Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 95-106
Иммуноадоптивный эффект индуцированной инфузией донорских лимфоцитов острой реакции «трансплантат против хозяина» у детей с острыми лейкозами
https://doi.org/10.24287/1726-1708-2024-23-4-95-106Аннотация
Инфузия донорских лимфоцитов (ИДЛ) с профилактической целью способствует усилению иммуноадоптивного противоопухолевого эффекта, за счет чего наблюдается снижение рисков возникновения рецидива после аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) у пациентов с острыми лейкозами. Одним из основных лимитирующих факторов при использовании ИДЛ является риск развития реакции «трансплантат против хозяина» (РТПХ). По данным исследований, частота возникновения данного осложнения после применения ИДЛ находится диапазоне от 15 до 45% для острой РТПХ (оРТПХ) и от 10 до 50% для хронической формы (хрРТПХ). Развитие РТПХ после ИДЛ также приводит к усилению противоопухолевого эффекта и позволяет снизить риски возникновения рецидива. В то же время повышенный риск рецидива ассоциирован с потерей HLA-гетерозиготности после гаплоидентичной ТГСК, роль РТПХ в становлении этого состояния не изучена. В данном одноцентровом ретроспективном исследовании был выполнен сравнительный анализ рисков возникновения костномозговых и экстрамедуллярных рецидивов у пациентов детского возраста с острым лимфобластным и острым миелоидным лейкозами, которым проводилась ИДЛ с профилактической целью после аллогенной ТГСК, выполнена оценка тяжести течения ИДЛ-индуцированной оРТПХ, частоты развития и тяжести хрРТПХ, а также исследован вопрос связи оРТПХ с потерей HLA-гетерозиготности. Было сформировано 2 группы пациентов: в основную группу вошли пациенты, получившие профилактические ИДЛ (n = 41), в группу сравнения – пациенты, не получившие их (n = 46). Получено согласие пациентов/ законных представителей на включение в исследование. Протокол (№249 от 31.05.2021) зарегистрирован в этическом комитете ФГБОУ ВО ПСПбГМУ им. И.П. Павлова Минздрава России. Все пациенты были разделены на 4 подгруппы в зависимости от применения ИДЛ и развития оРТПХ: +ИДЛ – с ИДЛ без оРТПХ (n = 34); +ИДЛр – с ИДЛ-индуцированной оРТПХ (n = 7); –ИДЛ – без ИДЛ и оРТПХ (n = 34); –ИДЛр – без ИДЛ и с оРТПХ в анамнезе (n = 12). Всего зафиксировано 7 (17%) случаев ИДЛ-индуцированной оРТПХ. Не было обнаружено статистически значимых различий при поражении желудочно-кишечного тракта (р = 1) и печени (р = 0,75) в 2 группах, в группе без ИДЛ оказалось больше пациентов с III–IV степенью поражения кожных покровов (р = 0,06). Не было зафиксировано ни одного летального исхода, связанного с течением ИДЛ-индуцированной РТПХ. Медиана числа использованных линий терапии оРТПХ (2 (1–4) и 1 (1–2); р = 0,2) и времени терапии данного осложнения (63 (23–1455) дня и 70 (44–111) дней; р = 0,72) были схожими в 2 группах. Частота развития хрРТПХ в группе с ИДЛ (n = 7; 17%) и в группе сравнения (n = 12; 26%) значимо не различались (р = 0,45). При развитии оРТПХ было обнаружено статистически значимое снижение кумулятивной частоты костномозговых рецидивов у пациентов как после применения ИДЛ, так и без ее использования (–ИДЛ 63% (95% доверительный интервал (ДИ) 43–77), +ИДЛ 41% (95% ДИ 24–57), –ИДЛр 21% (95% ДИ 5–46), +ИДЛр 14% (95% ДИ 1–50%) (р = 0,003)). Не зафиксировано значимых различий в кумулятивной частоте экстрамедуллярных рецидивов в исследуемых группах, значения которой уложились в диапазон 16–29% (р = 0,8). Общая выживаемость у пациентов из подгрупп с оРТПХ (–ИДЛр и +ИДЛр) составила 86% (95% ДИ 33–98) и 84% (95% ДИ 50–96) соответственно и статистически значимо отличалась от подгрупп без оРТПХ (+ИДЛ и –ИДЛ): 54% (95% ДИ 35–70%) и 38% (95% ДИ 20–56) соответственно (р = 0,012). Среди 55 пациентов с установленным рецидивом в посттрансплантационном периоде оценка потери HLA-гетерозиготности была проведена в 22 (40%) случаях. Из них потеря HLAгаплотипа зафиксирована у 7 (32%) пациентов: 3 (42,9%) были из подгруппы +ИДЛ, 2 (28,6%) – из подгруппы –ИДЛ и 2 (28,6%) – из подгруппы –ИДЛр. Из 15 человек без потери HLA предшествующая оРТПХ была у 1 (6,7%) пациента без проведения ИДЛ в анамнезе (p = 0,57). Таким образом, ИДЛ с профилактической целью у детей с острым лимфобластным и острым миелоидным лейкозами показывает свою эффективность в предотвращении возникновения костномозговых рецидивов после аллогенной ТГСК. Развитие оРТПХ обладает потенцирующим эффектом, приводя к усилению иммуноадоптивной активности донорских лимфоцитов. Тяжесть и характер ИДЛ-индуцированной оРТПХ в детской возрастной группе значимо не отличаются от классической формы данного осложнения, развивающегося в ранние сроки после трансплантации.
Список литературы
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Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 95-106
Immunoadoptive effect of donor lymphocyte infusion-induced acute graft-versus-host disease in children with acute leukemia
https://doi.org/10.24287/1726-1708-2024-23-4-95-106Abstract
Donor lymphocyte infusion (DLI) for prophylactic purposes enhances the immunoadoptive antitumor effect, thereby reducing the risk of relapse after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute leukemia. One of the main limiting factors for the use of DLI is the risk of developing graft-versus-host disease (GVHD). According to studies, the incidence of this complication of DLI ranges from 15% to 45% for acute GVHD (aGVHD) and from 10% to 50% for the chronic form. The development of GVHD after DLI also leads to enhancement of the antitumor effect and reduces the risk of relapse. At the same time, an increased risk of relapse is associated with the loss of HLA heterozygosity after haploidentical HSCT, and the role of GVHD in this process has not been investigated yet. In this single-center retrospective study, we performed a comparative analysis of the risk of bone marrow and extramedullary relapses in pediatric patients with acute lymphoblastic leukemia and acute myeloid leukemia who had received prophylactic DLI after allogeneic HSCT. We also assessed the severity of DLI-induced aGVHD and the incidence and severity of chronic GVHD, and investigated the relationship between aGVHD and the loss of HLA heterozygosity. We identified two groups of patients: those who had received prophylactic DLI (an intervention group; n = 41) and those who had not (a comparison group; n = 46). Informed consent to the inclusion in the study was obtained from all the patients/legal representatives. Protocol (No. 249 dated 31.05.2021) was registered in the Ethics Committee of the I.P. Pavlov First Saint Petersburg State Medical University of Ministry of Healthcare of the Russian Federation. All the patients were divided into four subgroups according the use of IDL and the development of aGVHD: +DLI – patients with DLI and without aGVHD (n = 34); +DLIGVHD – patients with DLI-induced aGVHD (n = 7); –DLI – patients without DLI and aGVHD (n = 34); –DLIGVHD – patients without DLI and with a history of aGVHD (n = 12). A total of 7 (17%) cases of DLI-induced aGVHD were recorded. There were no statistically significant differences in the incidence and severity of gastrointestinal tract involvement (p = 1) and liver involvement (p = 0.75) between the 2 groups. The incidence of grade III–IV skin GVHD (p = 0.06) was higher in the non-DLI group. No deaths associated with DLI-induced GVHD were recorded. The