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 Leukemia

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

Bone Marrow Transplantation volume 51, pages 793–798 (2016)Cite this article

Subjects

Abstract

Ibrutinib, a recently approved inhibitor of Bruton’s tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cell-mediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT.

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
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Dreger P, Corradini P, Kimby E, Michallet M, Milligan D, Schetelig J et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21: 12–17.

    Article  CAS  Google Scholar 

  2. Dreger P, Schetelig J, Andersen N, Corradini P, van Gelder M, Gribben J et al. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood 2014; 124: 3841–3849.

    Article  CAS  Google Scholar 

  3. Cameron F, Sanford M . Ibrutinib: first global approval. Drugs 2014; 74: 263–271.

    Article  CAS  Google Scholar 

  4. 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  Google Scholar 

  5. 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  Google Scholar 

  6. Herman S, Gordon A, Hertlein E, Ramanunni A, Zhang X, Jaglowski S et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 2011; 117: 6287–6297.

    Article  CAS  Google Scholar 

  7. Ponader S, Chen S, Buggy J, Balakrishnan K, Gandhi V, Wierda W et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 2012; 119: 1182–1190.

    Article  CAS  Google Scholar 

  8. Herman SEM, Mustafa RZ, Jones J, Wong DH, Farooqui M, Wiestner A . Treatment with ibrutinib inhibits BTK and VLA-4 dependent adhesion of chronic lymphocytic leukemia cells in vivo. Clin Cancer Res 2015; 21: 4642–4651.

    Article  CAS  Google Scholar 

  9. Ansell S . Two targets for the price of one. Blood 2013; 122: 2529–2531.

    Article  CAS  Google Scholar 

  10. 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: 2539–2550.

    Article  CAS  Google Scholar 

  11. Nishimori H, Maeda Y, Tanimoto M . Chronic graft-versus-host disease: disease biology and novel therapeutic strategies. Acta Med Okayama 2013; 67: 1–8.

    CAS  PubMed  Google Scholar 

  12. Yeh S-P, Liao Y-M, Lo W-J, Lin C-L, Bai L-Y, Lin C-Y et al. Kinetics of T helper subsets and associated cytokines correlate well with the clinical activity of graft-versus-host disease. PLoS ONE 2012; 7: e44416.

    Article  CAS  Google Scholar 

  13. Hayashida J-N, Nakamura S, Toyoshima T, Moriyama M, Sasaki M, Kawamura E et al. Possible involvement of cytokines, chemokines and chemokine receptors in the initiation and progression of chronic GVHD. Bone Marrow Transplant 2013; 48: 115–123.

    Article  CAS  Google Scholar 

  14. Yi T, Chen Y, Wang L, Du G, Huang D, Zhao D et al. Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease. Blood 2009; 114: 3101–3113.

    Article  CAS  Google Scholar 

  15. Hallek M, Cheson B, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia. Blood 2008; 111: 5446–5457.

    Article  CAS  Google Scholar 

  16. Rozovski U, Benjamini O, Jain P, Thompson PA, Wierda WG, O’Brien S et al. Outcomes of patients with chronic lymphocytic leukemia and Richter’s transformation after transplantation failure. J Clin Oncol 2015; 33: 1557–1563.

    Article  Google Scholar 

  17. Richardson SE, Khan I, Rawstron A, Sudak J, Edwards N, Verfuerth S et al. Risk-stratified adoptive cellular therapy following allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukaemia. Br J Haematol 2013; 160: 640–648.

    Article  CAS  Google Scholar 

  18. Hahn M, Böttcher S, Dietrich S, Hegenbart U, Rieger M, Stadtherr P et al. Allogeneic hematopoietic stem cell transplantation for poor-risk CLL: dissecting immune-modulating strategies for disease eradication and treatment of relapse. Bone Marrow Transplant 2015; 50: 1279–1285.

    Article  CAS  Google Scholar 

  19. Mehta RS, Di Stasi A, Hosing C, Shah N, Rezvani K, Alousi et al. Lenalidomide-induced graft-vs.-Leukemia effect in a patient with chronic lymphocytic leukemia who relapsed after allogeneic stem cell transplant. Clin Lymphoma Myeloma Leuk 2014; 14: e105–e109.

    Article  Google Scholar 

  20. Toze CL, Dalal CB, Nevill TJ, Gillan TL, Abou Mourad YR, Barnett MJ et al. Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20-year cohort. Br J Haematol 2012; 158: 174–185.

