Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2019; 18: 22-29
Оценка эффективности использования абатацепта для профилактики острой реакции «трансплантат против хозяина» после трансплантации гемопоэтических стволовых клеток у детей с незлокачественными заболеваниями
https://doi.org/10.24287/1726-1708-2019-18-2-22-29Аннотация
Реакция «трансплантат против хозяина» (РТПХ) – одно из наиболее значимых осложнений алло- генной трансплантации гемопоэтических стволовых клеток (ТГСК). Абатацепт представляет собой растворимую гибридную белковую молекулу, состоящую из двух компонентов – внеклеточного домена CTLA4 человека и модифицированного Fc фрагмента IgG1. Связываясь с CD80/СD86, он блокирует костимуляторный сигнал с антигенпрезентирующей клетки на СD28 Т-лимфоцита и предотвращает его активацию. Таким образом, применение абатацепта может влиять на ранний этап патогенеза острой РТПХ. Цель исследования – изучение эффективности и безопасности применения абатацепта в качестве дополнительного иммуносупрессивного агента в стандартных для клиники протоколах профилактики острой РТПХ у пациентов с незлокачественными заболеваниями. Данное исследование поддержано Независимым этическим комитетом и утверждено решением Ученого совета НМИЦ ДГОИ (протокол № 9/2013 от 01.10.2013). С 2013 по 2018 год в исследование были включены 62 пациента; в 30 случаях в качестве дополнительного препарата использовали абатацепт, включенный в стандартный протокол профилактики РТПХ. При анализе эффективности абатацепта для профилактики острой РТПХ в исследуемой группе (n = 30) продемонстрированы значительные его преимущества (р = 0,018) по сравнению с контрольной группой (n = 32). При стратификации пациентов в зависимости от технологии подготовки трансплантата в группе пациентов, которым проводили TCRαβ+/СD19+ деплецию трансплантата, данных об эффективности абатацепта не получено (p = 0,28). При применении неманипулированного трансплантата (n = 23) преимущества использования абатацепта имели статистически достоверную значимость (p = 0,024). Абатацепт можно рекомендовать для включения в режимы профилактики РТПХ в качестве дополнительного агента при аллогенной ТГСК у пациентов с незлокачественными заболеваниями.
Список литературы
1. Hill L., Alousi A., Kebriaei P., Mehta R., Rezvani K., Shpall E. New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol 2017; 9 (1): 21–46.
2. Flowers M.E.D., Inamoto Y., Carpenter P.A., Lee S.J., Kiem H.-P., Petersdorf E.W., et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versushost disease according to National Institutes of Health consensus criteria. Blood 2011; 117 (11): 3214–9.
3. Cahn J.Y., Klein J.P., Lee S.J., Milpied N., Blaise D., Antin J.H., et al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: A joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood 2005; 106: 1495–500.
4. Holtan S.G., Pasquini M., Weisdorf D.J. Acute graft-versus-host disease: a benchto- bedside update. Blood 2014; 124 (3): 363–73.
5. Ferrara J.L., Levine J.E., Reddy P., Holler E. Graft-versus-host disease. Lancet 2009; 373 (9674): 1550–61.
6. Ingelfinger J.R., Schwartz R.S. Immunosuppression – the Promise of Specificity. New Engl J Med 2005; 353 (8): 836–9.
7. Alegre M.L., Frauwirth K.A., Thompson C.B. T‐cell regulation by CD28 and CTLA‐4. Nat Rev Immunol 2001; 1: 220–8.
8. Briones J., Novelli S., Sierra J. T-cell costimulatory molecules in acutegraft- versus host disease: therapeutic implications. Bone Marrow Res 2010; 2011: 976793.
9. Gardner D., Jeffery L.E., Sansom D.M. Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade. Am J Transplant 2014; 14: 1985–91.
10. Auchincloss H., Turka L.A. CTLA-4: Not All Costimulation Is Stimulatory. The Journal of Immunology 2011; 187 (7): 3457–8.
11. Chitale S., Moots R. Abatacept: the first T-lymphocyte co-stimulation modulator, for the treatment of rheumatoid arthritis. Expert Opin Biol Ther 2008; 8 : 115–22.
12. Koura D.T., Horan J.T., Langston A.A., Qayed M., Mehta A., Khoury H.J., et al. In vivo T-cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial. Biol Blood Marrow Transplant 2013; 19 (11): 1638–49.
