Top

Published in:

Open Access 01-12-2021 | Acute Lymphoblastic Leukemia | Original Article

CD19 CAR-T cell treatment conferred sustained remission in B-ALL patients with minimal residual disease

Authors: Wenyi Lu, Yunxiong Wei, Yaqing Cao, Xia Xiao, Qing Li, Hairong Lyu, Yili Jiang, Huan Zhang, Xin Li, Yanyu Jiang, Juanxia Meng, Ting Yuan, Haibo Zhu, Xiaoyuan He, Xin Jin, Rui Sun, Tao Sui, Kaiqi Liu, Mingfeng Zhao

Published in: Cancer Immunology, Immunotherapy | Issue 12/2021

Abstract

The persistence or recurrence of minimal residual disease (MRD) after chemotherapy predicts relapse of B-cell acute lymphoblastic leukemia (B-ALL). CD19-directed chimeric antigen receptor T (CD19 CAR-T) cells have shown promising responses in B-ALL. However, their role in chemotherapy-refractory MRD-positive B-ALL remains unclear. Here we aimed to assess the effectiveness and safety of CD19 CAR-T cells in MRD-positive B-ALL patients. From January 2018, a total of 14 MRD-positive B-ALL patients received one or more infusions of autogenous CD19 CAR-T cells. Among them, 12 patients achieved MRD-negative remission after one cycle of CAR-T infusion. At a median follow-up time of 647 days (range 172–945 days), the 2-year event-free survival rate in MRD-positive patients was 61.2% ± 14.0% and the 2-year overall survival was 78.6 ± 11.0%, which were significantly higher than patients with active disease (blasts ≥ 5% or with extramedullary disease). Moreover, patients with MRD had a lower grade of cytokine release syndrome (CRS) than patients with active disease. However, the peak expansion of CAR-T cells in MRD positive patients showed no statistical difference compared to patients with active disease. Five patients received two or more CAR-T cell infusions and these patients showed a decreased peak expansion of CAR-T cell in subsequent infusions. In conclusion, pre-emptive CD19 CAR-T cell treatment is an effective and safe approach and may confer sustained remission in B-ALL patients with chemotherapy-refractory MRD. The trials were registered at www.chictr.org.cn as ChiCTR-ONN-16009862 (November 14, 2016) and ChiCTR1800015164 (March 11, 2018).

Available only for authorised users

Bassan R, Bruggemann M, Radcliffe HS, Hartfield E, Kreuzbauer G, Wetten S (2019) A systematic literature review and meta-analysis of minimal residual disease as a prognostic indicator in adult B-cell acute lymphoblastic leukemia. Haematologica 104(10):2028–2039. https://doi.org/10.3324/haematol.2018.201053CrossRefPubMedPubMedCentral

Raff T, Gokbuget N, Luschen S, Reutzel R, Ritgen M, Irmer S, Bottcher S, Horst HA, Kneba M, Hoelzer D, Bruggemann M, Group GS (2007) Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials. Blood 109(3):910–915. https://doi.org/10.1182/blood-2006-07-037093CrossRefPubMed

Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509–1518. https://doi.org/10.1056/NEJMoa1215134CrossRefPubMedPubMedCentral

Davila ML, Brentjens RJ (2016) CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Clin Adv Hematol Oncol 14(10):802–808PubMedPubMedCentral

He X, Xiao X, Li Q, Jiang Y, Cao Y, Sun R, Jin X, Yuan T, Meng J, Ma L, Lu W, Lyu C, Liu K, Zhao M (2019) Anti-CD19 CAR-T as a feasible and safe treatment against central nervous system leukemia after intrathecal chemotherapy in adults with relapsed or refractory B-ALL [letter]. Leukemia 33(8):2102–2104. https://doi.org/10.1038/s41375-019-0437-5CrossRefPubMedPubMedCentral

Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA (2018) Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378(5):439–448. https://doi.org/10.1056/NEJMoa1709866CrossRefPubMedPubMedCentral

Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, Roshal M, Maslak P, Davila M, Brentjens RJ, Sadelain M (2018) Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 378(5):449–459. https://doi.org/10.1056/NEJMoa1709919CrossRefPubMedPubMedCentral

Lee DW, III, Stetler-Stevenson M, Yuan CM, Shah NN, Delbrook C, Yates B, Zhang H, Zhang L, Kochenderfer JN, Rosenberg SA, Fry TJ, Stroncek D, Mackall CL (2016) Long-term outcomes following CD19 CAR T cell therapy for B-ALL are superior in patients receiving a fludarabine/cyclophosphamide preparative regimen and post-car hematopoietic stem cell transplantation [abstract]. Blood 128 (22): Abstract 218

Cheng Y, Chen Y, Yan C, Wang Y, Zhao X, Chen Y, Han W, Xu L, Zhang X, Liu K, Wang S, Chang L, Xiao L, Huang X (2019) Donor-derived CD19-targeted T cell infusion eliminates B cell acute lymphoblastic leukemia minimal residual disease with no response to donor lymphocytes after allogeneic hematopoietic stem cell transplantation. Engineering 5(1):150–155. https://doi.org/10.1016/j.eng.2018.12.006CrossRef

10.

Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124(2):188–195. https://doi.org/10.1182/blood-2014-05-552729CrossRefPubMedPubMedCentral

11.

Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, Komanduri KV, Lin Y, Jain N, Daver N, Westin J, Gulbis AM, Loghin ME, de Groot JF, Adkins S, Davis SE, Rezvani K, Hwu P, Shpall EJ (2018) Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol 15(1):47–62. https://doi.org/10.1038/nrclinonc.2017.148CrossRefPubMed

12.

Jin X, Cao Y, Wang L, Sun R, Cheng L, He X, Xiao X, Jiang Y, Li Q, Zhang H, Lu W, Lyu C, Jiang Y, Meng J, Zhao M (2020) HLA-matched and HLA-haploidentical allogeneic CD19-directed chimeric antigen receptor T-cell infusions are feasible in relapsed or refractory B-cell acute lymphoblastic leukemia before hematopoietic stem cell transplantation [letter]. Leukemia 34(3):909–913. https://doi.org/10.1038/s41375-019-0610-xCrossRefPubMed

13.

Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M, Qu J, Wasielewska T, He Q, Fink M, Shinglot H, Youssif M, Satter M, Wang Y, Hosey J, Quintanilla H, Halton E, Bernal Y, Bouhassira DC, Arcila ME, Gonen M, Roboz GJ, Maslak P, Douer D, Frattini MG, Giralt S, Sadelain M, Brentjens R (2014) Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. https://doi.org/10.1126/scitranslmed.3008226CrossRefPubMedPubMedCentral

14.

Liu SY, Deng BP, PAN J, Yin ZC, Lin YH, Ling ZJ, Wu T, Gao ZY, Song YZ, Zhao YQ, Tong CR (2019) Corticosteroids do not influence the efficacy and kinetics of CAR-T cells for B-cell acute lymphoblastic leukemia [Abstract]. Blood 134 (Supplement_1): Abstract 228

15.

Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, Borquez-Ojeda O, Qu J, Wasielewska T, He Q, Bernal Y, Rijo IV, Hedvat C, Kobos R, Curran K, Steinherz P, Jurcic J, Rosenblat T, Maslak P, Frattini M, Sadelain M (2013) CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. https://doi.org/10.1126/scitranslmed.3005930CrossRefPubMedPubMedCentral

16.

Maude SL, Teachey DT, Porter DL, Grupp SA (2015) CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 125(26):4017–4023. https://doi.org/10.1182/blood-2014-12-580068CrossRefPubMedPubMedCentral

17.

Wei G, Hu Y, Pu C, Yu J, Luo Y, Shi J, Cui Q, Wu W, Wang J, Xiao L, Wu Z, Huang H (2018) CD19 targeted CAR-T therapy versus chemotherapy in re-induction treatment of refractory/relapsed acute lymphoblastic leukemia: results of a case-controlled study. Ann Hematol 97(5):781–789. https://doi.org/10.1007/s00277-018-3246-4CrossRefPubMed

18.