median number of aGVHD treatment lines (2 (1–4) and 1 (1–2); p = 0.2) and the duration of treatment (63 (23–1455) days and 70 (44–111) days; p = 0.72) were similar in the 2 groups. The incidence of chronic GVHD in the DLI group (n = 7; 17%) and in the comparison group (n = 12; 26%) did not differ significantly (p = 0.45). The cumulative incidence of bone marrow relapses was significantly lower in those patients who developed aGVHD, after DLI or without DLI (–DLI 63% (95% confidence interval (CI) 43–77), +DLI 41% (95% CI 24–57), –DLIGVHD 21% (95% CI 5–46), +DLIGVHD 14% (1–50%) (p = 0.003)). There were no significant differences between the study groups in terms of the cumulative incidence of extramedullary relapses that ranged from 16% to 29% (p = 0.8). The overall survival of the patients with aGVHD (from the –DLIGVHD and +DLIGVHD groups) was 86% (95% CI 33–98) and 84% (95% CI 50–96), respectively, and it was statistically significantly different from the overall survival of the patients without aGVHD: 54% (95% CI 35–70) and 38% (95% CI 20–56) in the +DLI and –DLI subgroups, respectively (p = 0.012). The loss of HLA heterozygosity was evaluated in 22 (40%) out of 55 patients with a post-transplant relapse. In total, HLA haplotype loss was detected in 7 (32%) patients, 3 of whom were from the +DLI group (42.9%), 2 from the –DLI group (28.6%), and another 2 from the –DLIGVHD group (28.6%). Out of 15 individuals without HLA loss, one patient (6.7%) had a history aGVHD and did not receive DLI (p = 0.57). Thus, prophylactic DLI in children with acute lymphoblastic leukemia and acute myeloid leukemia is shown to be effective in preventing bone marrow relapses after allogeneic HSCT. The development of aGVHD has a potentiating effect resulting in increased immunoadoptive activity of donor lymphocytes. The severity and clinical manifestations of DLI-induced aGVHD in pediatric patients do not differ significantly from those patients who develop classical aGVHD early after transplantation.
References
1. Passweg J.R., Baldomero H., Chabannon C., Basak G.W., de la Cámara R., Corbacioglu S., et al. Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years. Bone Marrow Transplant 2021; 56: 1651–64.
2. Zubarovskaya L.S., Moiseev I.S., Vladovskaya M.D., Mikhailova N.B., Morozova E.V., Bykova T.A., et al. Trends in Outcome of Hematopoietic Stem Cell Transplantation: 5000 Transplantations and 30 Years of Single-Center Experience. Cancers (Basel) 2023; 15 (19): 4758.
3. Leung W., Pui C.H., Coustan-Smith E., Yang J., Pei D., Gan K., et.al. Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia. Blood 2012; 120 (2): 468–72.
4. Schmid C., Labopin M., Nagler A., Niederwieser D., Castagna L., Tabrizi R., et al.; Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood 2012; 119 (6): 1599–606.
5. Spyridonidis A., Labopin M., Schmid C., Volin L., Yakoub-Agha I., Stadler M., et al.; Immunotherapy Subcommittee of Acute Leukemia Working Party. Outcomes and prognostic factors of adults with acute lymphoblastic leukemia who relapse after allogeneic hematopoietic cell transplantation. An analysis on behalf of the Acute Leukemia Working Party of EBMT. Leukemia 2012; 26 (6): 1211–7.
6. Barnes D.W., Corp M.J., Loutit J.F., Neal F.E. Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication. Br Med J 1956; 2: 626–7.
7. Jenq R.R., van den Brink M.R. Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat Rev Cancer 2010; 10 (3): 213– 21. DOI: 10.1038/nrc2804. Erratum in: Nat Rev Cancer 2010; 10 (3). DOI: 10.1038/nrc2825
8. Kolb H.J., Mittermüller J., Clemm C., Holler E., Ledderose G., Brehm G., et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76 (12): 2462–5.
