Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2023; 22: 46-52
Опыт применения инотузумаба озогамицина у детей с рецидивами и рефрактерным течением В-линейного острого лимфобластного лейкоза
https://doi.org/10.24287/1726-1708-2023-22-1-46-52Аннотация
В настоящее время результаты терапии острого лимфобластного лейкоза (ОЛЛ) являются весьма обнадеживающими, но, несмотря на это, у 10–15% пациентов развивается рецидив заболевания. Успешное лечение рецидива зависит от полноты эрадикации опухолевого клона перед проведением трансплантации гемопоэтических стволовых клеток (ТГСК). Появление иммунотерапевтических агентов сделало возможным достижение ремиссии с отрицательной минимальной остаточной болезнью (МОБ) даже у пациентов, рефрактерных к химиотерапии. Примером такого препарата является конъюгат инотузумаб озогамицин (ИнО) – анти-CD22-моноклональное антитело, связанное с цитотоксическим агентом калихеамицином. В работу были включены 17 пациентов в возрасте до 18 лет с рецидивами или рефрактерными формами ОЛЛ из В-клеточных предшественников (ВП-ОЛЛ), получившие терапию ИнО в ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России с 01.10.2016 по 01.09.2022. Исследование одобрено независимым этическим комитетом и утверждено решением ученого совета НМИЦ ДГОИ им. Дмитрия Рогачева. Оценка эффективности терапии проводилась по морфологическому ответу, достижению МОБ-негативности и общей выживаемости. Анализ токсичности проводился согласно CTCAE 5.0 (Common Terminology Criteria for Adverse Events). Статистическая обработка выполнялась на программном обеспечении XLSTAT 2016. Ответ на терапию был зафиксирован в большинстве случаев (75%). Среди всех пациентов отрицательный МОБ-статус был достигнут в 41,2% случаев. Общая однолетняя выживаемость пациентов составила 40,3% (95% доверительный интервал 14,8–65,7). Токсичность препарата была приемлемой, однако стоит отметить развитие веноокклюзионной болезни печени/синдрома синусоидальной обструкции у 33% пациентов, получавших ИнО в стандартной дозе с последующей ТГСК. Данное исследование продемонстрировало достаточно высокую эффективность ИнО в качестве как терапии «спасения» у пациентов с рецидивами и рефрактерным течением ВП-ОЛЛ, так и «бридж-терапии» перед ТГСК.
Список литературы
1. Henze G., v Stackelberg A., Eckert C. ALL-REZ BFM-The consecutive trials for children with relapsed acute lymphoblastic leukemia. Klin Padiatr 2013; 225 Suppl 1: S73–8.
2. Möricke A., Zimmermann M., Reiter A., Henze G., Schrauder A. Gadner H., et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010; 24 (2): 265–84.
3. Oskarsson T., Söderhäll S., Arvidson J., Forestier E., Montgomery S., Bottai M., et al. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome. Haematologica 2016; 101 (1): 68–76.
4. Parker C., Waters R., Leighton C., Hancock J., Sutton R., Moorman A.V., et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomized trial. Lancet 2010; 376 (9757): 2009–17.
5. Ko R.H., Ji L., Barnette P., Bostrom B., Hutchinson R., Raetz E., et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. J Clin Oncol 2010; 28 (4): 648–54.
6. Mejstríková E., Hrusak O., Borowitz M.J., Whitlock J.A., Brethon B., Trippett T.M., et al. CD19-negative relapse of pediatric B-cell precursor acute lymphoblastic leukemia following blinatumomab treatment. Blood Cancer J 2017; 7 (12): 659.
7. Dourthe M.E., Rabian F., Yakouben K., Chevillon F., CabannesHamy A., Méchinaud F., et al. Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia 2021; 35 (12): 3383–93.
8. DiJoseph J.F., Armellino D.C., Boghaert E.R., Khandke K., Dougher M.M., Sridharan L., et al. Antibody-targeted chemotherapy with CMC-544: A CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 2004; 103 (5): 1807–14.
9. De Vries J.F., Zwaan C.M., De Bie M., Voerman J.S.A., den Boer M.L., van Dongen J.J.M., et al. The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells. Leukemia 2012; 26 (2): 255–64.
10. Kantarjian H.M., DeAngelo D.J., Stelljes M., Liedtke M., Stock W., Gökbuget N., et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INOVATE study. Cancer 2019; 125 (14): 2474–87.
