Актуальные вопросы применения блинатумомаба у детей с острыми лейкозами. Обзор по материалам сателлитного симпозиума «Лечение лейкозов. Вчера, сегодня, завтра»

1. Hunger S.P., Mullighan C.G. Acute Lymphoblastic Leukemia in Children. N Engl J Med. 2015;373(16):1541–52. doi: 10.1056/NEJMra1400972.

2. Tallen G., Ratei R., Mann G., Kaspers G., Niggli F., Karachunsky A., Ebell W., Escherich G., Schrappe M., Klingebiel T., Fengler R., Henze G., von Stackelberg A. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. 2010;28(14):2339–47. doi: 10.1200/JCO.2009.25.1983.

3. von Stackelberg A., Völzke E., Kühl J.S., Seeger K., Schrauder A., Escherich G., Henze G., Tallen G.; ALL-REZ BFM Study Group. Outcome of children and adolescents with relapsed acute lymphoblastic leukaemia and non-response to salvage protocol therapy: a retrospective analysis of the ALL-REZ BFM Study Group. Eur J Cancer. 2011;47(1):90–7. doi: 10.1016/j.ejca.2010.09.020.

4. Rabinovich G.A., Gabrilovich D., Sotomayor E.M. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–96. doi: 10.1146/annurev.immunol.25.022106.141609.

5. Baeuerle P.A., Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009;69(12):4941–4. doi: 10.1158/0008-5472.CAN-09-0547.

6. Bargou R., Leo E., Zugmaier G., Klinger M., Goebeler M., Knop S., Noppeney R., Viardot A., Hess G., Schuler M., Einsele H., Brandl C., Wolf A., Kirchinger P., Klappers P., Schmidt M., Riethmüller G., Reinhardt C., Baeuerle P.A., Kufer P. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321(5891):974–7. doi: 10.1126/science.1158545.

7. Topp M.S., Gökbuget N., Zugmaier G., Klappers P., Stelljes M., Neumann S., Viardot A., Marks R., Diedrich H., Faul C., Reichle A., Horst H.A., Brüggemann M., Wessiepe D., Holland C., Alekar S., Mergen N., Einsele H., Hoelzer D., Bargou R.C. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134–40. doi: 10.1200/JCO.2014.56.3247.

8. von Stackelberg A., Locatelli F., Zugmaier G., Handgretinger R., Trippett T.M., Rizzari C., Bader P., OʼBrien M.M., Brethon B., Bhojwani D., Schlegel P.G., Borkhardt A., Rheingold S.R., Cooper T.M., Zwaan C.M., Barnette P., Messina C., Michel G., DuBois S.G., Hu K., Zhu M., Whitlock J.A., Gore L. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/ Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016;34(36):4381–9. doi: 10.1200/JCO.2016.67.3301.

9. Locatelli F., Zugmaier G., Mergen N., Bader P., Jeha S., Schlegel P.G., Bourquin J.P., Handgretinger R., Brethon B., Rossig C., Chen-Santel C. Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the RIALTO trial, an expanded access study. Blood Cancer J. 2020;10(7):77. doi: 10.1038/s41408-020-00342-x. Erratum in: Blood Cancer J. 2021;11(2):28. doi: 10.1038/s41408-021-00413-7. Erratum in: Blood Cancer J. 2021;11(10):173. doi: 10.1038/s41408-021-00567-4.

10. Locatelli F., Zugmaier G., Rizzari C., Morris J.D., Gruhn B., Klingebiel T., Parasole R., Linderkamp C., Flotho C., Petit A., Micalizzi C., Mergen N., Mohammad A., Kormany W.N., Eckert C., Möricke A., Sartor M., Hrusak O., Peters C., Saha V., Vinti L., von Stackelberg A. 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;325(9):843–54. doi: 10.1001/jama.2021.0987.

11. DiNardo C.D., Konopleva M.Y. A venetoclax bench-to-bedside story. Nat Cancer. 2021;2(1):3–5. doi: 10.1038/s43018-020-00165-6.

