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

Response to the conjugate pneumococcal vaccine (PCV13) in patients with chronic lymphocytic leukemia (CLL)

Leukemia volume 35, pages 737–746 (2021)Cite this article

Subjects

Abstract

Pneumococcal (PC) vaccination is recommended for patients with chronic lymphocytic leukemia (CLL). However, response to vaccines has been investigated in a small series of CLL patients. We analyzed the antibody response and outcomes of 112 CLL patients who received the 13-valent pneumococcal conjugate vaccine (PCV13). An immune response was defined by a twofold increase in the PC-IgG levels assessed by ELISA. The median age of patients was 68 years, 23.2% showed IgG levels ≤ 400 mg/L, 6.3% progressive disease, 52% unmutated IGHV. Twenty-two (19.6%) patients were treatment-naïve and 90 (80.4%) previously treated (40.2% front-line chemoimmunotherapy; ibrutinib first/advanced-line, 9.8%/21.4%; idelalisib advanced-line, 8.9%). Nine (8%) patients developed an immune response, eight treatment-naive, and one on front-line ibrutinib. No responses were observed in patients previously treated with chemoimmunotherapy. Age ≥ 60 years (p = 0.007), IgG levels < 400 mg/L (p < 0.0001), prior treatment (p < 0.0001), and signs of disease progression (p = 0.04) were associated with a lower response rate. Pneumonia-free survival was significantly shorter in patients with clinical signs of progressive disease (HR, 8.39), prior pneumonia (HR, 7.03), and TP53 disruption (HR, 2.91). In conclusion, our results suggest that vaccination should be offered at diagnosis to CLL patients with early stage and stable disease who have better resources for an effective immune response.

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
Fig. 2: Survival probability.
Fig. 3: Pneumonia-Free Survival (PnFS).

Similar content being viewed by others

References

  1. National Cancer Institute. Surveillance, Epidemiology and End Results Program; 2007–2013. https://seer.cancer.gov/statfacts/html/clyl.html.

  2. Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG, et al. Chronic lymphocytic leukaemia. Nat Rev Dis Prim. 2017;3:17008.

    Article  PubMed  Google Scholar 

  3. Ravandi F, O’Brien S. Immune defects in patients with chronic lymphocytic leukemia. Cancer Immunol Immunother. 2006;55:197–209.

    Article  PubMed  Google Scholar 

  4. Forconi F, Moss P. Perturbation of the normal immune system in patients with CLL. Blood. 2015;126:573–81.

    Article  CAS  PubMed  Google Scholar 

  5. Rozman C, Montserrat E, Viñolas N. Serum immunoglobulins in B-chronic lymphocytic leukemia. Nat Hist Progn Signif Cancer. 1988;15;61:279–83.

    Google Scholar 

  6. Shvidel L, Tadmor T, Braester A, Bairey O, Rahimi-Levene N, Herishanu Y, et al. Serum immunoglobulin levels at diagnosis have no prognostic significance in stage A chronic lymphocytic leukemia: a study of 1113 cases from the Israeli CLL Study Group. Eur J Haematol. 2014;93:29–33.

    Article  CAS  PubMed  Google Scholar 

  7. Parikh SA, Leis JF, Chaffee KG, Call TG, Hanson CA, Ding W, et al. Hypogammaglobulinemia in newly diagnosed chronic lymphocytic leukemia: natural history, clinical correlates, and outcomes. Cancer. 2015;1;121:2883–91.

    Article  CAS  Google Scholar 

  8. Reda G, Cassin R, Gentile M, Mauro FR, Giannarelli D, Fattizzo B, et al. IgA hypogammaglobulinemia predicts outcome in chronic lymphocytic leukemia. Leukemia. 2019;33:1519–22.

