Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2023; 22: 62-72
Роль блинатумомаба в лечении В-клеточных рецидивов острого лимфобластного лейкоза у детей: собственный опыт применения
https://doi.org/10.24287/1726-1708-2023-22-1-62-72Аннотация
Острый лимфобластный лейкоз (ОЛЛ) является самым распространенным онкологическим заболеванием у детей. Несмотря на значимые улучшения в терапии ОЛЛ за последние годы, лечение рецидивов остается проблемой, сохраняется плохой прогноз с высокой частотой развития рефрактерности к терапии и высокой смертностью. Новые иммунотерапевтические подходы к лечению ОЛЛ изменили результаты и прогноз таких пациентов. Блинатумомаб, представляющий собой биспецифическое антитело, селективно связывающееся с антигеном CD19, экспрессируемым на поверхности В-клеток, и антигеном CD3, экспрессируемым на поверхности Т-клеток, показал свою эффективность в терапии рецидивов В-клеточного ОЛЛ, особенно в качестве «мостика» для трансплантации гемопоэтических стволовых клеток. Результаты лечения пациентов группы высокого риска остаются далекими от оптимальных из-за рефрактерности к химиотерапии, ее высокой токсичности и летальных исходов от инфекционных осложнений. В данной статье представлены результаты нашего опыта применения блинатумомаба у детей с рецидивами В-клеточного ОЛЛ, получавших терапию в рамках группы высокого риска по протоколу ALL-REZ 2016. Исследование одобрено независимым этическим комитетом и утверждено решением ученого совета НМИЦ ДГОИ им. Дмитрия Рогачева. Продемонстрированы эффективность и токсичность блоков с применением флударабина и клофарабина с последующей инфузией блинатумомаба. Показана эффективность инфузии аутологичных CD3+-лимфоцитов 1 раз в неделю во время непрерывной терапии блинатумомабом. Также представлены результаты применения блинатумомаба для лечения пациентов с рефрактерным к терапии 1-й линии рецидивирующим В-клеточным ОЛЛ и пациентов со вторым рецидивом ОЛЛ. Терапия 1-й линии у этих пациентов проводилась по протоколу ALL-REZ 2014. Наши результаты показали снижение минимальной остаточной болезни у пациентов с рефрактерным рецидивирующим В-клеточным ОЛЛ, а также увеличение бессобытийной выживаемости у детей с рецидивирующим В-клеточным ОЛЛ группы высокого риска.
Список литературы
1. Sigmund A.M., Sahasrabudhe K.D., Bhatnagar B. Evaluating Blinatumomab for the Treatment of Relapsed/Refractory ALL: Design, Development, and Place in Therapy. Blood Lymphat Cancer 2020; 10: 7–20.
2. Hoelzer D., Bassan R., Dombret H., Fielding A., Ribera J.M., Buske C., et al. Acute lymphoblastic leukaemia in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27 (suppl 5): v69–v82.
3. Topp M.S., Gökbuget N., Stein A.S., Zugmaier G., O'Brien S., Bargou R.C., et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 2015; 16 (1): 57–66.
4. Dhedin N., Huynh A., Maury S., Tabrizi R., Beldjord K., Asnafi V., et al. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood 2015; 125 (16): 2486–96; quiz 2586.
5. Topp M.S., Stelljes M., Zugmaier G., Barnette P., Heffner L.T. Jr, Trippett T., et al. Blinatumomab retreatment after relapse in patients with relapsed/ refractory B-precursor acute lymphoblastic leukemia. Leukemia 2018; 32 (2): 562–5.
6. Дьяконова Ю.Ю., Быданов О.И., Мякова Н.В., Абугова Ю.Г., Алейникова О.В., Аракаев О.Р. Результаты противорецидивной терапии острого лимфобластного лейкоза у детей по пилотному протоколу ALL-REZ-MB 2014. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2017; 16 (3): 7–14.
7. Дьяконова Ю.Ю., Быданов О.И., Мякова Н.В., Масчан М.А., Абугова Ю.Г., Евстратов Д.А. и др. Первые результаты исследования терапии рецидивов высокой группы риска у детей по пилотному протоколу ALL-REZ-2016. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2019; 18 (1): 12‒21.
8. Fleming S., Venn N., Reynolds J., et al. Preliminary minimal residual disease analysis of the australasian leukaemia & lymphoma group (ALLG) ALL8 study of front-line blinatumomab with chemotherapy in adults with Ph negative B-cell acute lymphoblastic leukaemia. Blood 2019; 134 (Suppl 1): 1300.
