Infections in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib: Incidence and Predisposing Factors

EA Dmitrieva1, EA Nikitin1, EE Markova1, NYu Dmitrieva2, VV Ptushkin1

1 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

2 Aston Consulting, 10 bld. 3 Shabolovka str., Moscow, Russian Federation, 119049

For correspondence: Evgenii Aleksandrovich Nikitin, MD, PhD, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: +7(916)572-06-44; e-mail:

For citation: Dmitrieva EA, Nikitin EA, Markova EE, et al. Infections in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib: Incidence and Predisposing Factors. Clinical oncohematology. 2019;12(4):438–48 (In Russ).

DOI: 10.21320/2500-2139-2019-12-4-438-448


Background. Infections are a common complication of chronic lymphocytic leukemia (CLL). The lack of recommendations for infection prevention in CLL patients treated with ibrutinib can be attributed by an insufficiency of data in the literature.

Aim. To assess the incidence and nature of infections in CLL patients treated with ibrutinib and to analyze predisposing factors.

Materials & Methods. The paper provides data on bacterial, viral, and fungal infections in CLL patients treated with ibrutinib for 4.2 years (November 2014 to December 2018) in a single center. Severity grade was determined according to CTCAE criteria (version 4).

Results. The trial included 240 CLL patients. Median age was 65 years (range 32–91), 86 (36 %) patients were female, and 117 (48 %) patients had Binet stage C. Ibrutinib as monotherapy was administered to 204 (85 %) patients, 36 (15 %) patients received it in combination with monoclonal anti-CD20 antibodies. Median follow-up was 14.8 months (range 1–54). Most patients (n = 224, 93 %) received ibrutinib for relapsed CLL. Median number of prior therapy lines was 3 (range 1–12). Neutropenia (specified as neutrophil level < 1000 cells/µL) before ibrutinib treatment was identified in 20 (8 %) patients. Glucocorticoid hormones (GCs) together with ibrutinib were administered to 20 patients. A total of 525 infectious episodes were registered in 183 patients. Out of them 381 (72.5 %) were bacterial/mixed, 115 (22 %) were viral, and 29 (5.5 %) were fungal infections. Among bacterial/mixed infections 121 (32 %) episodes were qualified as infection of grade 3 and 43 (11 %) episodes were qualified as grade 4. In 7 (1.8 %) patients infections were fatal. Within 12 months overall cumulative incidence of bacterial infections of grade 3/4 was 37 % (95% confidence interval [95% CI] 31–43 %), as for viral infections it was 28 % (95% CI 22–34 %), and as for fungal infections it was 8 % (95% CI 4–12 %). Higher cumulative incidence of bacterial infections of grade 3/4 was identified in patients with ≥ 3 lines of therapy before ibrutinib treatment (hazard ratio [HR] 2.0; 95% CI 1.36–2.97), with Binet stage C (HR 1.4; 95% CI 0.95–2.08), with ECOG status ≥ 2 (HR 2.4; 95% CI 1.6–3.6), baseline neutropenia (HR 1.25; 95% CI 0.73–2.13), as well as in men (HR 1.8; 95% CI 1.16–2.8; = 0.004). Multivariate analysis showed that male sex (HR 1.89; 95% CI 0.5–3.0; = 0.006), ECOG status ≥ 2 (HR 1.97; 95% CI 0.5–3.0), and baseline neutropenia (HR 1.76; 95% CI 0.99–3.1) were significant and independent risk factors. Cumulative incidence of any fungal infection was associated with simultaneous use of GCs (HR 6.0; 95% CI 5.85–14.7) and baseline neutropenia (HR 2.36; 95% CI 0.95–5.85). The only parameter significantly associated with viral infections was the number of prior therapy lines ≥ 3 (HR 1.74; 95% CI 1.06–2.86; = 0.029).

Conclusion. Patients with baseline neutropenia and ECOG status ≥ 2 face the highest risk of severe bacterial infections. We believe that antibacterial prophylaxis should be considered in such patients till ECOG status becomes < 2 and neutropenia resolves. Patients receiving GCs together with ibrutinib face the risk of fungal infections at any stage of treatment. In these patients the simultaneous antifungal prophylaxis should be considered.