    Article  CAS  PubMed  Google Scholar 

  9. Mauro FR, Morabito F, Vincelli ID, Petrucci L, Campanelli M, Salaroli A, et al. Clinical relevance of hypogammaglobulinemia, clinical and biologic variables on the infection risk and outcome of patients with stage A chronic lymphocytic leukemia. Leuk Res. 2017;57:65–71.

    Article  CAS  PubMed  Google Scholar 

  10. Morrison VA. Infections in patients with leukemia and lymphoma. Cancer Treat Res. 2014;161:319–49.

    Article  PubMed  Google Scholar 

  11. Wadhwa PD, Morrison VA. Infectious complications of chronic lymphocytic leukemia. Semin Oncol. 2006;33:240–9.

    Article  CAS  PubMed  Google Scholar 

  12. Pleyer C, Wiestner A, Sun C. Immunological changes with kinase inhibitor therapy for chronic lymphocytic leukemia. Leuk Lymphoma. 2018;59:2792–2800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Williams AM, Baran AM, Meacham PJ, Feldman MM, Valencia HE, Newsom-Stewart C, et al. Analysis of the risk of infection in patients with chronic lymphocytic leukemia in the era of novel therapies. Leuk Lymphoma. 2018;59:625–32.

    Article  PubMed  Google Scholar 

  14. Varughese T, Taur Y, Cohen N, Palomba ML, Seo SK, Hohl TM, et al. Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer. Clin Infect Dis. 2018;16;67:687–92.

    Article  CAS  Google Scholar 

  15. Teh BW, Tam CS, Handunnetti S, Worth LJ, Slavin MA. Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies. Blood Rev. 2018;32:499–507.

    Article  PubMed  Google Scholar 

  16. Rozenbaum MH, Pechlivanoglou P, Van der Werf TS, Lo-Ten-Foe JR, Postma MJ, Hak E. The role of Streptococcus pneumoniae in community-acquired pneumonia among adults in Europe: a meta-analysis. Eur J Clin Microbiol Infect Dis. 2013;32:305–16.

    Article  CAS  PubMed  Google Scholar 

  17. Curcio D, Cane A, Isturiz R. Redefining risk categories for pneumococcal disease in adults: critical analysis of the evidence. Int J Infect Dis. 2015;37:30–35.

    Article  PubMed  Google Scholar 

  18. Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;12;61:816–9.

    Google Scholar 

  19. Kobayashi M, Bennett NM, Gierke R, Gierke R, Almendares O, Moore MR, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015;4;64:944–7.

    Article  Google Scholar 

  20. Pedrazzoli P, Piralla A, Valentino F, Cinieri S, Baldanti F. Update of the recommendations of the Italian Society of Medical Oncology on vaccination for seasonal influenza and pneumococcal infection in patients with cancer: Focus on prevention of pneumonia. Eur J Cancer Care. 2018;27:e12817.

    Article  CAS  Google Scholar 

  21. Backhaus E, Berg S, Andersson R, Ockborn G, Malmström P, Dahl M, et al. Epidemiology of invasive pneumococcal infections: manifestations, incidence and case fatality rate correlated to age, gender and risk factors. BMC Infect Dis. 2016;3:367–79.

    Article  Google Scholar 

  22. Mikulska M, Cesaro S, de Lavallade H, Di Blasi R, Einarsdottir S, Gallo G, et al. European Conference on Infections in Leukaemia group. Vaccination of patients with haematological malignancies who did not have transplantations: guidelines from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19:e188–e199.

    Article  PubMed  Google Scholar 

  23. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;21;131:2745–60.

    Article  CAS  Google Scholar 

  24. Wierda WG, Zelenetz AD, Gordon LI, Abramson JS, Advani RH, Andreadis CB, et al. NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2017. J Natl Compr Canc Netw. 2017;15:293–311.

    Article  PubMed  Google Scholar 

  25. Eichhorst B, Robak T, Montserrat E, Ghia P, Hillmen P, Hallek M. et al. ESMO Guidelines Committee. appendix 6: chronic lymphocytic leukaemia: eUpdate published online September 2016. Ann Oncol. 2016;27v143–v144.