Amrolia PJ, Pule M (2015) Chimeric antigen receptor T cells for ALL. Lancet 385(9967):488–490. https://doi.org/10.1016/S0140-6736(14)61729-3CrossRefPubMed

19.

Zhao X, Yang J, Zhang X, Lu XA, Xiong M, Zhang J, Zhou X, Qi F, He T, Ding Y, Hu X, De Smet F, Lu P, Huang X (2020) Efficacy and safety of CD28- or 4–1BB-based CD19 CAR-T cells in B Cell acute lymphoblastic leukemia. Mol Ther Oncol 18:272–281. https://doi.org/10.1016/j.omto.2020.06.016CrossRef

20.

Zhang X, Lu XA, Yang J, Zhang G, Li J, Song L, Su Y, Shi Y, Zhang M, He J, Song D, Lv F, Li W, Wu Y, Wang H, Liu H, Zhou X, He T, Lu P (2020) Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features. Blood Adv 4(10):2325–2338. https://doi.org/10.1182/bloodadvances.2020001466CrossRefPubMedPubMedCentral

21.

Liu J, Zhang X, Zhong JF, Zhang C (2017) CAR-T cells and allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia. Immunotherapy 9(13):1115–1125. https://doi.org/10.2217/imt-2017-0072CrossRefPubMed

22.

Hu L, Charwudzi A, Li Q, Zhu W, Tao Q, Xiong S, Zhai Z (2021) Anti-CD19 CAR-T cell therapy bridge to HSCT decreases the relapse rate and improves the long-term survival of R/R B-ALL patients: a systematic review and meta-analysis. Ann Hematol 100(4):1003–1012. https://doi.org/10.1007/s00277-021-04451-wCrossRefPubMed

23.

Zhao XS, Liu YR, Xu LP, Wang Y, Zhang XH, Chen H, Chen YH, Han W, Sun YQ, Yan CH, Mo XD, Wang YZ, Fan QZ, Wang XY, Liu KY, Huang XJ, Chang YJ (2019) Minimal residual disease status determined by multiparametric flow cytometry pretransplantation predicts the outcome of patients with ALL receiving unmanipulated haploidentical allografts. Am J Hematol 94(5):512–521. https://doi.org/10.1002/ajh.25417CrossRefPubMed

24.

Liu J, Zhang X, Zhong JF, Zhang C (2019) Use of chimeric antigen receptor T cells in allogeneic hematopoietic stem cell transplantation. Immunotherapy 11(1):37–44. https://doi.org/10.2217/imt-2018-0089CrossRefPubMed

25.

Schubert ML, Huckelhoven A, Hoffmann JM, Schmitt A, Wuchter P, Sellner L, Hofmann S, Ho AD, Dreger P, Schmitt M (2016) Chimeric antigen receptor T cell therapy targeting CD19-positive leukemia and lymphoma in the context of stem cell transplantation. Hum Gene Ther 27(10):758–771. https://doi.org/10.1089/hum.2016.097CrossRefPubMed

26.

Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, Rossi G, Borlenghi E, Pogliani EM, Terruzzi E, Fabris P, Cassibba V, Lambertenghi-Deliliers G, Cortelezzi A, Bosi A, Gianfaldoni G, Ciceri F, Bernardi M, Gallamini A, Mattei D, Di Bona E, Romani C, Scattolin AM, Barbui T, Rambaldi A (2009) Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood 113(18):4153–4162. https://doi.org/10.1182/blood-2008-11-185132CrossRefPubMed

27.

Gokbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, Diedrich H, Topp MS, Bruggemann M, Horst HA, Havelange V, Stieglmaier J, Wessels H, Haddad V, Benjamin JE, Zugmaier G, Nagorsen D, Bargou RC (2018) Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood 131(14):1522–1531. https://doi.org/10.1182/blood-2017-08-798322CrossRefPubMedPubMedCentral

28.