12. DiNardo C.D., Pratz K., Pullarkat V., Jonas B.A., Arellano M., Becker P.S., Frankfurt O., Konopleva M., Wei A.H., Kantarjian H.M., Xu T., Hong W.J., Chyla B., Potluri J., Pollyea D.A., Letai A. Venetoclax combined with decitabine or azacitidine in treatmentnaive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. doi: 10.1182/blood-2018-08-868752.

13. Karol S.E., Alexander T.B., Budhraja A., Pounds S.B., Canavera K., Wang L., Wolf J., Klco J.M., Mead P.E., Das Gupta S., Kim S.Y., Salem A.H., Palenski T., Lacayo N.J., Pui C.H., Opferman J.T., Rubnitz J.E. Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. Lancet Oncol. 2020;21(4):551–60. doi: 10.1016/S1470-2045(20)30060-7.

14. Winters A.C., Maloney K.W., Treece A.L., Gore L., Franklin A.K. Single-center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia. Pediatr Blood Cancer. 2020;67(10):e28398. doi: 10.1002/pbc.28398.

15. Bobeff K., Pastorczak A., Urbanska Z., Balwierz W., Juraszewska E., Wachowiak J., Derwich K., Samborska M., Kalwak K., Dachowska- Kalwak I., Laguna P., Malinowska I., Smalisz K., Gozdzik J., Oszer A., Urbanski B., Zdunek M., Szczepanski T., Mlynarski W., Janczar S. Venetoclax use in paediatric haemato-oncology centres in Poland: a 2022 survey. Children (Basel). 2023;10(4):745. doi: 10.3390/children10040745.

16. Pfeiffer T., Li Y., Karol S.E. Venetoclax-based combination therapy as a bridge to allogeneic hematopoietic stem cell transplant in children with relapsed/refractory AML. Transplant Cell Ther. 2022;28(3):S120–S121.

17. Place A.E., Karol S.E., Forlenza C.J., Cooper T.M., Fraser C., Cario G., OʼBrien M.M., Gerber N.U., Bourquin J.P., Reinhardt D., Rubnitz J.E., Opferman J.T., Sunkersett G., Onishi M., Dunshee D.R., Chen X., Unnebrink K., Vishwamitra D., Dunbar F., Badawi M., Ross J.A., Loh M.L. Venetoclax Combined With Chemotherapy in Pediatric and Adolescent/Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. Pediatr Blood Cancer. 2025;72(6):e31630. doi: 10.1002/pbc.31630.

18. Ma J., Luong A., Doan A., Lin T.Y., Ji L., Wang C.P., Yoon S.J., Rushing T., Duong A., Villa M., Parekh C. T-cell dysfunction during blinatumomab therapy in pediatric acute lymphoblastic leukemia. Blood Adv. 2025;9(15):3689–93. doi: 10.1182/bloodadvances.2025015894.

19. Глуханюк Е.В., Степанов А.В., Попов А.М., Масчан М.А. Механизмы резистентности В-линейного острого лимфобластного лейкоза при применении CD19-направленной иммунотерапии. Онкогематология. 2018;13(4):27–36. doi: 10.17650/1818-8346-2019- 13-4-27-36.

20. Sotillo E., Barrett D.M., Black K.L., Bagashev A., Oldridge D., Wu G., Sussman R., Lanauze C., Ruella M., Gazzara M.R., Martinez N.M., Harrington C.T., Chung E.Y., Perazzelli J., Hofmann T.J., Maude S.L., Raman P., Barrera A., Gill S., Lacey S.F., Melenhorst J.J., Allman D., Jacoby E., Fry T., Mackall C., Barash Y., Lynch K.W., Maris J.M., Grupp S.A., Thomas-Tikhonenko A. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5(12):1282–95. doi: 10.1158/2159-8290.CD-15-1020.

21. Braig F., Brandt A., Goebeler M., Tony H.P., Kurze A.K., Nollau P., Bumm T., Böttcher S., Bargou R.C., Binder M. Resistance to antiCD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood. 2017;129(1):100–4. doi: 10.1182/blood-2016-05-718395.

