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.

  • Article
  • Published:

CHRONIC LYMPHOCYTIC LEUKEMIA

A phase two study of high dose blinatumomab in Richter’s syndrome

Leukemia volume 36, pages 2228–2232 (2022)Cite this article

Subjects

Abstract

Richter’s Syndrome (RS) is an aggressive transformation of CLL, usually clonally-related diffuse large B-cell lymphoma (DLBCL), characterized by frequent TP53 mutations, intrinsic chemoresistance and poor survival. TP53-independent treatments are needed. We conducted a single center, phase 2, investigator-initiated study of high dose blinatumomab (maximum 112 mcg/d after initial, weekly dose escalation), NCT03121534, given for an 8-week induction and 4-week consolidation cycle. Responses were assessed by Lugano 2014 criteria. Serial multi-parameter flow cytometry from blood was performed to identify patient-specific biomarkers for response. Nine patients were treated. Patients had received a median of 4 and 2 prior therapies for CLL and RS, respectively. Five of 9 had del(17p) and 100% had complex karyotype. Four patients had reduction in nodal disease, including one durable complete response lasting >1 y. Treatment was well tolerated, with no grade >3 cytokine release syndrome and 1 case of grade 3, reversible neurotoxicity. Immunophenotyping demonstrated the majority of patients expressed multiple immune checkpoints, especially PD1, TIM3 and TIGIT. The patient who achieved CR had the lowest levels of immune checkpoint expression. Simultaneous targeting with immune checkpoint blockade, especially PD1 inhibition, which has already demonstrated single-agent efficacy in RS, could achieve synergistic killing and enhance outcomes.

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: Immune profiling in each patient sample.
Fig. 2: Clustering of cell populations via viSNE analysis on immune markers in all 42 patient samples and a control.

Similar content being viewed by others

Data availability

Deidentified data will be shared with other researchers upon reasonable request to the corresponding author (pathompson2@mdanderson.org). The sharing will require a detailed proposal to the study investigators, and a data transfer agreement must be signed.

References

  1. Rossi D, Spina V, Gaidano G. Biology and treatment of Richter syndrome. Blood. 2018;131:2761–72.

    Article  CAS  Google Scholar 

  2. Younes A, Brody J, Carpio C, Lopez-Guillermo A, Ben-Yehuda D, Ferhanoglu B, et al. Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study. Lancet Haematol. 2019;6:e67–78.

    Article  Google Scholar 

  3. Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131:1522–31.

    Article  Google Scholar 

  4. Topp MS, Gokbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57–66.

    Article  CAS  Google Scholar 

  5. Viardot A, Goebeler M-E, Hess G, Neumann S, Pfreundschuh M, Adrian N, et al. Phase 2 study of bispecific T-cell engager (BiTE®) antibody blinatumomab in relapsed/refractory diffuse large B cell lymphoma. Blood. 2016;127:1410–6.

  6. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059–68.

    Article  Google Scholar 

  7. Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for monitoring multiple outcomes in clinical trials. Stat Med. 1998;17:1563–80.

    Article  CAS  Google Scholar 

  8. Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M, Lundh S, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018;24:563–71.

    Article  CAS  Google Scholar 

  9. Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy. Nature reviews. Clin Oncol. 2019;16:372–85.

    CAS  Google Scholar 

  10. Hutchings M, Morschhauser F, Iacoboni G, Carlo-Stella C, Offner FC, Sureda A, et al. Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell–Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. J Clin Oncol. 2021;39:1959–70.

    Article  CAS  Google Scholar 

  11. Hutchings M, Mous R, Clausen MR, Johnson P, Linton KM, Chamuleau MED, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet 2021;398:1157–69.

    Article  CAS  Google Scholar 

  12. Ying Z, Huang XF, Xiang X, Liu Y, Kang X, Song Y, et al. A safe and potent anti-CD19 CAR T cell therapy. Nat Med. 2019;25:947–53.

    Article  CAS  Google Scholar 

  13. Kittai AS, Bond DA, William B, Saad A, Penza S, Efebera Y, et al. Clinical activity of axicabtagene ciloleucel in adult patients with Richter syndrome. Blood Adv. 2020;4:4648–52.

    Article  Google Scholar 

  14. Ding W, LaPlant BR, Call TG, Parikh SA, Leis JF, He R, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood 2017;129:3419.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This was supported, in part, by M.D. Anderson Cancer Center Support Grant P30 CA016672. The study drug and funding for the study was provided by Amgen. Amgen had no role in the conduct or analysis of the study or the writing of the paper.

Author information

Author notes

  1. These authors contributed equally: Philip A. Thompson, Xianli Jiang.

  2. These authors jointly supervised this work: Katayoun Rezvani, William G. Wierda.

Authors and Affiliations

  1. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Philip A. Thompson, Alessandra Ferrajoli, Michael J. Keating, Michael Andreeff & William G. Wierda

  2. Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Xianli Jiang & Ken Chen

  3. Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Pinaki Banerjee, Rafet Basar & Katayoun Rezvani

  4. Abdominal Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Naveen Garg

  5. Stem Cell Transplantation Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Mecit Kaplan, Vandana Nandivada & Ana Karen Nunez Cortes

  6. Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Christine B. Peterson

Authors
  1. Philip A. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xianli Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pinaki Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rafet Basar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naveen Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ken Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mecit Kaplan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vandana Nandivada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ana Karen Nunez Cortes
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alessandra Ferrajoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael J. Keating
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christine B. Peterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michael Andreeff
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Katayoun Rezvani
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. William G. Wierda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PAT designed and wrote the protocol, provided clinical care to patients, analyzed results and wrote the paper; XJ performed bioinformatic analysis of flow cytometry data and wrote the paper; KC developed the strategic plan for the computational analysis team; PB and KR designed and performed experiments and co-wrote the paper; RB performed experiments and assisted in data analysis; MK, VN and AKNC performed experiments; AF, MK and MA provided clinical care to patients; CBP provided the statistical design for the protocol; NG centrally analyzed PETCT results; WGW assisted in protocol design and planning, provided clinical care to patients and co-wrote the paper. All authors provided intellectual input, critically evaluated the final draft and approved it for submission.

Corresponding author

Correspondence to Philip A. Thompson.

Ethics declarations

Competing interests

PAT consulted for Amgen, Genentech and AbbVie. The remainder of the authors declare no relevant conflicts 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

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thompson, P.A., Jiang, X., Banerjee, P. et al. A phase two study of high dose blinatumomab in Richter’s syndrome. Leukemia 36, 2228–2232 (2022). https://doi.org/10.1038/s41375-022-01649-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-022-01649-3

This article is cited by

Search

Advanced search

Quick links