11. Lanza F., Maffini E., Rondoni M., Massari E., Faini A.C., Malavasi F. CD22 expression in b-cell acute lymphoblastic leukemia: Biological significance and implications for inotuzumab therapy in adults. Cancers 2020; 12 (2): 303.
12. Iwamoto S., Deguchi T., Ohta H., Kiyokawa N., Tsurusawa M., Yamada T., et al. Flow cytometric analysis of de novo acute lymphoblastic leukemia in childhood: Report from the Japanese Pediatric Leukemia/Lymphoma Study Group. Int J Hematol 2011; 94 (2): 185–92.
13. Shah N.N., Stevenson M.S., Yuan C.M., Richards K., Delbrook C., Kreitman R.J., et al. Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatr Blood Cancer 2015; 62 (6): 964–9.
14. Bhojwani D., Sposto R., Shah N.N., Rodriguez V., Yuan C., Stetler-Stevenson M., et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia 2019; 33 (4): 884–92.
15. Calvo C., Cabannes-Hamy A., Adjaoud D., Bruno B., Blanc L., Boissel N., et al. Inotuzumab ozogamicin compassionate use for French paediatric patients with relapsed or refractory CD22-positive B-cell acute lymphoblastic leukaemia. Br J Haematol 2020; 190 (1): e53–6. DOI: 10.1111/bjh.16732
16. Brivio E., Locatelli F., LopezYurda M., Malone A., Diaz de Heredia C., Bielorai B., et al. A Phase I study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study). Blood 2021; 137 (12): 1582–90.
17. O’Brien M.M., Ji L., Shah N.N., Rheingold S.R., Bhojwani D., Yuan C.M., et al. Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children’s Oncology Group Protocol AALL1621. J Clin Oncol 2022; 40 (9): 956–67.
18. [Electronic resource]. URL: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf (accessed 20.02.2023).
19. Pennesi E., Michels N., Brivio E., van der Velden V.H.J., Jiang Y., Thano A., et al. Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial. Leukemia 2022; 36 (6): 1516–24.
20. Brivio E., Chantrain C.F., Gruber T.A., Thano A., Rialland F., Contet A., et al. Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series. Br J Haematol 2021;193 (6): 1172–7.
21. Маркова И.В., Бондаренко С.Н., Паина О.В., Бабенко Е.В., Гиндина Т.Л., Бархатов И.М. и др. Эффективность и безопасность терапии анти-CD22-моноклональным антителом при рецидивах и рефрактерных формах В-линейного острого лимфобластного лейкоза у детей и взрослых. Педиатрия. Журнал им. Г.Н. Сперанского 2020; 99 (4): 27–34.
Pediatric Hematology/Oncology and Immunopathology. 2023; 22: 46-52
The use of inotuzumab ozogamicin in children with relapsed/refractory B-lineage acute lymphoblastic leukemia
https://doi.org/10.24287/1726-1708-2023-22-1-46-52Abstract
Today, treatment results for acute lymphoblastic leukemia (ALL) look encouraging, yet 10–15% patients still end up relapsing. The success of relapse treatment is directly dependent on whether or not a tumor clone has been completely eradicated before hematopoietic stem cell transplantation (HSCT). Immunotherapy made it possible to achieve minimal residual disease (MRD) – negative remission even in refractory patients. One example of such immunotherapeutic agents is inotuzumab ozogamicin (InO), an anti-CD22 monoclonal antibody conjugated to the cytotoxic agent calicheamicin. We included 17 patients under the age of 18 with relapsed or refractory precursor B-cell ALL (pre-B ALL) who had been treated with InO at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of Russia from 01.10.2016 to 01.09.2022. 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 of the therapy was assessed based on the patients’ morphological response, MRD negativity and overall survival. Treatment toxicity was assessed according to CTCAE 5.0 (Common Terminology Criteria for Adverse Events). Statistical analysis was performed using the XLSTAT 2016 software. The majority of the patients (75%) responded to the therapy. MRD negativity was achieved in 41.2% of the study patients. The one-year overall survival rate was 40.3% (95% confidence interval 14.8–65.7). The treatment was well tolerated but 33% of the patients treated with standard-dose InO and subsequent HSCT developed veno-occlusive disease/sinusoidal obstruction syndrome. In our study, we demonstrated the high efficacy of InO both when used as a rescue therapy in patients with relapsed/refractory pre-B ALL and as a bridging therapy in patients before HSCT.