22. Susa K.J., Seegar T.C., Blacklow S.C., Kruse A.C. A dynamic interaction between CD19 and the tetraspanin CD81 controls B cell co-receptor trafficking. Elife. 2020;9:e52337. doi: 10.7554/eLife.52337.

23. Зеркаленкова Е.А., Илларионова О.И., Казакова А.Н., Пономарева Н.И., Байдун Л.В., Осипова Е.Ю., Дубровина М.Э., Попов А.М., Конюхова Т.В., Плясунова С.А., Мякова Н.В., Масчан А.А., Ольшанская Ю.В. Смена линейной дифференцировки в рецидиве острого лейкоза с перестройкой гена MLL (KMT2A). Обзор литературы и описание случаев. Онкогематология. 2016;11(2):21–9. doi: 10.17650/1818-8346-2016-11-2-21-29.

24. Rayes A., McMasters R.L., OʼBrien M.M. Lineage Switch in MLL-Rearranged Infant Leukemia Following CD19-Directed Therapy. Pediatr Blood Cancer. 2016;63(6):1113–5. doi: 10.1002/pbc.25953.

25. Глуханюк Е.В., Илларионова О.И., Кашпор С.A., Плясунова С.A., Мякова Н.В., Масчан А.А., Попов А.M. Изменение экспрессии CD19 опухолевыми клетками при применении блинатумомаба у детей с рецидивами и рефрактерным течением В-линейного острого лимфобластного лейкоза. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2017;16(4):21–6. doi: 10.24287/1726-1708-2017-16-4-21-26.

26. Gardner R., Wu D., Cherian S., Fang M., Hanafi L.A., Finney O., Smithers H., Jensen M.C., Riddell S.R., Maloney D.G., Turtle C.J. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127(20):2406–10. doi: 10.1182/blood-2015-08-665547.

27. Köhnke T., Krupka C., Tischer J., Knösel T., Subklewe M. Increase of PD-L1 expressing B-precursor ALL cells in a patient resistant to the CD19/CD3-bispecific T cell engager antibody blinatumomab. J Hematol Oncol. 2015;8:111. doi: 10.1186/s13045-015-0213-6.

28. Саяпина М.С. Иммунорегуляторные функции ингибиторов PD-1/ PD-L1 и развитие к ним резистентности. Злокачественные опухоли. 2017;(2):94–9. doi: 10.18027/2224-5057-2017-2-94-99.

29. Wunderlich M., Manning N., Sexton C., OʼBrien E., Byerly L., Stillwell C., Perentesis J.P., Mulloy J.C., Mizukawa B. PD-1 Inhibition Enhances Blinatumomab Response in a UCB/PDX Model of Relapsed Pediatric B-Cell Acute Lymphoblastic Leukemia. Front Oncol. 2021;11:642466. doi: 10.3389/fonc.2021.642466.

30. Zhang N., Hu W., Dai Y., Wang J., Qu L., Wang D., Liu B., Shao J., Shen S., Jiang H. Blinatumomab demonstrates MRD eradication in MRD-positive/chemotherapy-delayed pediatric B-ALL and high response in relapsed/refractory cases: a multicenter cohort study. Front Immunol. 2025;16:1607138. doi: 10.3389/fimmu.2025.1607138.

31. Duell J., Dittrich M., Bedke T., Mueller T., Eisele F., Rosenwald A., Rasche L., Hartmann E., Dandekar T., Einsele H., Topp M.S. Frequency of regulatory T cells determines the outcome of the T-cellengaging antibody blinatumomab in patients with B-precursor ALL. Leukemia. 2017;31(10):2181–90. doi: 10.1038/leu.2017.41.

32. Cheng Y., Liu A. Blinatumomab in pediatric B-acute lymphoblastic leukemia. Front Immunol. 2025;16:1611701. doi: 10.3389/fimmu.2025.1611701.