    Article  Google Scholar 

  21. Coutre S, O’Brien S, Byrd J, Hillmen P, Brown J, Dyer M et al. Safety and efficacy of ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma who have undergone prior allogeneic stem cell transplant. Blood 2014; 124: 4697.

    Google Scholar 

  22. Miklos DB, Coutre S, O’Brien S, Byrd JC, Hillmen P, Brown JR et al. Safety and efficacy of ibrutinib in patients with relapsedrefractory (RR) chronic lymphocytic leukemia (CLL)-small lymphocytic lymphoma (SLL) who have undergone prior allogeneic stem cell transplant. Biol Blood Marrow Transplant 2015; 21: S82–S83.

    Article  Google Scholar 

  23. Montserrat E, Dreger P . Hope for high-risk chronic lymphocytic leukemia relapsing after allogeneic stem-cell transplantation. J Clin Oncol 2015; 33: 1527–1529.

    Article  CAS  Google Scholar 

  24. Ryan CE, Logan AC, Rezvani A, Kamdar M, Nakasone H, Sahaf B et al. Ibrutinib treatment of relapsed CLL following allogeneic transplantation-sustained disease response and promising donor immune modulation. Blood 2014; 124: 1186.

    Google Scholar 

  25. Schetelig J, Thiede C, Bornhauser M, Schwerdtfeger R, Kiehl M, Beyer J et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 2003; 21: 2747–2753.

    Article  CAS  Google Scholar 

  26. Brown JR, Kim HT, Armand P, Cutler C, Fisher DC, Ho V et al. Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome. Leukemia 2013; 27: 362–369.

    Article  CAS  Google Scholar 

  27. De Jong J, Skee D, Murphy J, Sukbuntherng J, Hellemans P, Smit J et al. Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants. Pharmacol Res Perspect 2015; 3: e00156.

    Article  Google Scholar 

  28. Allen J, Tata P, Fore M, Wooten J, Rudra S, Deal et al. Increased BCR responsiveness in B cells from patients with chronic GVHD. Blood 2014; 123: 2108–2116.

    Article  CAS  Google Scholar 

  29. Sarantopoulos S, Ritz J . Aberrant B-cell homeostasis in chronic GVHD. Blood 2015; 125: 1703–1707.

    Article  CAS  Google Scholar 

  30. Dubovsky J, Flynn R, Du J, Harrington B, Zhong Y, Kaffenberger B et al. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 2014; 124: 4867–4876.

    Article  CAS  Google Scholar 

  31. Schutt SD, Fu J, Nguyen H, Bastian D, Heinrichs J, Wu Y et al. Inhibition of BTK and ITK with ibrutinib is effective in the prevention of chronic graft-versus-host disease in mice. PLoS ONE 2015; 10: e0137641.

    Article  Google Scholar 

  32. Miklos DB, Arora M, Cutler CS, Nakamura R, Juretic M, Li Y et al. A multicenter open-label phase 1b/2 study of ibrutinib in steroid dependent or refractory chronic graft versus host disease (cGVHD). J Clin Oncol 2015; 33: 7024.

    Google Scholar 

Download references

Author information

Author notes

  1. C S Link and R Teipel: These authors contributed equally to this work.

Authors and Affiliations

  1. Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    C S Link, R Teipel, F Heidenreich, E Rücker-Braun, M Schmiedgen, U Oelschlägel, M von Bonin, J M Middeke, A Muetherig, K Trautmann-Grill, U Platzbecker, M Bornhäuser & J Schetelig

  2. DFG Research Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany

    C S Link, J Reinhardt & M Bornhäuser

  3. DKMS Clinical Trials Unit, Dresden, Germany

    J Schetelig

Authors
  1. R Teipel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Heidenreich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Rücker-Braun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Schmiedgen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Reinhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. U Oelschlägel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M von Bonin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J M Middeke
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Muetherig
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K Trautmann-Grill
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. U Platzbecker
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Bornhäuser
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J Schetelig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C S Link.

Ethics declarations

Competing interests

JS has a conflict of interest; he gives a talk for Janssen Pharmaceutical Company.

Additional information

Supplementary Information accompanies this paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Link, C., Teipel, R., Heidenreich, F. et al. Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation. Bone Marrow Transplant 51, 793–798 (2016). https://doi.org/10.1038/bmt.2015.339

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2015.339

This article is cited by

Search

Advanced search

Quick links