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:

Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study

Leukemia volume 28, pages 2188–2196 (2014)Cite this article

Subjects

Abstract

Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further investigation. Here we report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes (LNs), spleen and bone marrow, assessed phenotypic changes of circulating cells and measured whole-blood viscosity. With just one dose of ibrutinib, the average increase in ALC was 66%, and in>40% of patients the ALC peaked within 24 h of initiating treatment. Circulating CLL cells on day 2 showed increased Ki67 and CD38 expression, indicating an efflux of tumor cells from the tissue compartments into the blood. The kinetics and degree of the treatment-induced lymphocytosis was highly variable; interestingly, in patients with a high baseline ALC the relative increase was mild and resolution rapid. After two cycles of treatment the disease burden in the LN, bone marrow and spleen decreased irrespective of the relative change in ALC. Whole-blood viscosity was dependent on both ALC and hemoglobin. No adverse events were attributed to the lymphocytosis.

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
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Chiorazzi N, Rai KR, Ferrarini M . Chronic lymphocytic leukemia. N Engl J Med 2005; 352: 804–815.

    Article  CAS  Google Scholar 

  2. NIH. NCI Surveillance Epidemiology and End Results. Department of Health & Human Services: Bethesda, MD, USA, 2012, seer.cancer.gov.

  3. Howlader N, Ries LA, Mariotto AB, Reichman ME, Ruhl J, Cronin KA . Improved estimates of cancer-specific survival rates from population-based data. J Natl Cancer Inst 2010; 102: 1584–1598.

    Article  Google Scholar 

  4. Wierda WG, O'Brien S, Wang X, Faderl S, Ferrajoli A, Do KA et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood 2007; 109: 4679–4685.

    Article  CAS  Google Scholar 

  5. Rosenquist R, Cortese D, Bhoi S, Mansouri L, Gunnarsson R . Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand? Leuk Lymphoma 2013; 54: 2351–2364.

    Article  CAS  Google Scholar 

  6. Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G . B-cell receptor signaling in chronic lymphocytic leukemia. Blood 2011; 118: 4313–4320.

    Article  CAS  Google Scholar 

  7. Wiestner A . Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood 2012; 120: 4684–4691.

    Article  CAS  Google Scholar 

  8. 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  Google Scholar 

  9. Fais F, Ghiotto F, Hashimoto S, Sellars B, Valetto A, Allen SL et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest 1998; 102: 1515–1525.

    Article  CAS  Google Scholar 

  10. Tobin G, Thunberg U, Karlsson K, Murray F, Laurell A, Willander K et al. Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia. Blood 2004; 104: 2879–2885.

    Article  CAS  Google Scholar 

  11. Messmer BT, Albesiano E, Efremov DG, Ghiotto F, Allen SL, Kolitz J et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med 2004; 200: 519–525.

    Article  CAS  Google Scholar 

  12. Agathangelidis A, Darzentas N, Hadzidimitriou A, Brochet X, Murray F, Yan XJ et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood 2012; 119: 4467–4475.

    Article  CAS  Google Scholar 

  13. Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011; 117: 563–574.

    Article  CAS  Google Scholar 

  14. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F . The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood 2009; 114: 3367–3375.

    Article  CAS  Google Scholar 

  15. Niemann CU, Wiestner A . B-cell receptor signaling as a driver of lymphoma development and evolution. Semin Cancer Biol 2013; 23: 410–421.

    Article  CAS  Google Scholar 

  16. Young RM, Staudt LM . Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov 2013; 12: 229–243.

    Article  CAS  Google Scholar 

  17. Buggy JJ, Elias L . Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol 2012; 31: 119–132.

    Article  CAS  Google Scholar 

  18. Humphries LA, Dangelmaier C, Sommer K, Kipp K, Kato RM, Griffith N et al. Tec kinases mediate sustained calcium influx via site-specific tyrosine phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 3 linker. J Biol Chem 2004; 279: 37651–37661.

    Article  CAS  Google Scholar 

  19. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463: 88–92.

    Article  CAS  Google Scholar 

  20. Woyach JA, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker KA et al. Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood 2013; 123: 1207–1213.

