Блинатумомаб в лечении острого лимфобластного лейкоза у пациентов детского возраста: опыт одного центра

Актуальность. Несмотря на достигнутые успехи в лечении B-клеточного острого лимфобластного лейкоза (В-ОЛЛ), актуальными вопросами остаются преодоление токсичности стандартных режимов химиотерапии и лечение рефрактерных и рецидивирующих (р/р) форм заболевания. Наиболее перспективной опцией является применение иммунотерапии (ИТ), в том числе моноклонального антитела блинатумомаба (БМ).

Цель исследования. Проанализировать показания к применению, эффективность и переносимость БМ у детей с В-ОЛЛ.

Материалы и методы. За период c апреля 2016 по январь 2024 гг. выполнена ретроспективная оценка случаев применения БМ у детей с В-ОЛЛ в отделении химиотерапии онкогематологических заболеваний и ТКМ для детей ФГБУ «НМИЦ им. В. А. Алмазова» Минздрава России.

Результаты. В исследование включено 53 пациента, из них 28 (53 %) девочек и 25 (47 %) мальчиков с медианой возраста 7,7 (2,08–19,8) года. Показаниями к назначению БМ были следующие: 1) консолидация ремиссии (КР) при первичном В-ОЛЛ (n = 17, 32 %); 2) персистенция минимальной остаточной болезни (МОБ) (n = 23, 43 %) после завершения индукционной химиотерапии (ХТ) или перед этапом аллогенная трансплантация гемопоэтических стволовых клеток (аллоТГСК); 3) замена стандартной КР в связи с предшествующей токсичностью ХТ или иными противопоказаниями к ее проведению (n = 12, 23 %); 4) терапия спасения при р/р ОЛЛ (n = 1, 1,9 %). Статус МОБ-негативной ремиссии после 1-го курса ИТ достигнут в 89 % случаев. Терапия с применением БМ у пациента с р/р формой ОЛЛ и тотальной бластной инфильтрацией костного мозга была эффективной и позволила редуцировать опухолевую популяцию до 7,2 % к 15 дню терапии, тем не менее, имел место летальный исход, обусловленный предшествующим развитием и прогрессированием тяжелой инфекции. Наиболее частыми вариантами токсичности III–IV степени были лейко-/нейтропения (28 %) и нейротоксичность (3,7 %). Редукция дозы БМ с целью купирования токсичности потребовалась 19 % пациентов, при этом медиана дней терапии с редукцией дозы составила 4. Глюкокортикостероиды с указанной целью применялись в 11 % случаев, антибактериальная терапия — в 13 %. На момент оценки результатов в исследуемой группе больных рецидивов заболевания зарегистрировано не было. В статье проанализирован международный опыт использования БМ у пациентов с В-ОЛЛ.

Заключение. Наш опыт и представленные литературные данные демонстрируют обоснованное расширение показаний к применению БМ у детей с В-ОЛЛ с высокой эффективностью и удовлетворительным профилем токсичности.

1. Pfister SM, et al. A summary of the inaugural WHO classification of pediatric tumors: transitioning from the optical into the molecular era //Cancer discovery. 2022. Vol. 12. No. 2. P. 331–355.

2. Ferlay J, et al. Cancer statistics for the year 2020: An overview //International journal of cancer. 2021. Vol. 149. No. 4. P. 778–789.

3. Moorman AV, et al. Time to cure for childhood and young adult acute lymphoblastic leukemia is independent of early risk factors: long-term follow-up of the UKALL2003 trial //Journal of Clinical Oncology. 2022. Vol. 40. No. 36. P. 4228–4239.

4. Jeha S, et al. Improved CNS control of childhood acute lymphoblastic leukemia without cranial irradiation: St Jude Total Therapy Study 16 //Journal of Clinical Oncology. 2019. Vol. 37. No. 35. P. 3377.

5. Inaba H, Pui CH. Advances in the diagnosis and treatment of pediatric acute lymphoblastic leukemia // Journal of clinical medicine. 2021. Vol. 10. No. 9. P. 1926.

6. Lew G, et al. Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children’s Oncology Group phase III study AALL0433 //Haematologica. 2021. Vol. 106. No. 1. P. 46.

7. Locatelli F, et al. Effect of blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse B-cell acute lymphoblastic leukemia: a randomized clinical trial //Jama. 2021. Vol. 325. No. 9. P. 843–854.

8. Li B, et al. Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia //Blood, The Journal of the American Society of Hematology. 2020. Vol. 135. No. 1. P. 41–55.

9. Ekpa QL, et al. A Review of Acute Lymphocytic Leukemia (ALL) in the Pediatric Population: Evaluating Current Trends and Changes in Guidelines in the Past Decade //Cureus. 2023. Vol. 15. No. 12.

10. Lejman M, et al. Targeted Therapy in the Treatment of Pediatric Acute Lymphoblastic Leukemia — Therapy and Toxicity Mechanisms //International Journal of Molecular Sciences. 2021. Vol. 22. No. 18. P. 9827.