13. Watkins B., Qayed M., Bratrude B., Betz K., Brown M., Rhodes J., et al. T-cell Costimulation Blockade with Abatacept Nearly Eliminates Early Severe Acute Graft Versus Host Disease after HLAMismatched (7/8 HLA Matched) Unrelated Donor Transplant, with a Favorable Impact on Disease-Free and Overall Survival. Presented at ASH 2017; Abstract 212.
14. Jaiswal S.R., Zaman S., Chakrabarti A., Sehrawat A., Bansal S., Gupta M., et al. T-cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation. Transpl Immunol 2016; 39: 46–51.
15. Jaiswal S.R., Bhakuni P., Zaman Sh., Bansal S., Bharadwaj P., Bhargava S., et al. T-cell co-stimulation blockade promotes transplantation tolerance in combination with sirolimus and posttransplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. Transplant Immunology 2017; 43–44: 54–9.
16. 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.
17. Maschan M., Shelikhova L., Ilushina M., Kurnikova E., Boyakova E., Balashov D., et al. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant 2016; 51 (5): 668–74.
18. Balashov D., Shcherbina A., Maschan M., Trakhtman P., Skvortsova Y., Shelikhova L., et al. Single-Center Experience of Unrelated and Haploidentical Stem Cell Transplantation with TCRαβ and CD19 Depletion in Children with Primary Immunodeficiency Syndromes. Biol Blood Marrow Transplant 2015; 21: 1955–62.
19. Balashov D., Laberko A., Shcherbina A., Trakhtman P., Abramov D., Gutovskaya E., et al. A Conditioning Regimen with Plerixafor Is Safe and Improves the Outcome of TCRαβ+ and CD19+ Cell- Depleted Stem Cell Transplantation in Patients with Wiskott–Aldrich Syndrome. Biol Blood Marrow Transplant 2018 Mar 14. pii: S1083–8791 (18) 30119–8.
20. Bertaina A., Merli P., Rutella S., Pagliara D., Bernardo M.E., Masetti R., et al. HLAhaploidentical stem cell transplantation after removal of αβ+ T and B-cells in children with nonmalignant disorders. Blood 2014; 124: 822–6.
21. Shah R.M., Elfeky R., Nademi Z., Qasim W., Amrolia P., Chiesa R., et al. T-cell receptor αβ+ and CD19+ cell– depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency. Journal of Allergy and Clinical Immunology 2018; 141 (4): 1417–26.e1.
Pediatric Hematology/Oncology and Immunopathology. 2019; 18: 22-29
Evaluation of abatacept for GVHD prophylaxis in patients with non-malignant diseases after hematopoietic stem cell transplantation
https://doi.org/10.24287/1726-1708-2019-18-2-22-29Abstract
Graft-versus-host diseases (GVHD) is one of most significant complication after allogeneic hematopoietic stem cells transplantation (HSCT). T-cell activation is a major stage in the GVHD pathogenesis. T-cells require 2 signals for activation: cognate antigen/MHC binding T-cell receptors and positive costimulatory signals from antigen-presenting cells (APC). The predominant positive costimulatory signal to human CD4 T0-cells comes through the CD28 receptor. This signal can be blocked by fusion proteins (such as CTLA4-Ig). Abatacept is a soluble fusion protein, which links the extracellular domain of human CTLA-4 to the modified Fc portion of human IgG1. We present results of single-center prospective randomized study to evaluate the efficacy of adding abatacept to the GVHD prophylaxis protocol after hemopoietic stem cell transplantation in patients with non-malignant diseases. Study was approved by Ethics Committee and Scientific Council of the Institute (protocol # 9/2013 from 01.10.2013). During 4 years we included 62 patients, 30 of them received abatacept as additional agent. Cumulative incidence of acute GVHD was significantly lower in this group in compare with control group (p = 0,018). When we stratified patients in dependents of graft processing technology, we did not see any advantages of abatacept in patients after transplantation with TCRαβ+/СD19+ graft depletion. However, after HSCT with non-manipulated graft the abatacept showed significant efficacy in aGVHD prophylaxis compared with control group (p = 0,024). Abatacept can be recommended as effective additional agent for GVHD prophylaxis after allogeneic HSCT in patients with non-malignant diseases.
References
1. Hill L., Alousi A., Kebriaei P., Mehta R., Rezvani K., Shpall E. New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol 2017; 9 (1): 21–46.