33. Webster J., Luskin M., Prince G., Dezern A., DeAngelo D., Levis M., Blackford A., Sharon E., Streicher H., Luznik L., Gojo I. Blinatumomab in Combination with Immune Checkpoint Inhibitors of PD-1 and CTLA-4 in Adult Patients with Relapsed/Refractory (R/R) CD19 Positive B-Cell Acute Lymphoblastic Leukemia (ALL): Preliminary Results of a Phase I Study. Blood. 2018;132:557. doi: 10.1182/blood-2018-99-111845.

34. Stolz S.M., Hofer K.D., Rösler W., Deuel J., Schwotzer R., Schneidawind C., Schneidawind D., Manz M.G., Rieger M.J. Tyrosine kinase inhibitors with blinatumomab versus chemotherapy in Philadelphia-positive acute B-lymphoblastic leukemia. Int J Cancer. 2025;157(6):1197–204. doi: 10.1002/ijc.35468.

35. Kong J., Miao W., Lu J., Liu Y., Kong X., Qiu H., Song B. Shorter Duration of Blinatumomab Administration to 14 Days Has Same Efficacy and Safety Profile in Treatment of Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: A Retrospective Single-Center Study. Acta Haematol. 2025;148(4):437–42. doi: 10.1159/000542060.

36. Hall A.G., Rau R.E. Blinatumomab use in pediatric B-ALL: where are we now? Blood Adv. 2025;9(15):3946–54. doi: 10.1182/bloodadvances.2024014043.

37. Handgretinger R., Zugmaier G., Henze G., Kreyenberg H., Lang P., von Stackelberg A. Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia. Leukemia. 2011;25(1):181–4. doi: 10.1038/leu.2010.239.

38. Locatelli F., Zugmaier G., Mergen N., Bader P., Jeha S., Schlegel P.G., Bourquin J.P., Handgretinger R., Brethon B., Rössig C., Kormany W.N., Viswagnachar P., Chen-Santel C. Blinatumomab in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis. Blood Adv. 2022;6(3):1004–14. doi: 10.1182/bloodadvances.2021005579.

39. Hogan L.E., Brown P.A., Ji L., Xu X., Devidas M., Bhatla T., Borowitz M.J., Raetz E.A., Carroll A., Heerema N.A., Zugmaier G., Sharon E., Bernhardt M.B., Terezakis S.A., Gore L., Whitlock J.A., Hunger S.P., Loh M.L. Childrenʼs Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. J Clin Oncol. 2023;41(25):4118–29. doi: 10.1200/JCO.22.02200.

40. Queudeville M., Ebinger M. Blinatumomab in Pediatric Acute Lymphoblastic Leukemia-From Salvage to First Line Therapy (A Systematic Review). J Clin Med. 2021;10(12):2544. doi: 10.3390/jcm10122544.

41. van der Sluis I.M., de Lorenzo P., Kotecha R.S., Attarbaschi A., Escherich G., Nysom K., Stary J., Ferster A., Brethon B., Locatelli F., Schrappe M., Scholte-van Houtem P.E., Valsecchi M.G., Pieters R. Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia. N Engl J Med. 2023;388(17):1572–81. doi: 10.1056/NEJMoa2214171.

42. Martins M.V., de Lorenzo P., Kotecha R.S., Attarbaschi A., Escherich G., Nysom K., Stary J., Ferster A., Brethon B., Locatelli F., Schrappe M., Scholte-van Houtem P.E., Valsecchi M.G., Huitema A.D.R., Pieters R., van der Sluis I.M. Sustained Benefit of Blinatumomab in Infants With KMT2A-Rearranged ALL: Long-Term Outcomes, Toxicity, and Pharmacokinetics. J Clin Oncol. 2026;44(5):370–4. doi: 10.1200/JCO-25-01806.

43. Gupta S., Rau R.E., Kairalla J.A., Rabin K.R., Wang C., Angiolillo A.L., Alexander S., Carroll A.J., Conway S., Gore L., Kirsch I., Kubaney H.R., Li A.M., McNeer J.L., Militano O., Miller T.P., Moyer Y., OʼBrien M.M., Okada M., Reshmi S.C., Shago M., Wagner E., Winick N., Wood B.L., Haworth-Wright T., Zaman F., Zugmaier G., Zupanec S., Devidas M., Hunger S.P., Teachey D.T., Raetz E.A., Loh M.L. Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. N Engl J Med. 2025;392(9):875–91. doi: 10.1056/NEJMoa2411680.

