Frequent occurrence of CD19-negative relapse after CD19 CAR T and consolidation therapy in 14 TP53-mutated r/r B-ALL children (2024)

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.

References

  1. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.

    Article Google Scholar

  2. Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24:20–8.

    Article CAS Google Scholar

  3. Kenderian SS, Porter DL, Gill S. Chimeric antigen receptor T cells and hematopoietic cell transplantation: how not to put the CART before the horse. Biol Blood Marrow Transpl. 2017;23:235–46.

    Article CAS Google Scholar

  4. Pan J, Zuo S, Deng B, Xu X, Li C, Zheng Q, et al. Sequential CD19-22 CAR T therapy induces sustained remission in children with r/r B-ALL. Blood. 2020;135:387–91.

    Article Google Scholar

  5. Pan J, Niu Q, Deng B, Liu S, Wu T, Gao Z, et al. CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia. Leukemia. 2019;33:2854–66.

    Article CAS Google Scholar

  6. Pan J, Yang JF, Deng BP, Zhao XJ, Zhang X, Lin YH, et al. High efficacy and safety of low dose CD19 directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients. Leukemia. 2017;31:2587–93.

    Article CAS Google Scholar

  7. Schultz LM, Davis KL, Baggott C, Chaudry C, Marcy AC, Mavroukakis S, et al. Phase 1 study of CD19/CD22 bispecific chimeric antigen receptor (CAR) therapy in children and young adults with B cell acute lymphoblastic leukemia (ALL). Blood. 2018;132(Suppl 1):898. (abstract 612)

    Article Google Scholar

  8. Yang J, Li J, Zhang X, LV F, Guo X, Wang Q, et al. A feasibility and safety study of CD19 and CD22 chimeric antigen receptors-modified T cell co*cktail for therapy of B cell acute lymphoblastic leukemia. Blood. 2018;132(Suppl 1):277. (abstract 614)

    Article Google Scholar

  9. Wang N, Hu X, Cao W, Li C, Xiao Y, Cao Y, et al. Efficacy and safety of CAR19/22 T-cell “co*cktail” therapy in patients with refractory/relapsed B-Cell malignancies. Blood. 2020;135:17–27.

    Article Google Scholar

  10. Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518:552–5.

    Article CAS Google Scholar

  11. Hof J, Krentz S, van Schewick C, Körner G, Shalapour S, Rhein P, et al. Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia. J Clin Oncol. 2011;29:3185–93.

    Article Google Scholar

  12. Qian M, Cao X, Devidas M, Yang W, Cheng C, Dai Y, et al. TP53 germline variations influence the predisposition and prognosis of B-Cell acute lymphoblastic leukemia in children. J Clin Oncol. 2018;36:591–9.

    Article CAS Google Scholar

  13. Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B -ALL from CD19 CAR-T-cell therapy. Blood. 2016;127:2406–10.

    Article CAS Google Scholar

  14. Shah NN. The one-two punch (of CAR T cells). Blood. 2020;135:303–4.

    Article CAS Google Scholar

Download references

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).

Author information

Author notes

See Also
False-positive HIV nucleic acid amplification testing during CAR T-cell therapyEthical Considerations in the Translation of CAR-T Cell TherapiesCAR-T failure: beyond antigen loss and T cellsCAR T-cell Therapy and Its Side Effects

  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

Authors

  1. Jing Pan

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  2. Yue Tan

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  3. Biping Deng

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  4. Chunrong Tong

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  5. Lin Hua

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  6. Zhuojun Ling

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  7. Weiliang Song

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  8. Jinlong Xu

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  9. Jiajia Duan

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  10. Zelin Wang

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  11. Huilin Guo

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  12. Xinjian Yu

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  13. Alex H. Chang

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  14. Qinlong Zheng

    View author publications

    You can also search for this author in PubMedGoogle Scholar

  15. Xiaoming Feng

    View author publications

    You can also search for this author in PubMedGoogle Scholar

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.

Corresponding authors

Correspondence to Jing Pan, Qinlong Zheng or Xiaoming Feng.

Ethics declarations

Conflict of interest

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

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

About this article

Frequent occurrence of CD19-negative relapse after CD19 CAR T and consolidation therapy in 14 TP53-mutated r/r B-ALL children (1)

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-020-0831-z

Frequent occurrence of CD19-negative relapse after CD19 CAR T and consolidation therapy in 14 TP53-mutated r/r B-ALL children (2024)
Top Articles
a farmgirl's dabbles Rømmegrøt | easy rømmegrøt recipe
Crown Royal Vanilla Recipes
(PDF) Roll of Successful Examinees in the L.E.T. - ELEMENTARY - All … · 2016. 11. 28. · Roll of Successful Examinees in the L.E.T. - ELEMENTARY - All Regions Held on SEPTEMBER 25, - DOKUMEN.TIPS
Behind the scenes at the party of the year
Latest Posts
Spicy Thai Noodle Soup Recipe [EASY] - Masala Herb
Roasted Radishes Recipe + Everything to Know About Radishes
Article information

Author: Allyn Kozey

Last Updated:

Views: 5805

Rating: 4.2 / 5 (43 voted)

Reviews: 82% of readers found this page helpful

Author information

Name: Allyn Kozey

Birthday: 1993-12-21

Address: Suite 454 40343 Larson Union, Port Melia, TX 16164

Phone: +2456904400762

Job: Investor Administrator

Hobby: Sketching, Puzzles, Pet, Mountaineering, Skydiving, Dowsing, Sports

Introduction: My name is Allyn Kozey, I am a outstanding, colorful, adventurous, encouraging, zealous, tender, helpful person who loves writing and wants to share my knowledge and understanding with you.