    Article  Google Scholar 

  21. Kil LP, de Bruijn MJ, van Hulst JA, Langerak AW, Yuvaraj S, Hendriks RW . Bruton's tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res 2013; 3: 71–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. Chem Med Chem 2007; 2: 58–61.

    Article  CAS  Google Scholar 

  23. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013; 31: 88–94.

    Article  CAS  Google Scholar 

  24. Wiestner A . Targeting B-Cell receptor signaling for anticancer therapy: the Bruton's tyrosine kinase inhibitor ibrutinib induces impressive responses in B-cell malignancies. J Clin Oncol 2013; 31: 128–130.

    Article  CAS  Google Scholar 

  25. 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 

  26. Herman SE, Gordon AL, 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: 6287–6296.

    Article  CAS  Google Scholar 

  27. de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 2012; 119: 2590–2594.

    Article  CAS  Google Scholar 

  28. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG 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: 1182–1189.

    Article  CAS  Google Scholar 

  29. de Gorter DJ, Beuling EA, Kersseboom R, Middendorp S, van Gils JM, Hendriks RW et al. Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity 2007; 26: 93–104.

    Article  CAS  Google Scholar 

  30. Herman SE, Sun X, McAuley EM, Hsieh MM, Pittaluga S, Raffeld M et al. Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy. Leukemia 2013; 27: 1769–1773.

    Article  CAS  Google Scholar 

  31. Davids MS, Brown JR . Targeting the B cell receptor pathway in chronic lymphocytic leukemia. Leuk Lymphoma 2012; 53: 2362–2370.

    Article  CAS  Google Scholar 

  32. Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol 2012; 30: 2820–2822.

    Article  CAS  Google Scholar 

  33. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010; 115: 2578–2585.

    Article  CAS  Google Scholar 

  34. Zhang B, Lewis SM . The splenomegaly of myeloproliferative and lymphoproliferative disorders: splenic cellularity and vascularity. Eur J Haematol 1989; 43: 63–66.

    Article  CAS  Google Scholar 

  35. Sambuceti G, Brignone M, Marini C, Massollo M, Fiz F, Morbelli S et al. Estimating the whole bone-marrow asset in humans by a computational approach to integrated PET/CT imaging. Eur J Nucl Med Mol Imaging 2012; 39: 1326–1338.

    Article  Google Scholar 

  36. Pesic V, Plecas-Solarovic B, Radojevic K, Kosec D, Pilipovic I, Perisic M et al. Long-term beta-adrenergic receptor blockade increases levels of the most mature thymocyte subsets in aged rats. Int Immunopharmacol 2007; 7: 674–686.

    Article  CAS  Google Scholar 

  37. Nadler SB, Hidalgo JH, Bloch T . Prediction of blood volume in normal human adults. Surgery 1962; 51: 224–232.

    PubMed  Google Scholar 

  38. Woyach JA, Smucker K, Smith LL, Lozanski A, Zhong Y, Ruppert AS et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014; 123: 1810–1817.

    Article  CAS  Google Scholar 

  39. Kuse R, Lueb H . Gastrointestinal involvement in patients with chronic lymphocytic leukemia. Leukemia 1997; 11 (Suppl 2): S50–S51.

    PubMed  Google Scholar 

  40. Baumhoer D, Tzankov A, Dirnhofer S, Tornillo L, Terracciano LM . Patterns of liver infiltration in lymphoproliferative disease. Histopathology 2008; 53: 81–90.

    Article  CAS  Google Scholar 

  41. Brandtzaeg P, Farstad IN, Johansen FE, Morton HC, Norderhaug IN, Yamanaka T . The B-cell system of human mucosae and exocrine glands. Immunol Rev 1999; 171: 45–87.

    Article  CAS  Google Scholar 

  42. Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest 2005; 115: 755–764.

    Article  CAS  Google Scholar 

  43. Calissano C, Damle RN, Hayes G, Murphy EJ, Hellerstein MK, Moreno C et al. In vivo intraclonal and interclonal kinetic heterogeneity in B-cell chronic lymphocytic leukemia. Blood 2009; 114: 4832–4842.

    Article  CAS  Google Scholar 

  44. Chang BY, Francesco M, De Rooij MF, Magadala P, Steggerda SM, Huang MM et al. Egress of CD19+CD5+ cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood 2013; 122: 2412–2424.

