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Acute lymphoblastic leukemia

Frequent occurrence of CD19-negative relapse after CD19 CAR T and consolidation therapy in 14 TP53-mutated r/r B-ALL children

Leukemia volume 34, pages 3382–3387 (2020)Cite this article

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Despite high remission rates after CD19 CAR T-cell therapy in patients with refractory or relapsed B acute lymphoblastic leukemia (r/r B-ALL), relapses were commonly observed [1,2,3,4]. To improve long-term disease-free survival (DFS), our and other centers have conducted post-CD19 CAR consolidations with allogeneic hematopoietic stem cell transplantation (allo-HCT) or CD22 CAR T-cell infusion [5,6,7,8,9]. However, some patients still relapsed, but it is unknown which factors caused their relapses. TP53 mutation predicts nonresponse and poor outcome in childhood B-ALL during traditional therapies. Genomic instability caused by TP53 mutation induces leukemia cells to undergo genomic evolution to survive stress and treatment [10,11,12]. In our previous studies, CAR T therapy can overcome genetic adverse features including TP53 mutation to induce remission [5, 6], but it is unknown whether the long-term outcome would be influenced by TP53 mutation and other genetic aberrations.

Incorporating 17 gene mutations occurred in ≥3 patients, ten clinical high-risk features referring to NCCN guideline and five parameters of CAR T cells, we performed univariate and multivariate analysis to identify factors associated with DFS (Approaches in Supplemental methods pp7 and Supplementary Tables. 4 and 5). TP53 mutation, STAG2 mutation, and mutated gene numbers were identified as independent prognostic factors (Fig. 1d). TP53-mutated patients had significantly poorer DFS than unmutated patients (P < 0.001, Fig. 1e). We also compared the DFS of subgroups divided by TP53 mutation and other independent factors. In STAG2 wide-type subgroup, TP53 mutation still led to a poor outcome (P = 0.001, Fig. 1f). There was no significant difference of co-mutation gene numbers between TP53 mutation and wide-type patients (P = 0.672, two non-TP53 gene mutations/patient). The adverse impact of TP53 mutation was obvious regardless of number of co-mutations (P = 0.004 and P = 0.035, Fig. 1g), and lack of TP53 mutation indicated a favorable outcome despite of a large number of mutated genes. Patients with TP53 mutation exhibited poorer DFS and higher relapse rate no matter allo-HCT or CD22 CAR T cell consolidations were conducted (Fig. 1h and Supplementary Fig. 1d). These results support that TP53 mutation predispose to a poor outcome.

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Fig. 1: Genetic features associated with the outcome of patients after CD19 CAR-based therapies.
Fig. 2: Association of TP53 mutation with CD19 antigen loss relapse.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2019YFA0110200), the Tianjin Science Funds for Distinguished Young Scholars (17JCJQJC45800), the CAMS Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-1-003; 2017-I2M-1-015), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT32034 and 2019-RC-HL-013).

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  1. These authors contributed equally: Jing Pan, Qinlong Zheng, Xiaoming Feng

Authors and Affiliations

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

    Jing Pan

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

    Yue Tan & Xiaoming Feng

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

    Biping Deng

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

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

  5. School of Biomedical Engineering, Capital Medical University, 100069, Beijing, China

    Lin Hua

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

    Huilin Guo, Xinjian Yu & Qinlong Zheng

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

    Alex H. Chang

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

    Xiaoming Feng

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Contributions

JP, YT contributed to data collection, data analyses, data interpretation. QZ, HG performed NGS sequencing and analyzed the sequencing data. BD, AHC contributed to CAR T-cell manufacture. JP, CT, ZL, WS, JX, JD, ZW contributed to clinical protocol. XY was responsible for leukemic cell immunophenotyping. JP, YT, LH were responsible for all statistical analyses. The all statistical analyses were in collaboration with biostatisticians from Capital Medical University and eStart Medical Technology CO., Ltd to review raw data and statistical analyses. JP and XF designed and directed the study and wrote the draft of the paper and had final responsibility to submit for publication.

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Correspondence to Jing Pan, Qinlong Zheng or Xiaoming Feng.

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

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Pan, J., Tan, Y., Deng, B. et al. Frequent occurrence of CD19-negative relapse after CD19 CAR T and consolidation therapy in 14 TP53-mutated r/r B-ALL children. Leukemia 34, 3382–3387 (2020). https://doi.org/10.1038/s41375-020-0831-z

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