov@mail.ru

doi 10.18620/ctt-1866-8836-2023-12-3-1-176

Summary

Genetic loss of patient-specific HLA haplotype by leukemic cells is one of the tumor escape mechanisms from the immune surveillance of donor cells. This phenomenon is observed in approximately 30% of cases of acute leukemia relapses in adult patients after mismatched allogeneic hematopoietic stem cell transplantation (HSCT). In children this mechanism has not yet been widely studied. Analysis of HLA loss of heterozygosity (LoH) in relapse of acute lymphoblastic leukemia (ALL) in children can help choosing the optimal therapeutic strategy after allo-HSCT. Our aim was to study the incidence, time of development and risk factors for the LoH in children with relapse ALL after haplo-HSCT.

Patients and methods

The retrospective analysis included 49 children with relapse of ALL (38 B-ALL, 11 T-ALL) after haplo-HSCT. The median age at the time of allo-HSCT was 7.5 years (1-16). Haplo-HSCT was performed in 1-2 remission of the disease in 33 (67%) patients, in disease progression – in 16 patients (33%). Myeloablative conditioning regimen was performed in 32 patients (65%). GvHD prophylaxis based on post-transplant cyclophosphamide was used in 45 patients (92%). Short tandem repeated (STR) loci were detected using 6 STR loci assay for the HLA regions: D6S473, D6S291, D6S273, D6S265, D6S105, D6S277. Samples of peripheral blood cells of patients and donors before allo-HSCT and bone marrow of patients at relapse after allo-HSCT were collected. We assessed the associations between incidence of LoH HLA and following factors: patient gender, donor gender, number of previous lines of therapy, disease status before allo-HSCT, ABO incompatibility, conditioning regimen, CD34+/kg and CD3+/kg in graft, number of HLA mismatched loci, GvHD before relapse, persistence of MRD after allo-HSCT, immunoadoptive prophylactic therapy after allo-HSCT.

Results

All included patients were divided into 2 groups: relapse with loss of HLA heterozygosity and without (“classic” type of relapse). Loss of heterozygosity of HLA genes was found in 14/49 (28.5%) patients: 10/38 (26%) with B-ALL, 4/11 (36%) with T-ALL (p=0.5). Relapses with LoH occurred later if compared to the “classic” type of relapse. The median time for the development of relapse with LoH was 8.8 (2-63) months after haplo-HSCT, without LoH – 6.2 (1-30) months, p=0.07. Chronic GvHD was associated with loss of the HLA haplotype in ALL relapse after haplo-HSCT, p=0.03. With a median follow-up of 5.5 (0.5-68) months we did not find significant difference in relapse-free survival (RFS) from relapse to disease progression/next relapse between groups: 14% in LoH group and 23% in the group without LoH HLA. The median RFS was 2.4 months (95% CI 0.9-3.8) in the LoH group and 3.8 months in the classical group (95% CI 0.7-6.8), p=0.63. Overall survival (OS) at a median follow-up of 5.5 months was 29% in the group with LoH and 34% in the group without HLA haplotype loss. Median OS was 4.5 months (95% CI 0-9) and 8.3 months (95% CI 2.4-14), respectively, p=0.5. At the time of the last follow up, among 14 patients with HLA loss, 4 were alive, two of which (50%) underwent secondary haplo-HSCT with a donor change. Among patients without HLA loss, 12 patients are alive, 4 (33%) of which underwent second haplo-HSCT with a donor change.

Conclusions

Frequency of relapses with the loss of the HLA haplotype was 28.5% among all relapses after haplo-HSCT in children with ALL. Chronic GvHD is a risk factor for the loss of HLA heterozygosity, compared with the classical type of relapse, p=0.03. OS and RFS after the first relapse were similar between the groups. Second allo-HSCT with donor change is crucial for recovering HLA heterozygosity and the graft-versus-leukemia reaction.

Keywords

Children, acute lymphoblastic leukemia, hematopoietic stem cell transplantation, haploidentical, loss of heterozygosity, HLA genes.


Supplement 12-3
09/30/2023

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doi 10.18620/ctt-1866-8836-2023-12-3-1-176

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