References
1. Henze G., v Stackelberg A., Eckert C. ALL-REZ BFM-The consecutive trials for children with relapsed acute lymphoblastic leukemia. Klin Padiatr 2013; 225 Suppl 1: S73–8.
2. Möricke A., Zimmermann M., Reiter A., Henze G., Schrauder A. Gadner H., et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010; 24 (2): 265–84.
3. Oskarsson T., Söderhäll S., Arvidson J., Forestier E., Montgomery S., Bottai M., et al. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome. Haematologica 2016; 101 (1): 68–76.
4. Parker C., Waters R., Leighton C., Hancock J., Sutton R., Moorman A.V., et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomized trial. Lancet 2010; 376 (9757): 2009–17.
5. Ko R.H., Ji L., Barnette P., Bostrom B., Hutchinson R., Raetz E., et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. J Clin Oncol 2010; 28 (4): 648–54.
6. Mejstríková E., Hrusak O., Borowitz M.J., Whitlock J.A., Brethon B., Trippett T.M., et al. CD19-negative relapse of pediatric B-cell precursor acute lymphoblastic leukemia following blinatumomab treatment. Blood Cancer J 2017; 7 (12): 659.
7. Dourthe M.E., Rabian F., Yakouben K., Chevillon F., CabannesHamy A., Méchinaud F., et al. Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia 2021; 35 (12): 3383–93.
8. DiJoseph J.F., Armellino D.C., Boghaert E.R., Khandke K., Dougher M.M., Sridharan L., et al. Antibody-targeted chemotherapy with CMC-544: A CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 2004; 103 (5): 1807–14.
9. De Vries J.F., Zwaan C.M., De Bie M., Voerman J.S.A., den Boer M.L., van Dongen J.J.M., et al. The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells. Leukemia 2012; 26 (2): 255–64.
10. Kantarjian H.M., DeAngelo D.J., Stelljes M., Liedtke M., Stock W., Gökbuget N., et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INOVATE study. Cancer 2019; 125 (14): 2474–87.
11. Lanza F., Maffini E., Rondoni M., Massari E., Faini A.C., Malavasi F. CD22 expression in b-cell acute lymphoblastic leukemia: Biological significance and implications for inotuzumab therapy in adults. Cancers 2020; 12 (2): 303.
12. Iwamoto S., Deguchi T., Ohta H., Kiyokawa N., Tsurusawa M., Yamada T., et al. Flow cytometric analysis of de novo acute lymphoblastic leukemia in childhood: Report from the Japanese Pediatric Leukemia/Lymphoma Study Group. Int J Hematol 2011; 94 (2): 185–92.
13. Shah N.N., Stevenson M.S., Yuan C.M., Richards K., Delbrook C., Kreitman R.J., et al. Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatr Blood Cancer 2015; 62 (6): 964–9.
14. Bhojwani D., Sposto R., Shah N.N., Rodriguez V., Yuan C., Stetler-Stevenson M., et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia 2019; 33 (4): 884–92.
15. Calvo C., Cabannes-Hamy A., Adjaoud D., Bruno B., Blanc L., Boissel N., et al. Inotuzumab ozogamicin compassionate use for French paediatric patients with relapsed or refractory CD22-positive B-cell acute lymphoblastic leukaemia. Br J Haematol 2020; 190 (1): e53–6. DOI: 10.1111/bjh.16732
16. Brivio E., Locatelli F., LopezYurda M., Malone A., Diaz de Heredia C., Bielorai B., et al. A Phase I study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study). Blood 2021; 137 (12): 1582–90.
17. O’Brien M.M., Ji L., Shah N.N., Rheingold S.R., Bhojwani D., Yuan C.M., et al. Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children’s Oncology Group Protocol AALL1621. J Clin Oncol 2022; 40 (9): 956–67.
18. [Electronic resource]. URL: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf (accessed 20.02.2023).
19. Pennesi E., Michels N., Brivio E., van der Velden V.H.J., Jiang Y., Thano A., et al. Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial. Leukemia 2022; 36 (6): 1516–24.
20. Brivio E., Chantrain C.F., Gruber T.A., Thano A., Rialland F., Contet A., et al. Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series. Br J Haematol 2021;193 (6): 1172–7.
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