44. Maude S.L., Laetsch T.W., Buechner J., Rives S., Boyer M., Bittencourt H., Bader P., Verneris M.R., Stefanski H.E., Myers G.D., Qayed M., De Moerloose B., Hiramatsu H., Schlis K., Davis K.L., Martin P.L., Nemecek E.R., Yanik G.A., Peters C., Baruchel A., Boissel N., Mechinaud F., Balduzzi A., Krueger J., June C.H., Levine B.L., Wood P., Taran T., Leung M., Mueller K.T., Zhang Y., Sen K., Lebwohl D., Pulsipher M.A., Grupp S.A. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):439–48. doi: 10.1056/NEJMoa1709866.

45. Laetsch T.W., Maude S.L., Rives S., Hiramatsu H., Bittencourt H., Bader P., Baruchel A., Boyer M., De Moerloose B., Qayed M., Buechner J., Pulsipher M.A., Myers G.D., Stefanski H.E., Martin P.L., Nemecek E., Peters C., Yanik G., Khaw S.L., Davis K.L., Krueger J., Balduzzi A., Boissel N., Tiwari R., OʼDonovan D., Grupp S.A. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial. J Clin Oncol. 2023;41(9):1664–9. doi: 10.1200/JCO.22.00642.

46. Li A.M., Maude S.L. With BiTEs at the kiddie table, where do CARs come in for pediatric B-ALL? Hematology Am Soc Hematol Educ Program. 2025;2025(1):443–9. doi: 10.1182/hematology.2025000735.

47. Myers R.M., Taraseviciute A., Steinberg S.M., Lamble A.J., Sheppard J., Yates B., Kovach A.E., Wood B., Borowitz M.J., Stetler-Stevenson M., Yuan C.M., Pillai V., Foley T., Chung P., Chen L., Lee D.W., Annesley C., DiNofia A., Grupp S.A., John S., Bhojwani D., Brown P.A., Laetsch T.W., Gore L., Gardner R.A., Rheingold S.R., Pulsipher M.A., Shah N.N. Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL. J Clin Oncol. 2022;40(9):932–44. doi: 10.1200/JCO.21.01405.

48. Qi Y., Liu H., Li X., Shi Y., Mu J., Li J., Wang Y., Deng Q. Blinatumomab as salvage therapy in patients with relapsed/refractory B-ALL who have failed/progressed after anti-CD19-CAR T therapy. Ann Med. 2023;55(1):2230888. doi: 10.1080/07853890.2023.2230888.

49. Cao W., Li N., Wang G., Xu H., Yang Y., Wang J., Xu J., Li Y., Zhang Y., Cao Y., Wang N. Efficacy and safety comparison of CAR-T and blinatumomab immunotherapy as bridge-to-transplant strategies in relapsed/refractory B cell acute lymphoblastic leukemia. J Transl Med. 2025;23(1):391. doi: 10.1186/s12967-025-06399-1.

50. Leahy A.B., Newman H., Li Y., Liu H., Myers R., DiNofia A., Dolan J.G., Callahan C., Baniewicz D., Devine K., Wray L., Aplenc R., June C.H., Grupp S.A., Rheingold S.R., Maude S.L. CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials. Lancet Haematol. 2021;8(10):e711–22. doi: 10.1016/S2352-3026(21)00238-6.

51. Burtsev E.A., Filina O.A., Juravel M.R., Kurmanov B.M., Tiganova O.A., Kondratchik K.L., Tenovskaya T.А., Gorev V.V., Valieva S.I., Gadjieva S.M., Kumirova E.V. Initial experience of successful usage of industrial CAR-T therapy with the tisagenlecleucel product in children with refractory B-ALL. Cellular Therapy and Transplantation. 2025;14(4):56–63. doi: 10.18620/ctt-1866-8836-2025-14-4-56-63.