9. Pagliuca S., Schmid C., Santoro N., Simonetta F., Battipaglia G., Guillaume T., et al.; Practice Harmonization and Guidelines Committee and the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Donor lymphocyte infusion after allogeneic haematopoietic cell transplantation for haematological malignancies: basic considerations and best practice recommendations from the EBMT. Lancet Haematol 2024; 11 (6): e448–58.
10. Schmid C., Labopin M., Schaap N., Veelken H., Schleuning M., Stadler M., et al.; EBMT Acute Leukaemia Working Party. Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation in acute leukaemia - a matched pair analysis by the Acute Leukaemia Working Party of EBMT. Br J Haematol 2019; 184 (5): 782–7.
11. Kothari S., Artz A.S., Lee S.M., Fulton N., Park J.H., Stock W., et al. Dose escalation prophylactic donor lymphocyte infusion after T-cell depleted matched related donor allogeneic hematopoietic cell transplantation is feasible and results in higher donor chimerism, faster immune re-constitution, and prolonged progression-free survival. Bone Marrow Transplant 2020; 55 (6): 1161–8.
12. Radujkovic A., Guglielmi C., Bergantini S., Iacobelli S., van Biezen A., Milojkovic D., et al.; Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Donor Lymphocyte Infusions for Chronic Myeloid Leukemia Relapsing after Allogeneic Stem Cell Transplantation: May We Predict Graft-versus-Leukemia Without Graft-versus-Host Disease? Biol Blood Marrow Transplant 2015; 21 (7): 1230–6.
13. Krishnamurthy P., Potter V.T., Barber L.D., Kulasekararaj A.G., Lim Z.Y., Pearce R.M., et al. Outcome of donor lymphocyte infusion after T cell-depleted allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant 2013; 19: 562–8.
14. Jedlickova Z., Schmid C., Koenecke C., Hertenstein B., Baurmann H., Schwerdtfeger R., et al. Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation. Bone Marrow Transplant 2016; 51 (5): 663–7.
15. Santoro N., Mooyaart J.E., Devillier R., Koc Y., Vydra J., Castagna L., et al. Donor lymphocyte infusions after haploidentical stem cell transplantation with PTCY: A study on behalf of the EBMT cellular therapy & immunobiology working party. Bone Marrow Transplant 2023; 58 (1): 54–60.
16. Qi S.S., Chen Z., Du Y., Sun M., Wang Z., Long F., et al. Prophylactic donor lymphocyte infusion after haploidentical hematopoietic cell transplantation and post-transplant cyclophosphamide for treatment of high-risk myeloid neoplasms in children: A retrospective study. Pediatr Blood Cancer 2023; 70 (11): e30659.
17. Carlens S., Remberger M., Aschan J., Ringdén O. The role of disease stage in the response to donor lymphocyte infusions as treatment for leukemic relapse. Biol Blood Marrow Transplant 2001; 7 (1): 31–8.
18. Tsvetkova L.A., Evdokimov A.V., Barkhatov I.M., Paina O.V., Epifanovskaya O.S., Babenko E.V. i dr. Prognosticheskoe znachenie poteri geterozigotnosti HLA posle allogennoi transplantatsii gemopoeticheskikh stvolovykh kletok pri razvitii retsidiva ostrogo leikoza u detei. Voprosy gematologii/onkologii i immunopatologii v pediatrii 2023; 22 (2): 44–53. DOI: 10.24287/1726-1708-2023-22-2-44-53
19. Przepiorka D., Weisdorf D., Martin P., Klingemann H.G., Beatty P., Hows J., et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–8.
20. Filipovich A.H., Weisdorf D., Pavletic S., Socie G., Wingard J.R., Lee S.J., et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945– 56.
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