Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Acute lymphoblastic leukemia

Serial evaluation of CD19 surface expression in pediatric B-cell malignancies following CD19-targeted therapy

Leukemia volume 34, pages 3064–3069 (2020)Cite this article

Subjects

CD19-targeting immunotherapies including blinatumomab, a (CD19/CD3) bispecific T-cell engaging antibody, and CD19-chimeric antigen receptor (CAR) T cells have been highly effective for B-cell acute lymphoblastic leukemia (ALL) [1, 2]. However, up to 50% of B-cell ALL patients relapse after CD19-targeted therapies, the majority with CD19-negative disease [3,4,5]. Given increasing utilization of these newly FDA-approved therapies in standard treatment paradigms, serial evaluations of CD19 surface expression following these therapies will be necessary to monitor for changes in leukemic phenotype.

As a referral center for therapies targeting CD22, an alternate B-cell antigen, we have a unique population of children and young adults with relapse or refractory disease to CD19 targeting [6,7,8]. Utilizing this cohort, we retrospectively analyzed serial CD19 surface expression to evaluate for dynamic changes in surface expression following immunotherapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Changes in CD19 Expression.

References

  1. Maude SL, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018;378:439–48.

  2. Gokbuget N, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131:1522–31.

  3. Topp MS, Gokbuget N, Zugmaier G, Degenhard E, Goebeler ME, Klinger M, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120:5185–7.

    Article  CAS  Google Scholar 

  4. Aldoss I, Song J, Stiller T, Nguyen T, Palmer J, O’Donnell M, et al. Correlates of resistance and relapse during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. Am J Hematol. 2017;92:858–65.

    Article  CAS  Google Scholar 

  5. Majzner RG, Mackall CL. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 2018;8:1219–26.

    Article  CAS  Google Scholar 

  6. Ramakrishna S, Highfill SL, Walsh Z, Nguyen SM, Lei H, Shern JF, et al. Modulation of target antigen density improves CAR T-cell functionality and persistence. Clin Cancer Res. 2019;25:5329–41.

  7. 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 

  8. Wayne AS, Shah NN, Bhojwani D, Silverman LB, Whitlock JA, Stetler-Stevenson M, et al. Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia. Blood. 2017;130:1620–7.

    Article  CAS  Google Scholar 

  9. Mejstrikova E, Hrusak O, Borowitz MJ, Whitlock JA, Brethon B, Trippett TM, et al. CD19-negative relapse of pediatric B-cell precursor acute lymphoblastic leukemia following blinatumomab treatment. Blood Cancer J. 2017;7:659.

    Article  CAS  Google Scholar 

  10. Orlando EJ, Han X, Tribouley C, Wood PA, Leary RJ, Riester M, et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med. 2018;24:1504–6.

    Article  CAS  Google Scholar 

  11. Bhojwani D, Sposto R, Shah NN, Rodriguez V, Yuan C, Stetler-Stevenson M, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2019;33:884–92.

    Article  CAS  Google Scholar 

  12. Yates B, Shalabi H, Salem D, Delbrook C, Yuan CM, Stetler-Stevenson M, et al. Sequential CD22 targeting impacts CD22 CAR-T cell response. Blood. 2018;132 Suppl 1:282.

  13. Pillai V, Muralidharan K, Meng W, Bagashev A, Oldridge DA, Rosenthal J, et al. CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy. Blood Adv. 2019;3:3539–49.

    Article  Google Scholar 

  14. Rosenthal J, Naqvi AS, Luo M, Wertheim G, Paessler M, Thomas-Tikhonenko A, et al. Heterogeneity of surface CD19 and CD22 expression in B lymphoblastic leukemia. Am J Hematol. 2018;93:E352–5.

    Article  Google Scholar 

  15. Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21:581–90.

    Article  CAS  Google Scholar 

  16. Walker AJ, Majzner RG, Zhang L, Wanhainen K, Long AH, Nguyen SM, et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol Ther. 2017;25:2189–201.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the study participants and their families, referring medical care teams, the faculty and staff of the NIH Clinical Center who provide their expertise in the management of the study participants, and the data managers involved with this work. This work was supported in part by the Intramural Research Program, National Cancer Institute and NIH Clinical Center, National Institutes of Health. This research was made possible through the NIH Medical Research Scholars Program, a public–private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (DDCF Grant #2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, Elsevier, and other private donors. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Warren Grant Magnuson Clinical Center.

Author information

Authors and Affiliations

  1. Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD, USA

    Diane Libert, Haneen Shalabi, Bonnie Yates, Cindy Delbrook, Jack F. Shern, Terry J. Fry & Nirali N. Shah

  2. Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD, USA

    Constance M. Yuan, Pallavi Galera, Dalia Salem & Maryalice Stetler-Stevenson

  3. Oncogenomics Section, Genetics Branch, CCR, NCI, NIH, Bethesda, MD, USA

    Katherine E. Masih & Javed Khan

  4. Division of Human Immunology and Immunotherapy Initiative, Pediatric Hematology/Oncology, Children’s Hospital of Colorado, Aurora, CO, USA

    Terry J. Fry

Authors
  1. Diane Libert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Constance M. Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katherine E. Masih
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pallavi Galera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dalia Salem
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haneen Shalabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bonnie Yates
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cindy Delbrook
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jack F. Shern
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Terry J. Fry
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Javed Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Maryalice Stetler-Stevenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nirali N. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nirali N. Shah.

Ethics declarations

Conflict of interest

The authors declare that they have 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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Libert, D., Yuan, C.M., Masih, K.E. et al. Serial evaluation of CD19 surface expression in pediatric B-cell malignancies following CD19-targeted therapy. Leukemia 34, 3064–3069 (2020). https://doi.org/10.1038/s41375-020-0760-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-020-0760-x

This article is cited by

Search

Advanced search

Quick links