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.

  • Original Article
  • Published:

Chronic lymphocytic leukemia

Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia

Leukemia volume 30, pages 346–350 (2016)Cite this article

Subjects

Abstract

Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.

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

Figure 1

Similar content being viewed by others

References

  1. Hamblin TJ . Autoimmune complications of chronic lymphocytic leukemia. Semin Oncol 2006; 33: 230–239.

    Article  CAS  PubMed  Google Scholar 

  2. Moreno C, Hodgson K, Ferrer G, Elena M, Filella X, Pereira A et al. Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. Blood 2010; 116: 4771–4776.

    Article  CAS  PubMed  Google Scholar 

  3. Mauro FR, Foa R, Cerretti R, Giannarelli D, Coluzzi S, Mandelli F et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 2000; 95: 2786–2792.

    CAS  PubMed  Google Scholar 

  4. Visco C, Cortelezzi A, Moretta F, Falisi E, Maura F, Finotto S et al. Autoimmune cytopenias in chronic lymphocytic leukemia at disease presentation in the modern treatment era: is stage C always stage C? Leuk Lymphoma 2014; 55: 1261–1265.

    Article  CAS  PubMed  Google Scholar 

  5. D’Arena G, Laurenti L, Capalbo S, D’Arco AM, De Filippi R, Marcacci G et al. Rituximab therapy for chronic lymphocytic leukemia-associated autoimmune hemolytic anemia. Am J Hematol 2006; 81: 598–602.

    Article  PubMed  Google Scholar 

  6. Myint H, Copplestone JA, Orchard J, Craig V, Curtis D, Prentice AG et al. Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia. Br J Haematol 1995; 91: 341–344.

    Article  CAS  PubMed  Google Scholar 

  7. Weiss RB, Freiman J, Kweder SL, Diehl LF, Byrd JC . Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia. J Clin Oncol 1998; 16: 1885–1889.

    Article  CAS  PubMed  Google Scholar 

  8. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376: 1164–1174.

    Article  CAS  PubMed  Google Scholar 

  9. Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007; 370: 230–239.

    Article  CAS  PubMed  Google Scholar 

  10. Dearden C, Wade R, Else M, Richards S, Milligan D, Hamblin T et al. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood 2008; 111: 1820–1826.

    Article  CAS  PubMed  Google Scholar 

  11. Woyach JA, Johnson AJ, Byrd JC . The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood 2012; 120: 1175–1184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371: 213–223.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ibrutinib Full Prescribing Information. [Web Page] 1/2015 [cited 2/2015]; Available from http://www.imbruvica.com/docs/librariesprovider3/default-document-library/prescribing_information.pdf?sfvrsn=2 (accessed 1 February 2015).

  15. Wolach O, Bairey O, Lahav M . Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature. Medicine 2010; 89: 308–318.

    Article  PubMed  Google Scholar 

  16. Voog E, Morschhauser F, Solal-Celigny P . Neutropenia in patients treated with rituximab. N Engl J Med 2003; 348: 2691–2694, discussion 2691–2694.

    Article  PubMed  Google Scholar 

  17. Dunleavy K, Tay K, Wilson WH . Rituximab-associated neutropenia. Semin Hematol 2010; 47: 180–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Elwood JM . Causal Relationships in Medicine: A Practical System for Critical Appraisal. Oxford University Press: New York, NY, USA, 1988, xi+332 pp.

  19. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  CAS  PubMed  Google Scholar 

  20. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK . Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–1854.

    CAS  PubMed  Google Scholar 

  21. Thompson PA, Wierda WG, Ferrajoli A, Smith SC, O’Brien S, Burger JA et al. Complex karyotype, rather than Del(17p), is associated with inferior outcomes in relapsed or refractory CLL patients treated with ibrutinib-based regimens. Blood 2014; 124: 22–22.

    Google Scholar 

  22. Maura F, Visco C, Falisi E, Reda G, Fabris S, Agnelli L et al. B-cell receptor configuration and adverse cytogenetics are associated with autoimmune hemolytic anemia in chronic lymphocytic leukemia. Am J Hematol 2013; 88: 32–36.

    Article  CAS  PubMed  Google Scholar 

  23. Rogers KA, Woyach JA, Andritsos LA, Awan F, Blum KA, Flynn JM et al. Incidence of autoimmune cytopenias (AIC) in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) Patients (pts) treated with ibrutinib. Blood 2014; 124: 1997–1997.

