Using academic chimeric antigen receptor t-cells in adult patients with relapsed/refractory acute B-lymphoblastic leukemia/lymphoma

Introduction. Long-term survival rates in patients with refractory/relapsed acute B-lymphoblastic leukemia/lymphoma (r/r B-ALL/LBL) remain extremely poor. The introduction of Chimeric Antigen Receptor T-cell (CAR T) therapy into clinical practice offers a new promising treatment option for this group of patients.

Aim: to evaluate the efficacy of anti-CD19 and anti-CD19/22 CAR T-cell therapy in 8 adult patients with r/r B-ALL/LBL.

Materials and methods. Between January 1, 2020 and July 1, 2024, as part of the NRCH-CAR T-2020 pilot study the National Medical Research Center for Hematology conducted anti-CD19/anti-CD19/22 CAR T cell therapy for 8 adult patients with refractory B-ALL/LBL under the hospital exemption rule. The median age was 28 (19–37) years. The male to female ratio was 5:3. The median number of previous treatment lines was 3 (2–7). All patients underwent leukocytapheresis and lymphodepletion with fludarabine (120 mg/m2 ) and cyclophosphamide (750 mg/m2 ) on days –5 to –2 of therapy. Cytokine release syndrome (CRS) prophylaxis was administered with tocilizumab on day 0 before CAR-T lymphocyte administration.

Results. 8 patients with r/r B-ALL underwent 11 infusions of academic anti-CD19 and anti-CD19/22 CART-lymphocytes. Six patients were infused with anti-CD19 CAR T-cells, 2 patients with anti-CD19/CD22 CAR T-cells. Six patients underwent infusion of autologous CAR T-cells, and 2 patients with allogeneic CAR T-cells. The median of infused CAR T-lymphocytes was 0.625 (0.1–2.5) × 106 CAR+ cells/kg. Immune complications were noted in 3 of 8 patients (37.5 %): CRS in 2 patients, ICANS (immune effector cell-associated neurotoxicity syndrome) grade 3, and CRS grade 1 in 1 patient. All patients achieved complete remission by day 28 after CAR T-therapy. The median follow-up period was 12 months (2–42 months). Three patients (37.5 %) died from B-ALL/LBL relapse or progression. Five patients (62.5 %) are under observation. Three of these patients, who achieved complete remission after CAR T therapy, underwent allogeneic hematopoietic stem cell transplantation (alloHSCT).

Conclusion. CAR T-cell therapy is a promising treatment option for patients with r/r B-ALL. Allo-HSCT after CAR T likely resulted in optimistic long-term survival outcomes.

1. Jabbour E., Short N.J., Jain N., et al. The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades. J Hematol Oncol. 2023;16(1):22. DOI: 10.1186/s13045-023-01409-5.

2. Gökbuget N., Boissel N. Chiaretti, S., et al. Management of ALL in adults: 2024 ELN recommendations from a European expert panel. Blood. 2024;143(19):1903–30. DOI: 10.1182/blood.2023023568.

3. Frey N.V. Approval of brexucabtagene autoleucel for adults with relapsed and refractory acute lymphocytic leukemia. Blood. 2022;140(1):11–5. DOI: 10.1182/blood.2021014892.

4. Maude S.L., Laetsch T.W., Buechner J., et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):439–48. DOI: 10.1056/NEJMoa1709866.

5. Roddie С., Sandhu K., Tholouli E. Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia. 2024;391:2219–23. DOI: 10.1056/NEJMoa2406526.

6. Zhang X., Yang J., Li J., et al. Factors associated with treatment response to CD19 CAR-T therapy among a large cohort of B cell acute lymphoblastic leukemia. Cancer Immunol Immunother. 2022;71(3):689–703. DOI: 10.1007/s00262-021-03009-z.

7. Pasquini M.C, Hu Z.H., Curran K., et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4(21):5414–24. DOI: 10.1182/bloodadvances.2020003092.

8. Rafiq S., Brentjens R.J., Rivière I. CAR T-cell therapy for B-cell acute lymphoblastic leukemia: an update on clinical trials and new advances. Exp Rev Hematol. 2020;13(10):1081–93. DOI: 10.1080/17474086.2020.1819785.

9. Shah N.N., Johnson B.D., Schneider D., et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020:1569–75. DOI: 10.1038/s41591-020-1081-3.

10. Dai H., Wu Z., Jia H., et al. Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia. J Hematol Oncol. 2020;13(1):30. DOI: 10.1186/s13045-020-00856-8.

11. Willyanto S.E., Alimsjah Y.A., Tanjaya K., et al. Comprehensive analysis of the efficacy and safety of CAR T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: a systematic review and meta-analysis. Ann Med. 2024;56(1):2349796. DOI: 10.1080/07853890.2024.2349796.

12. Montagna, E., de Campos N.S.P., Porto V.A., et al. CD19 CAR T cells for B cell malignancies: a systematic review and meta-analysis focused on clinical impacts of CAR structural domains, manufacturing conditions, cellular product, doses, patient’s age, and tumor types. BMC Cancer. 2024;24:1037. DOI: 10.1186/s12885-024-12651-6.

13. Fielding A.K., Richards S.M., Chopra R., et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944–50. DOI: 10.1182/blood-2006-05-018192.

14. Cao L.Y., Zhao Y., Chen Y., et al. CAR-T cell therapy clinical trials: global progress, challenges, and future directions from ClinicalTrials.gov insights. Front Immunol. 2025;16:1583116. DOI: 10.3389/fimmu.2025.1583116.

15. https://clinline.ru/reestr-klinicheskih-issledovanij/536-11.11.2024.html

16. Myers R.M., Taraseviciute A., Steinberg S.M., et al. 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.

17. Ceolin V., Brivio E., van Tinteren H., et al. Outcome of chimeric antigen receptor T-cell therapy following treatment with inotuzumab ozogamicin in children with relapsed or refractory acute lymphoblastic leukemia. Leukemia. 2023;37(1):53–60. DOI: 10.1038/s41375-022-01740-9.

18. Gavrilina O.A., Galstyan G.M., Shchekina A.E. Chimeric antigen receptor T-cell therapy for adult patients with B-cell lymphoproliferative diseases. Gematologiya I Transfusiologiya. 2022;67(1):8–28 (In Russian). DOI: 10.35754/0234-5730-2022-67-1-8-28.

19. Shchekina A.E., Galstyan G.M., Gavrilina O.A., et al. Extracorporeal sorption of cytokines in cytokine release syndrome in a patient with acute lymphoblastic leukemia after therapy with chimeric antigen receptor T cells. Therapevticheskiy Arkhive. 2021;93(7):811–7 (In Russian). DOI: 10.26442/00403660.2021.07.200931.

20. Malakhova E.A., Pershin D.E., Vedmedskaia V.A., et al. Comparative characterization of the cell composition and functional properties of anti-CD19 biomedical cell products manufactured using the CliniMACS Prodigy and G-Rex platforms. Voprosy Gematologii/Onkologii I Immunopatologii v Pediatrii. 2024;23(2):128– 39 (In Russian). DOI: 10.24287/1726-1708-2024-23-2-128-139.