2. Flowers M.E.D., Inamoto Y., Carpenter P.A., Lee S.J., Kiem H.-P., Petersdorf E.W., et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versushost disease according to National Institutes of Health consensus criteria. Blood 2011; 117 (11): 3214–9.
3. Cahn J.Y., Klein J.P., Lee S.J., Milpied N., Blaise D., Antin J.H., et al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: A joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood 2005; 106: 1495–500.
4. Holtan S.G., Pasquini M., Weisdorf D.J. Acute graft-versus-host disease: a benchto- bedside update. Blood 2014; 124 (3): 363–73.
5. Ferrara J.L., Levine J.E., Reddy P., Holler E. Graft-versus-host disease. Lancet 2009; 373 (9674): 1550–61.
6. Ingelfinger J.R., Schwartz R.S. Immunosuppression – the Promise of Specificity. New Engl J Med 2005; 353 (8): 836–9.
7. Alegre M.L., Frauwirth K.A., Thompson C.B. T‐cell regulation by CD28 and CTLA‐4. Nat Rev Immunol 2001; 1: 220–8.
8. Briones J., Novelli S., Sierra J. T-cell costimulatory molecules in acutegraft- versus host disease: therapeutic implications. Bone Marrow Res 2010; 2011: 976793.
9. Gardner D., Jeffery L.E., Sansom D.M. Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade. Am J Transplant 2014; 14: 1985–91.
10. Auchincloss H., Turka L.A. CTLA-4: Not All Costimulation Is Stimulatory. The Journal of Immunology 2011; 187 (7): 3457–8.
11. Chitale S., Moots R. Abatacept: the first T-lymphocyte co-stimulation modulator, for the treatment of rheumatoid arthritis. Expert Opin Biol Ther 2008; 8 : 115–22.
12. Koura D.T., Horan J.T., Langston A.A., Qayed M., Mehta A., Khoury H.J., et al. In vivo T-cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial. Biol Blood Marrow Transplant 2013; 19 (11): 1638–49.
13. Watkins B., Qayed M., Bratrude B., Betz K., Brown M., Rhodes J., et al. T-cell Costimulation Blockade with Abatacept Nearly Eliminates Early Severe Acute Graft Versus Host Disease after HLAMismatched (7/8 HLA Matched) Unrelated Donor Transplant, with a Favorable Impact on Disease-Free and Overall Survival. Presented at ASH 2017; Abstract 212.
14. Jaiswal S.R., Zaman S., Chakrabarti A., Sehrawat A., Bansal S., Gupta M., et al. T-cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation. Transpl Immunol 2016; 39: 46–51.
15. Jaiswal S.R., Bhakuni P., Zaman Sh., Bansal S., Bharadwaj P., Bhargava S., et al. T-cell co-stimulation blockade promotes transplantation tolerance in combination with sirolimus and posttransplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. Transplant Immunology 2017; 43–44: 54–9.
16. 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.
17. Maschan M., Shelikhova L., Ilushina M., Kurnikova E., Boyakova E., Balashov D., et al. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant 2016; 51 (5): 668–74.
18. Balashov D., Shcherbina A., Maschan M., Trakhtman P., Skvortsova Y., Shelikhova L., et al. Single-Center Experience of Unrelated and Haploidentical Stem Cell Transplantation with TCRαβ and CD19 Depletion in Children with Primary Immunodeficiency Syndromes. Biol Blood Marrow Transplant 2015; 21: 1955–62.
19. Balashov D., Laberko A., Shcherbina A., Trakhtman P., Abramov D., Gutovskaya E., et al. A Conditioning Regimen with Plerixafor Is Safe and Improves the Outcome of TCRαβ+ and CD19+ Cell- Depleted Stem Cell Transplantation in Patients with Wiskott–Aldrich Syndrome. Biol Blood Marrow Transplant 2018 Mar 14. pii: S1083–8791 (18) 30119–8.
20. Bertaina A., Merli P., Rutella S., Pagliara D., Bernardo M.E., Masetti R., et al. HLAhaploidentical stem cell transplantation after removal of αβ+ T and B-cells in children with nonmalignant disorders. Blood 2014; 124: 822–6.
21. Shah R.M., Elfeky R., Nademi Z., Qasim W., Amrolia P., Chiesa R., et al. T-cell receptor αβ+ and CD19+ cell– depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency. Journal of Allergy and Clinical Immunology 2018; 141 (4): 1417–26.e1.