    Article  CAS  Google Scholar 

  45. Herman SE, Barr PM, McAuley EM, Liu D, Wiestner A, Friedberg JW . Fostamatinib inhibits B-cell receptor signaling, cellular activation and tumor proliferation in patients with relapsed and refractory chronic lymphocytic leukemia. Leukemia 2013; 27: 1769–1773.

    Article  CAS  Google Scholar 

  46. Herman SEM, Farooqui M, Bezabhie R, Aue G, Wiestner A . In vivo effects of ibrutinib on BCR signaling, tumor cell activation and proliferation in blood and tissue-resident cells of chronic lymphocytic leukemia patients. ASH Annu Meeting Abstracts 2012; 120: 185.

    Google Scholar 

  47. Cheng S, Ma J, Guo A, Lu P, Leonard JP, Coleman M et al. BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia 2013; 28: 649–657.

    Article  Google Scholar 

  48. Ganzel C, Becker J, Mintz PD, Lazarus HM, Rowe JM . Hyperleukocytosis, leukostasis and leukapheresis: practice management. Blood Rev 2012; 26: 117–122.

    Article  Google Scholar 

  49. Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008; 112: 975–980.

    Article  CAS  Google Scholar 

  50. Calissano C, Damle RN, Marsilio S, Yan XJ, Yancopoulos S, Hayes G et al. Intraclonal complexity in chronic lymphocytic leukemia: fractions enriched in recently born/divided and older/quiescent cells. Mol Med 2011; 17: 1374–1382.

    Article  CAS  Google Scholar 

  51. Cukierman T, Gatt ME, Libster D, Goldschmidt N, Matzner Y . Chronic lymphocytic leukemia presenting with extreme hyperleukocytosis and thrombosis of the common femoral vein. Leuk Lymphoma 2002; 43: 1865–1868.

    Article  Google Scholar 

  52. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369: 507–516.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank our patients for participating and donating samples to make this research possible. We thank Ajunae Wells for assistance in the clinic and Stephanie Housel, Adrian Byrnes and Allison Wise for protocol support. We acknowledge Pharmacyclics for providing study drug. This work was supported by the Intramural Research Program of NHLBI, NIH. CUN was supported by The Danish Cancer Society. JJ was supported by the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Leona M and Harry B Helmsley Charitable Trust and the Howard Hughes Medical Institute, as well as other private donors (http://www.fnih.org/work/programs-development/medical-research-scholars-program).

Author information

Author notes

  1. S E M Herman, C U Niemann and M Farooqui: These authors contributed equally to this work and are co-first authors.

Authors and Affiliations

  1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    S E M Herman, C U Niemann, M Farooqui, J Jones, R Z Mustafa, A Lipsky, N Saba, S Martyr, S Soto, J Valdez, J A Gyamfi, D Liu, G E Marti, G Aue & A Wiestner

  2. Medical Research Scholars Program, National Institutes of Health, Bethesda, MD, USA

    J Jones

  3. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA

    I Maric & K R Calvo

  4. Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    L B Pedersen & C H Geisler

Authors
  1. S E M Herman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C U Niemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Farooqui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Z Mustafa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Lipsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N Saba
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Martyr
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Soto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Valdez
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J A Gyamfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. I Maric
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. K R Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. L B Pedersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. C H Geisler
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. D Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. G E Marti
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. G Aue
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. A Wiestner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Wiestner.

Ethics declarations

Competing interests

CHG obtained research funding from Genzyme/Sanofi and is on advisory boards for Roche, Janssen, Celgene and GlaxoSmithKline. The other authors declare no conflict of interest.

Additional information

Author Contributions

SEMH, CUN and MF planned the research, performed experiments and analyzed data; JJ, RZM, AL, NS, CHG and SM were involved in planning and supporting components of the research; JG and LBP determined IGHV mutational status; IM and KRC performed pathology review; DL conducted statistical analyses; AW planned and supervised the research; and MF, SS, JV, GA, SM, GEM and AW implemented the clinical trial. SEMH, CUN and AW wrote the paper, with all the authors approving the final version.

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herman, S., Niemann, C., Farooqui, M. et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia 28, 2188–2196 (2014). https://doi.org/10.1038/leu.2014.122

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.122

This article is cited by

Search

Advanced search

Quick links