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Toxicity and effectiveness of CD19 CAR T therapy in children with high-burden central nervous system refractory B-ALL

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Abstract

Introduction

Although recent clinical trials have demonstrated the efficacy of CD19-directed chimeric antigen receptor (CAR) T-cell therapy for refractory or relapsed B acute lymphoblastic leukemia (r/r B-ALL), most trials exclude patients with high-burden CNS leukemia (CNSL) to avoid the risk of severe neurotoxicity. There were only sparse cases describing the effect of CAR T cells on low-burden CNSL, and the safety and effectiveness of CAR T cells in high-burden CNSL remains unknown.

Methods

Here, we retrospectively analyzed the results of CD19 CAR T-cell therapy in 12 pediatric patients that had low (Blasts < 20/μL in CSF) or high-burdens (Blasts or intracranial solid mass) of CNS B-ALL, that are enrolled in three clinical trials and one pilot study at Beijing Boren Hospital

Results

Eleven patients (91.7%) achieved complete remission (CR) on day 30, and one patient got CR on day 90 after infusion. Most patient experienced mild cytokine-release syndrome. However, of the five patients who retained > 5/μL blasts in CSF or a solid mass before CAR T-cell expansion, four developed severe (grade 3–4) neurotoxicity featured by persistent cerebral edema and seizure, and they fully recovered after intensive managements. Sustained remission was achieved in 9 of the 12 patients, resulted in a 6-month leukemia-free survival rate of 81.8% (95% CI 59.0–100). Only one patient has CNS relapse again.

Conclusion

Our study demonstrates that CAR T cells are effective in clearing both low- and high-burden CNSL, but a high CNSL burden before CAR T-cell expansion may cause severe neurotoxicity requiring intense intervention.

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Abbreviations

Allo-HCT:

Allo-hematopoietic stem-cell transplant

Ara-C:

Cytarabine

CAR:

Chimeric antigen receptor

CNS:

Central nervous system

CNSL:

Central nervous system leukemia

CR:

Complete remission

CRS:

Cytokine release syndrome

CSF:

Cerebrospinal fluid

Dex:

Dexamethasone

EMDs:

Extramedullary diseases

ICANS:

Immune effector cell-associated neurotoxicity syndrome

IDA:

Darubicin

IL-6:

Interleukin-6

IL-10:

Interleukin-10

IT:

Intrathecal injection

L-ASP:

L-Asparaginase

LFS:

Leukemia-free survival

MRD:

Minimal residual disease

MTX:

Methotrexate

OS:

Overall survival

r/r B-ALL:

Refractory or relapsed B-cell acute lymphoblastic leukemia

sCD25:

Soluble CD25

TNF-α:

Tumor necrosis factor-α

VDS:

Vindesine

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Acknowledgements

We thank the patients and their families who participated in this study. And we also thank all physicians, nurse, and other patient care providers involved in the care of these patients.

Funding

This work was supported by the National Key R&D Program of China (2019YFA0110200), the National Natural Science Foundation of China (81870090), the Tianjin Science Funds for Distinguished Young Scholars (17JCJQJC45800) and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT32034).

Author information

Author notes

  1. Yue Tan and Jing Pan contributed equally to this study.

Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Department of Hematology, Beijing Boren Hospital, Beijing, 100070, China

    Yue Tan

  2. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China

    Yue Tan, Jing Pan & Xiaoming Feng

  3. Cytology Laboratory, Beijing Boren Hospital, Beijing, 100070, China

    Biping Deng

  4. Department of Hematology, Beijing Boren Hospital, Beijing, 100070, China

    Zhuojun Ling, Weiliang Song, Jinlong Xu, Jiajia Duan & Zelin Wang

  5. Medical Laboratory, Beijing Boren Hospital, Beijing, 100070, China

    Xinjian Yu

  6. Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China

    Alex H. Chang

  7. Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China

    Xiaoming Feng

Authors
  1. Yue Tan
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  2. Jing Pan
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Contributions

YT and JP contributed to data collection, data analyses, data interpretation. BD and AHC contributed to CAR T-cell manufacture. JP, ZL, WS, JX, JD and ZW contributed to clinical protocol. XY was responsible for leukemic cell immunophenotyping. YT and JP were responsible for all statistical analyses. YT, JP and XF wrote the manuscript. JP and XF directed the study and had final responsibility to submit for publication. The authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jing Pan, Alex H. Chang or Xiaoming Feng.

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Conflict of interest

AHC is also a founding member of Shanghai YaKe Biotechnology Ltd. The remaining authors declare no conflict of interest.

Ethical approval and consent to participate

The study protocols were approved by the institutional review board at Beijing Boren hospital, and the patients provided written informed consent. This clinical investigation was conducted according to the principles of the Declaration of Helsinki.

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Tan, Y., Pan, J., Deng, B. et al. Toxicity and effectiveness of CD19 CAR T therapy in children with high-burden central nervous system refractory B-ALL. Cancer Immunol Immunother 70, 1979–1993 (2021). https://doi.org/10.1007/s00262-020-02829-9

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  • DOI: https://doi.org/10.1007/s00262-020-02829-9

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