Jen EY, Xu Q, Schetter A, Przepiorka D, Shen YL, Roscoe D, Sridhara R, Deisseroth A, Philip R, Farrell AT, Pazdur R (2019) FDA approval: blinatumomab for patients with B-cell precursor acute lymphoblastic leukemia in morphologic remission with minimal residual disease. Clin Cancer Res 25(2):473–477. https://doi.org/10.1158/1078-0432.CCR-18-2337CrossRefPubMed

29.

Foa R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS, Elia L, Paoloni F, Fazi P, Cimino G, Nobile F, Ferrara F, Castagnola C, Sica S, Leoni P, Zuffa E, Fozza C, Luppi M, Candoni A, Iacobucci I, Soverini S, Mandelli F, Martinelli G, Baccarani M, Party GALW (2011) Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 118(25):6521–6528. https://doi.org/10.1182/blood-2011-05-351403CrossRefPubMed

30.

Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foa R, Bassan R, Arslan O, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Bruggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS (2017) Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 376(9):836–847. https://doi.org/10.1056/NEJMoa1609783CrossRefPubMedPubMedCentral

31.

King AC, Pappacena JJ, Tallman MS, Park JH, Geyer MB (2019) Blinatumomab administered concurrently with oral tyrosine kinase inhibitor therapy is a well-tolerated consolidation strategy and eradicates measurable residual disease in adults with Philadelphia chromosome positive acute lymphoblastic leukemia. Leuk Res 79:27–33. https://doi.org/10.1016/j.leukres.2019.02.009CrossRefPubMedPubMedCentral

32.

Xiao X, He X, Li Q, Zhang H, Meng J, Jiang Y, Deng Q, Zhao M (2019) Plasma Exchange can be an alternative therapeutic modality for severe cytokine release syndrome after chimeric antigen receptor-T cell infusion: a case report. Clin Cancer Res 25(1):29–34. https://doi.org/10.1158/1078-0432.CCR-18-1379CrossRefPubMed

33.

Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E, Steevens NN, Chaney C, Soma L, Chen X, Yeung C, Wood B, Li D, Cao J, Heimfeld S, Jensen MC, Riddell SR, Maloney DG (2016) CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Investig 126(6):2123–2138. https://doi.org/10.1172/JCI85309CrossRefPubMedPubMedCentral

Title: CD19 CAR-T cell treatment conferred sustained remission in B-ALL patients with minimal residual disease
Authors: Wenyi Lu
Yunxiong Wei
Yaqing Cao
Xia Xiao
Qing Li
Hairong Lyu
Yili Jiang
Huan Zhang
Xin Li
Yanyu Jiang
Juanxia Meng
Ting Yuan
Haibo Zhu
Xiaoyuan He
Xin Jin
Rui Sun
Tao Sui
Kaiqi Liu
Mingfeng Zhao
Publication date: 01-12-2021
Publisher: Springer Berlin Heidelberg
Keywords: Acute Lymphoblastic Leukemia
Cytokines
Cytostatic Therapy
Leukemia
Published in: Cancer Immunology, Immunotherapy / Issue 12/2021
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-021-02941-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 12/2021

Exhaustion in tumor-infiltrating Mucosal-Associated Invariant T (MAIT) cells from colon cancer patients

CD16xCD33 Bispecific Killer Cell Engager (BiKE) as potential immunotherapeutic in pediatric patients with AML and biphenotypic ALL

The human anti-CD40 agonist antibody mitazalimab (ADC-1013; JNJ-64457107) activates antigen-presenting cells, improves expansion of antigen-specific T cells, and enhances anti-tumor efficacy of a model cancer vaccine in vivo

Megakaryoblastic leukemia: a study on novel role of clinically significant long non-coding RNA signatures in megakaryocyte development during treatment with phorbol ester

Stem cells-derived natural killer cells for cancer immunotherapy: current protocols, feasibility, and benefits of ex vivo generated natural killer cells in treatment of advanced solid tumors

Telomerase-based GX301 cancer vaccine in patients with metastatic castration-resistant prostate cancer: a randomized phase II trial

Keynote webinar | Spotlight on antibody–drug conjugates in cancer