9. Badar T., Szabo A., Advani A.S., Wadleigh M., Arslan S., Ali Khan M., et al. Real world outcomes of adult B-cell acute lymphocytic leukemia patients treated with blinatumomab. Blood 2019; 134 (Suppl 1): 3809.
10. Goebeler M.-E., Knop S., Viardot A., Kufer P., Topp M.S., Einsele H., et al. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-hodgkin lymphoma: final results from a phase i study. J Clin Oncol 2016; 34 (10): 1104–11. DOI: 10.1200/JCO.2014.59.1586
11. Gokbuget N., Dombret H., Bonifacio M., Reichle A., Graux C, Faul C., et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood 2018; 131 (14): 1522–31.
12. Huehls A.M., Coupet T.A., Sentman C.L. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol 2015; 93 (3): 290–6.
13. Kantarjian H., Stein A., Gökbuget N., Fielding A.K., Schuh A.C., Ribera J.-M., et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017; 376 (9): 836–47.
14. Gokbuget N., Zugmaier G., Klinger M., Kufer P., Stelljes M., Viardot A., et al. Long-term relapsefree survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia. Haematologica 2017; 102 (4): e132–5.
15. Hoelzer D., Bassan R., Dombret H., Fielding A., Ribera J.M., Buske C.; ESMO Guidelines Committee. Acute lymphoblastic leukaemia in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27 (suppl 5): v69–v82.
16. Klinger M., Brandl C., Zugmaier G., Hijazi Y., Bargou R.C., Topp M.S., et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood 2012; 119 (26): 6226–33.
17. Kontermann R.E. Dual targeting strategies with bispecific antibodies. MAbs 2012; 4 (2): 182–97.
18. Gore L., Locatelli F., Zugmaier G., Handgretinger R., O'Brien M.M., Bader P., et al. Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood Cancer J 2018; 8 (9): 80.
19. Nagorsen D., Kufer P., Baeuerle P.A., Bargou R. Blinatumomab: a historical perspective. Pharmacol Ther 2012; 136 (3): 334–42.
20. Richard-Carpentier G., Kantarjian H.M., Jorgensen J.L., et al. Phase II study of blinatumomab in patients with B-cell acute lymphoblastic leukemia (B-ALL) with positive measurable residual disease (MRD). Blood 2019; 134 (Suppl 1): 1299.
21. Zhu M., Wu B., Brandl C., et al. Blinatumomab, a bispecific T-cell engager (BiTE(®)) for CD-19 targeted cancer immunotherapy: clinical pharmacology and its implications. Clin Pharmacokinet 2016; 55 (10): 1271–88.
Pediatric Hematology/Oncology and Immunopathology. 2023; 22: 62-72
The role of blinatumomab in the treatment of B-cell relapses of acute lymphoblastic leukemia in children: own experience
https://doi.org/10.24287/1726-1708-2023-22-1-62-72Abstract
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Despite remarkable improvements in the treatment of pediatric acute lymphoblastic leukemia over last years, relapse still carries a poor prognosis with considerable morbidity and mortality. New immunotherapeutic approaches will change the way we treated our patients and the results we had. Blinatumomab is a bispecific T-cell-engaging antibody indicated for the treatment of relapsed/refractory B-cell lymphoblastic leukemia. The use of Blinatumomab in relapsed B-cell ALL has shown promising effects, especially as a bridging tool to hematopoietic stem cell transplantation. The therapy results for patients in the high risk group remain far from optimal due to refractoriness to chemotherapy, death from infectious complications, as well as acute chemotherapy toxicity. This article demonstrates the results of our experience of using Blinatumomab in children with the high-risk group relapsed B-cell ALL treated according to the ALL-REZ 2016 protocol. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The efficacy and toxicity of innovational blocks with the use of fludarabine and clofarabine with subsequent Blinatumomab infusion are shown. And we present the efficacy of autologous CD3+ lymphocytes infusion once a week during the continuous blinatumomab therapy. Also we demonstrate the results of using Blinatumomab for the treatment of patients with refractory to the first line therapy relapsed B-lymphoblastic leukemia and patients with a second relapse of B-cell ALL. The first line therapy in these patients was carried out according to the ALL-REZ 2014 protocol. Our results show an improved reduction in minimal residual disease in patients with refractory relapsed B-cell ALL as well as an increased event free survival in children with the high-risk group relapsed B-cell ALL.
References
1. Sigmund A.M., Sahasrabudhe K.D., Bhatnagar B. Evaluating Blinatumomab for the Treatment of Relapsed/Refractory ALL: Design, Development, and Place in Therapy. Blood Lymphat Cancer 2020; 10: 7–20.