11. Schmiegelow K, et al. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy //F1000Research. 2017. Vol. 6.

12. Elitzur S, et al. Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B-cell precursor acute lymphoblastic leukemia: report from the Israeli Study Group of Childhood Leukemia //Pediatric Blood & Cancer. 2019. Vol. 66. No. 10. P. e27898.

13. Mengxuan S, Fen Z, Runming J. Novel treatments for pediatric relapsed or refractory acute B-cell lineage lymphoblastic leukemia: precision medicine era // Frontiers in Pediatrics. 2022. Vol. 10. P. 923419.

14. Logan AC. Measurable residual disease in acute lymphoblastic leukemia: How low is low enough? //Best Practice & Research Clinical Haematology. 2022. Vol. 35. No. 4. P. 101407.

15. Truong TH, et al. Allogeneic hematopoietic stem cell transplantation for children with acute lymphoblastic leukemia: shifting indications in the era of immunotherapy //Frontiers in Pediatrics. 2021. Vol. 9. P. 782785.

16. Olsson RF, et al. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies Leukemia. 2015. Vol. 29. No. 8. P. 1754–1762.

17. Inaba H, Pui CH. Immunotherapy in pediatric acute lymphoblastic leukemia //Cancer and Metastasis Reviews. 2019. Vol. 38. No. 4. P. 595–610.

18. Queudeville M, Ebinger M. Blinatumomab in pediatric acute lymphoblastic leukemia — from salvage to first line therapy (a systematic review) //Journal of clinical medicine. 2021. Vol. 10. No. 12. P. 2544.

19. Mocquot P, et al. The pharmacology of blinatumomab: state of the art on pharmacodynamics, pharmacokinetics, adverse drug reactions and evaluation in clinical trials //Journal of Clinical Pharmacy and Therapeutics. 2022. Vol. 47. No. 9. P. 1337–1351.

20. Ojemolon PE, et al. Cytokine release syndrome following blinatumomab therapy //Cureus. 2022. Vol. 14. No. 1.

21. Jen EY, et al. FDA approval: blinatumomab for patients with B-cell precursor acute lymphoblastic leukemia in morphologic remission with minimal residual disease //Clinical Cancer Research. 2019. Vol. 25. No. 2. P. 473–477.

22. von Stackelberg A, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/ refractory acute lymphoblastic leukemia //Journal of Clinical Oncology. 2016. Vol. 34. No. 36. P. 4381–4389.

23. Locatelli F, et al. Blinatumomab in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis //Blood advances. 2022. Vol. 6. No. 3. P. 1004–1014.

24. Zeng Y, Katsanis E. Potential niche indications for blinatumomab as a bridge to hematopoietic cell transplantation //Bone Marrow Transplantation. 2017. Vol. 52. No. 12. P. 1671–1673.

25. Clinicaltrials.gov. Blinatumomab in Pediatric B-cell Acute Lymphoblastic Leukemia (ALL) With Minimal Residual Disease (MRD). Available at: www.clinicaltrials. gov (NCT04604691).

26. Clinicaltrials.gov. Diagnosed From 0 to 365 Days of Life (ALL-Baby-2021). Available at: www.clinicaltrials. gov (NCT05029531).

27. Cinicaltrials.gov. Blinatumomab Maintenance Following Allogeneic Hematopoietic Cell Transplantation for Patients With Acute Lymphoblastic Leukemia. Available at: www.clinicaltrials.gov (NCT02807883).

28. Brown PA, et al. A randomized phase 3 trial of blinatumomab vs. chemotherapy as post-reinduction therapy in high and intermediate risk (HR/IR) first relapse of B-acute lymphoblastic leukemia (B-ALL) in children and adolescents/young adults (AYAs) demonstrates superior efficacy and tolerability of blinatumomab: a report from Children’s Oncology Group Study AALL1331 //Blood. 2019. Vol. 134. P. LBA-1.

29. Locatelli F, et al. Effect of blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse B-cell acute lymphoblastic leukemia: a randomized clinical trial //Jama. 2021. Vol. 325. No. 9. P. 843–854.

30. Clesham K, et al. Blinatumomab for infant acute lymphoblastic leukemia //Blood, The Journal of the American Society of Hematology. 2020. Vol. 135. No. 17. P. 1501–1504.

31. Hodder A, et al. Blinatumomab As Toxicity Sparing First Line Treatment of Children and Young Persons with B-Precursor Acute Lymphoblastic Leukaemia (B-ALL) // Blood. 2022. Vol. 140. No. Supplement 1. P. 8987-8988.

32. Li AM, et al. Blinatumomab associated seizure risk in patients with Down syndrome and B-lymphoblastic leukemia: an interim report from Children’s Oncology Group (COG) study AALL1731 // Blood. 2021. Vol. 138. P. 2304.

33. Rabin KR, et al. Treatment-Related Mortality (TRM) in children with down syndrome (DS) and B-lymphoblastic leukemia (B-ALL): an interim report from the children’s oncology group trials AALL0932 and AALL1131 //Blood. 2015. Vol. 126. No. 23. P. 2502.