    Article  CAS  PubMed  Google Scholar 

  26. Schuh AH, Parry-Jones N, Appleby N, Bloor A, Dearden CE, Fegan C, et al. Guideline for the treatment of chronic lymphocytic leukaemia: a British Society for Haematology Guideline. Br J Haematol. 2018;182:344–59.

    Article  PubMed  Google Scholar 

  27. Sinisalo M, Aittoniemi J, Oivanen P, Käyhty H, Ölander R, Vilpo J. Response to vaccination against different types of antigens in patients with chronic lymphocytic leukaemia. Br J Haematol. 2001;114:107–10.

    Article  CAS  PubMed  Google Scholar 

  28. Hartkamp A, Mulder AH, Rijkers GT, van Velzen-Blad H, Biesma DH. Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia. Vaccine. 2001;19:1671–7.

    Article  CAS  PubMed  Google Scholar 

  29. Pasiarski M, Rolinski J, Grywalska E, Stelmach-Goldys A, Korona-Glowniak I, Gozdz S, et al. Antibody and plasmablast response to 13-valent pneumococcal conjugate vaccine in chronic lymphocytic leukemia patients-preliminary report. PLoS ONE. 2014;9:e114966.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Svensson T, Kättström M, Hammarlund Y, Roth D, Andersson PO, Svensson M, et al. Pneumococcal conjugate vaccine triggers a better immune response than pneumococcal polysaccharide vaccine in patients with chronic lymphocytic leukemia A randomized study by the swedish CLL group. Vaccine. 2018;36:3701–7.

    Article  CAS  PubMed  Google Scholar 

  31. Andrick B, Alwhaibi A, DeRemer DL, Quershi S, Khan R, Bryan LJ, et al. Lack of adequate pneumococcal vaccination response in chronic lymphocytic leukaemia patients receiving ibrutinib. Br J Haematol. 2018;182:712–4.

    Article  PubMed  Google Scholar 

  32. Sun C, Gao J, Couzens L, Tian X, Farooqui MZ, Eichelberger MC, et al. Seasonal influenza vaccination in patients with chronic lymphocytic leukemia treated with Ibrutinib. JAMA Oncol. 2016;1;2:1656–7.

    Article  Google Scholar 

  33. Douglas AP, Trubiano JA, Barr I, Leung V, Slavin MA, Tam CS. Ibrutinib may impair serological responses to influenza vaccination. Haematologica. 2017;102:e397–e399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kapetanovic MC, Nagel J, Nordström I, Saxne T, Geborek P, Rudin A. Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B cells in rheumatoid arthritis after vaccination with a conjugate pneumococcal vaccine. Vaccine. 2017;35:903–8.

    Article  CAS  PubMed  Google Scholar 

  35. Winthrop KL, Bingham CO 3rd, Komocsar WJ, Bradley J, Issa M, Klar R, et al. Evaluation of pneumococcal and tetanus vaccine responses in patients with rheumatoid arthritis receiving baricitinib: results from a long-term extension trial substudy. Arthritis Res Ther. 2019;18;21:102.

    Article  Google Scholar 

  36. Parker AR, Park MA, Harding S, Abraham RS. The total IgM, IgA and IgG antibody responses to pneumococcal polysaccharide vaccination (Pneumovax®23) in a healthy adult population and patients diagnosed with primary immunodeficiencies. Vaccine. 2019;28;37:1350–5.

    Article  CAS  Google Scholar 

  37. Moreira J, Rabe KG, Cerhan JR, Kay NE, Wilson JW, Call TG, et al. Infectious complications among individuals with clinical monoclonal B-cell lymphocytosis (MBL): a cohort study of newly diagnosed cases compared to controls. Leukemia. 2013;27:136–41.