2. Hoelzer D., Bassan R., Dombret H., Fielding A., Ribera J.M., Buske C., et al. Acute lymphoblastic leukaemia in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27 (suppl 5): v69–v82.
3. Topp M.S., Gökbuget N., Stein A.S., Zugmaier G., O'Brien S., Bargou R.C., et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 2015; 16 (1): 57–66.
4. Dhedin N., Huynh A., Maury S., Tabrizi R., Beldjord K., Asnafi V., et al. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood 2015; 125 (16): 2486–96; quiz 2586.
5. Topp M.S., Stelljes M., Zugmaier G., Barnette P., Heffner L.T. Jr, Trippett T., et al. Blinatumomab retreatment after relapse in patients with relapsed/ refractory B-precursor acute lymphoblastic leukemia. Leukemia 2018; 32 (2): 562–5.
6. D'yakonova Yu.Yu., Bydanov O.I., Myakova N.V., Abugova Yu.G., Aleinikova O.V., Arakaev O.R. Rezul'taty protivoretsidivnoi terapii ostrogo limfoblastnogo leikoza u detei po pilotnomu protokolu ALL-REZ-MB 2014. Voprosy gematologii/onkologii i immunopatologii v pediatrii 2017; 16 (3): 7–14.
7. D'yakonova Yu.Yu., Bydanov O.I., Myakova N.V., Maschan M.A., Abugova Yu.G., Evstratov D.A. i dr. Pervye rezul'taty issledovaniya terapii retsidivov vysokoi gruppy riska u detei po pilotnomu protokolu ALL-REZ-2016. Voprosy gematologii/onkologii i immunopatologii v pediatrii 2019; 18 (1): 12‒21.
8. Fleming S., Venn N., Reynolds J., et al. Preliminary minimal residual disease analysis of the australasian leukaemia & lymphoma group (ALLG) ALL8 study of front-line blinatumomab with chemotherapy in adults with Ph negative B-cell acute lymphoblastic leukaemia. Blood 2019; 134 (Suppl 1): 1300.
9. Badar T., Szabo A., Advani A.S., Wadleigh M., Arslan S., Ali Khan M., et al. Real world outcomes of adult B-cell acute lymphocytic leukemia patients treated with blinatumomab. Blood 2019; 134 (Suppl 1): 3809.
10. Goebeler M.-E., Knop S., Viardot A., Kufer P., Topp M.S., Einsele H., et al. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-hodgkin lymphoma: final results from a phase i study. J Clin Oncol 2016; 34 (10): 1104–11. DOI: 10.1200/JCO.2014.59.1586
11. Gokbuget N., Dombret H., Bonifacio M., Reichle A., Graux C, Faul C., et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood 2018; 131 (14): 1522–31.
12. Huehls A.M., Coupet T.A., Sentman C.L. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol 2015; 93 (3): 290–6.
13. Kantarjian H., Stein A., Gökbuget N., Fielding A.K., Schuh A.C., Ribera J.-M., et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017; 376 (9): 836–47.
14. Gokbuget N., Zugmaier G., Klinger M., Kufer P., Stelljes M., Viardot A., et al. Long-term relapsefree survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia. Haematologica 2017; 102 (4): e132–5.
15. Hoelzer D., Bassan R., Dombret H., Fielding A., Ribera J.M., Buske C.; ESMO Guidelines Committee. Acute lymphoblastic leukaemia in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27 (suppl 5): v69–v82.
16. Klinger M., Brandl C., Zugmaier G., Hijazi Y., Bargou R.C., Topp M.S., et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood 2012; 119 (26): 6226–33.
17. Kontermann R.E. Dual targeting strategies with bispecific antibodies. MAbs 2012; 4 (2): 182–97.
18. Gore L., Locatelli F., Zugmaier G., Handgretinger R., O'Brien M.M., Bader P., et al. Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood Cancer J 2018; 8 (9): 80.
19. Nagorsen D., Kufer P., Baeuerle P.A., Bargou R. Blinatumomab: a historical perspective. Pharmacol Ther 2012; 136 (3): 334–42.
20. Richard-Carpentier G., Kantarjian H.M., Jorgensen J.L., et al. Phase II study of blinatumomab in patients with B-cell acute lymphoblastic leukemia (B-ALL) with positive measurable residual disease (MRD). Blood 2019; 134 (Suppl 1): 1299.
21. Zhu M., Wu B., Brandl C., et al. Blinatumomab, a bispecific T-cell engager (BiTE(®)) for CD-19 targeted cancer immunotherapy: clinical pharmacology and its implications. Clin Pharmacokinet 2016; 55 (10): 1271–88.