    Article  Google Scholar 

  24. Montillo M, O’Brien S, Tedeschi A, Hillmen P, Dearden C, Gill D et al. Autoimmune hemolytic anemia and immune mediated thrombocytopenia in the phase III RESONATETM study of ibrutinib vs ofatumumab in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma, including a case report. Blood 2014; 124: 5654–5654.

    Google Scholar 

  25. Zent CS, Ding W, Reinalda MS, Schwager SM, Hoyer JD, Bowen DA et al. Autoimmune cytopenia in chronic lymphocytic leukemia/small lymphocytic lymphoma: changes in clinical presentation and prognosis. Leuk Lymphoma 2009; 50: 1261–1268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hall AM, Vickers MA, McLeod E, Barker RN . Rh autoantigen presentation to helper T cells in chronic lymphocytic leukemia by malignant B cells. Blood 2005; 105: 2007–2015.

    Article  CAS  PubMed  Google Scholar 

  27. Centola M, Lin K, Sutton C, Berenson JR, Kunkel LA, Rosen L et al. Production of anti-erythrocyte antibodies by leukemic and nonleukemic B cells in chronic lymphocytic leukemia patients. Leuk Lymphoma 1996; 20: 465–469.

    Article  CAS  PubMed  Google Scholar 

  28. Lad DP, Varma S, Varma N, Sachdeva MU, Bose P, Malhotra P . Regulatory T-cells in B-cell chronic lymphocytic leukemia: their role in disease progression and autoimmune cytopenias. Leuk Lymphoma 2013; 54: 1012–1019.

    Article  CAS  PubMed  Google Scholar 

  29. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013; 122: 2539–2549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fagiolo E, Toriani-Terenzi C . Th1 and Th2 cytokine modulation by IL-10/IL-12 imbalance in autoimmune haemolytic anaemia (AIHA). Autoimmunity 2002; 35: 39–44.

    Article  CAS  PubMed  Google Scholar 

  31. Feng M, Chen JY, Weissman-Tsukamoto R, Volkmer JP, Ho PY, McKenna KM et al. Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc Natl Acad Sci USA 2015; 112: 2145–2150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Four Winds Foundation, D. Warren Brown Foundation, Mr and Mrs Michael Thomas, Mr Al and Mrs Midge Lipkin, the Harry Mangurian Foundation, the Sullivan CLL Research Foundation, the Leukemia and Lymphoma Society, and R01 CA177292 and K23 CA178183 from the National Cancer Institute. Included clinical trials were funded by Pharmacyclics, Janssen, the Leukemia and Lymphoma Society, D. Warren Brown Foundation, Mr and Mrs Michael Thomas, the Harry T. Mangurian Foundation, P50 CA140158 and P01 CA095426 from the National Cancer Institute, Pelotonia, Conquer Cancer Foundation, and the American Society of Hematology.

Author information

Author notes

  1. J A Woyach and J A Jones: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, The Ohio State University, Columbus, OH, USA

    K A Rogers, A S Ruppert, L A Andritsos, F T Awan, K A Blum, J M Flynn, S M Jaglowski, K J Maddocks, J C Byrd, J A Woyach & J A Jones

  2. BMT Program, The Ohio State University, Columbus, OH, USA

    A Bingman

  3. Department of Pathology, The Ohio State University, Columbus, OH, USA

    G Lozanski

Authors
  1. K A Rogers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A S Ruppert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Bingman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L A Andritsos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F T Awan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K A Blum
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J M Flynn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S M Jaglowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G Lozanski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K J Maddocks
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J C Byrd
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J A Woyach
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J A Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J A Jones.

Ethics declarations

Competing interests

JAJ has served as a consultant for Pharmacyclics and Janssen. KJM has received research support from Pharmacyclics. KAB has received research funding from Pharmacyclics and Janssen. SMJ has received research funding and has served as a consultant for Pharmacyclics. The remaining authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rogers, K., Ruppert, A., Bingman, A. et al. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia. Leukemia 30, 346–350 (2016). https://doi.org/10.1038/leu.2015.273

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.273

This article is cited by

Search

Advanced search

Quick links