    Article  CAS  PubMed  Google Scholar 

  38. Hensel M, Kornacker M, Yammeni S, Egerer G, Ho AD. Disease activity and pretreatment, rather than hypogammaglobulinaemia, are major risk factors for infectious complications in patients with chronic lymphocytic leukaemia. Br J Haematol. 2003;122:600–6.

    Article  PubMed  Google Scholar 

  39. Visentin A, Imbergamo S, Gurrieri C, Frezzato F, Trimarco V, Martini V, et al. Major infections, secondary cancers and autoimmune diseases occur in different clinical subsets of chronic lymphocytic leukaemia patients. Eur J Cancer. 2017;72:103–11.

    Article  PubMed  Google Scholar 

  40. Smolej L. Efficacy of pneumococcal vaccination in chronic lymphocytic leukemia: should we rey on surrogate markers? Vaccine. 2008;10;26:1407.

    Article  CAS  Google Scholar 

  41. O’Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;26;131:1910–9.

    Article  CAS  Google Scholar 

  42. Sun C, Tian X, Lee YS, Gunti S, Lipsky A, Herman SE, et al. Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood. 2015;126:2213–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Coutre SE, Byrd JC, Hillmen P, Barrientos JC, Barr PM, Devereux S, et al. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv. 2019;25;3:1799–807.

    Article  CAS  Google Scholar 

  44. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;29;123:3390–7.

    Article  CAS  Google Scholar 

  45. EM Agency. EMA recommends new safety measures for Zydelig. European Medicines Agency; 2016. https://www.ema.europa.eu/en/documents/referral/zydelig-article-20-procedure-chmp-confirms-recommendations-use-zydelig_en-0.pdf.

  46. Maschmeyer G, De Greef J, Mellinghoff SC, Nosari A, Thiebaut-Bertrand A, Bergeron A, et al. European Conference on Infections in Leukemia (ECIL). Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology. A position paper by the European Conference on Infections in Leukemia (ECIL). Leukemia 2019;33:844–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Reinwald M, Silva JT, Mueller NJ, Fortún J, Garzoni C, de Fijter JW, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors). Clin Microbiol Infect. 2018;24(Suppl 2):S53–S70.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the ‘Sapienza’ University of Rome and the Fellowship Program of Gilead, who provided financial support for the management of this study.

Author information

Authors and Affiliations

  1. Hematology, Department of Translational and Precision Medicine, ‘Sapienza’ University, Rome, Italy

    Francesca Romana Mauro, Costantino Riemma, Serena Rosati, Marika Porrazzo, Sara Pepe, Sara Raponi, Alessandra Micozzi & Giuseppe Gentile

  2. Biostatistic Unit, Regina Elena National Cancer Institute, IRCCS, Rome, Italy

    Diana Giannarelli

  3. National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy

    Clementina Maria Galluzzo & Silvia Baroncelli

  4. Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy

    Candida Vitale & Marta Coscia

  5. Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy

    Andrea Visentin & Livio Trentin

  6. Hematology and Oncology Department, Biotechnology Research Unit, Cosenza, Italy

    Massimo Gentile

Authors
  1. Francesca Romana Mauro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diana Giannarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clementina Maria Galluzzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Candida Vitale
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrea Visentin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Costantino Riemma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Serena Rosati
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marika Porrazzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sara Pepe
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marta Coscia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Livio Trentin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Massimo Gentile
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sara Raponi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alessandra Micozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Giuseppe Gentile
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Silvia Baroncelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesca Romana Mauro.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics

This study was carried out according to the local requirements for safety reporting to Health Authorities and or Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs).

Informed consent

Patients were asked to provide informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mauro, F.R., Giannarelli, D., Galluzzo, C.M. et al. Response to the conjugate pneumococcal vaccine (PCV13) in patients with chronic lymphocytic leukemia (CLL). Leukemia 35, 737–746 (2021). https://doi.org/10.1038/s41375-020-0884-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-020-0884-z

This article is cited by

Search

Advanced search

Quick links