34. Buitenkamp TD, et al. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group //Blood, The Journal of the American Society of Hematology. 2014. Vol. 123. No. 1. P. 70–77.

35. Sora F, et al. Blinatumomab as a successful and safe therapy in Down syndrome patients with relapsed/ refractory b-precursor acute lymphoblastic leukaemia: case reports and literature review //Pediatric blood & cancer. 2021. Vol. 68. No. 7. P. e29044.

36. Collignon C, et al. Temporary contraindication to chemotherapy due to toxicity: blinatumomab’s effectiveness in paediatric patients with B-acute lymphoblastic leukaemia //British journal of haematology. 2023. Vol. 201. No. 4. P. e42–e45.

37. van der Sluis IM, et al. Blinatumomab added to chemotherapy in infant lymphoblastic leukemia //New England Journal of Medicine. 2023. Vol. 388. No. 17. P.

38. –1581. 38. Pieters R, et al. Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the interfant-06 protocol: results from an international phase III randomized study //Journal of clinical oncology. 2019. Vol. 37. No. 25. P. 2246–2256.

39. Elitzur S, et al. Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B‐cell precursor acute lymphoblastic leukemia: report from the Israeli Study Group of Childhood Leukemia //Pediatric Blood & Cancer. 2019. Vol. 66. No. 10. P. e27898.

40. Zeng Y, Katsanis E. Potential niche indications for blinatumomab as a bridge to hematopoietic cell transplantation //Bone Marrow Transplantation. 2017. Vol. 52. No. 12. P. 1671–1673.

41. Queudeville M, et al. Blinatumomab in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia //European Journal of Haematology. 2021. Vol. 106. No. 4. P. 473–483.

42. Clinicaltrials.gov. Acute Lymphoblastic Leukemia Treatment Protocol Moscow-Berlin 2019 Pilot. The head of the protocol and principal investigator — Doctor of Medical Sciences, Professor A. I. Karachunsky. Available at: www.clinicaltrials.gov (NCT04723342).

43. Institute NC. Common terminology criteria for adverse events (CTCAE), version 5.0. National Cancer Institute; 2017, Nov 27. Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Common terminology criteria for adverse events (CTCAE), version 5.0. National Cancer Institute; 2017, Nov 27.

44. Zhao Y, et al. Tumor-intrinsic and-extrinsic determinants of response to blinatumomab in adults with B-ALL //Blood, The Journal of the American Society of Hematology. 2021. Vol. 137. No. 4. P. 471–484.

45. Mirfakhraie R, et al. All about blinatumomab: the bispecific T cell engager immunotherapy for B cell acute lymphoblastic leukemia //Hematology, Transfusion and Cell Therapy. 2023.

46. ‐mpatzidou ‐, et al. Insights from the Greek experience of the use of Blinatumomab in pediatric relapsed and refractory acute lymphoblastic leukemia patients //Neoplasma. 2020. Vol. 67. No. 6. P. 1424–1430.

47. Philipp N, et al. T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals //Blood, The Journal of the American Society of Hematology. 2022. Vol. 140. No. 10. P. 1104–1118.

48. Wei AH, et al. Biomarkers associated with blinatumomab outcomes in acute lymphoblastic leukemia //Leukemia. 2021. Vol. 35. No. 8. P. 2220–2231.

49. Chauvet P, et al. Combining blinatumomab and donor lymphocyte infusion in B-ALL patients relapsing after allogeneic hematopoietic cell transplantation: a study of the SFGM-TC //Bone marrow transplantation. 2023. Vol. 58. No. 1. P. 72–79.

50. Muriano F, et al. P350: Blinatumomab and donor lymphocyte infusion (DLI) for molecular relapse after hematopoietic stem cell transplantation in pediatric patients //HemaSphere. 2022. Vol. 6. P. 250–251.

51. Clinicaltrials.gov. A Phase 2 Study of Blinatumomab in Combination With Nivolumab, a Checkpoint Inhibitor of PD-1, in B-ALL Patients Aged ≥ 1 to 31 Years Old With First Relapse. Available at: www. clinicaltrials.gov (NCT04546399).

52. Choi HJ, et al. Combination therapy with chemotherapy, donor lymphocyte infusion with concurrent Blinatumomab in relapsed/refractory acute precursor B-lymphoblastic leukemia //Journal of Pediatric Hematology/Oncology. 2021. Vol. 43. No. 2. P. e280–e283.

53. Xie J, et al. Short-course blinatumomab for refractory/relapse precursor B acute lymphoblastic leukemia in children //Frontiers in Pediatrics. 2023. Vol. 11.

54. Collignon C, et al. Temporary contraindication to chemotherapy due to toxicity: blinatumomab’s effectiveness in paediatric patients with B-acute lymphoblastic leukaemia //British journal of haematology. 2023. Vol. 201. No. 4. P. e42–e45.