Keywords: chronic lymphocytic leukemia, infections, ibrutinib.

Received: March 27, 2019

Accepted: September 19, 2019

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  1. Molica S. Infections in chronic lymphocytic leukemia: risk factors, and impact on survival, and treatment. Leuk Lymphoma. 1994;13(3–4):203–14. doi: 10.3109/10428199409056283.

  2. da Cunha-Bang, C, Simonsen J, Geisler C, et al. Improved survival for patients diagnosed with chronic lymphocytic leukemia in the era of chemo-immunotherapy: a Danish population-based study of 10455 patients. Blood Cancer J. 2016;6(11):e499. doi: 10.1038/bcj.2016.105.

  3. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25):2425–37. doi: 10.1056/NEJMoa1509388.

  4. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–23. doi: 10.1056/NEJMoa1400376.

  5. Winqvist M, Asklid A, Andersson P, et al. Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group. Haematologica. 2016;101(12):1573–80. doi: 10.3324/haematol.2016.144576.

  6. Perkins JG, Flynn JM, Howard RS, Byrd JC. Frequency and type of serious infections in fludarabine-refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma: implications for clinical trials in this patient population. Cancer. 2002;94(7):2033–9. doi: 10.1002/cncr.0680.

  7. Mohamed AJ, Yu L, Backesjo C-M, et al. Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009;228(1):58–73. doi: 10.1111/j.1600-065x.2008.00741.x.

  8. Niemann CU, Herman SEM, Maric I, et al. Disruption of in vivo Chronic Lymphocytic Leukemia Tumor-Microenvironment Interactions by Ibrutinib-Findings from an Investigator-Initiated Phase II Study. Clin Cancer Res. 2016;22(7):1572–82. doi: 10.1158/1078-0432.ccr-15-1965.

  9. Chun J-K, Lee TJ, Song JW, et al. Analysis of clinical presentations of Bruton disease: a review of 20 years of accumulated data from pediatric patients at Severance Hospital. Yonsei Med J. 2008;49(1):28–36. doi: 10.3349/ymj.2008.49.1.28.

  10. Chan TS, Au-Yeung R, Chim C-S, et al. Disseminated fusarium infection after ibrutinib therapy in chronic lymphocytic leukaemia. Ann Hematol. 2017;96(5):871–2. doi: 10.1007/s00277-017-2944-7.

  11. Arthurs B, Wunderle K, Hsu M, Kim S. Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia. Respir Med Case Rep. 2017;21:27–9. doi: 10.1016/j.rmcr.2017.03.011.

  12. Okamoto K, Proia LA, Demarais PL. Disseminated Cryptococcal Disease in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib. Case Rep Infect Dis. 2016;2016:1–3. doi: 10.1155/2016/4642831.

  13. Lee R, Nayernama A, Jones SC, et al. Ibrutinib-associated Pneumocystis jirovecii pneumonia. Am J Hematol. 2017;92(11):E646–E648.

  14. Ahn IE, Jerussi T, Farooqui M, et al. Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. Blood. 2016;128(15):1940–3.

  15. Ruchlemer R, Ami BR, Lachish T. Ibrutinib for Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374(16):1593–4. doi: 10.1056/nejmc1600328.

  16. Chamilos G, Lionakis MS, Kontoyiannis DP. Call for Action: Invasive Fungal Infections Associated With Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways. Clin Infect Dis. 2018;66(1):140–8. doi: 10.1093/cid/cix687.

  17. Ghez D, Calleja A, Protin C, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018;131(17):1955–9. doi: 10.1182/blood-2017-11-818286.

  18. Baron M, Zini JM, Challan BT, et al. Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis. Leuk Lymphoma. 2017;58(12):2981–2. doi: 10.1080/10428194.2017.1320710.

  19. Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200–11. doi: 10.1016/s1470-2045(15)00465-9.

  20. Sun C, Tian X, Lee YS, et al. Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood. 2015;126(19):2213–9. doi: 10.1182/blood-2015-04-639203.

  21. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813–21. doi: 10.1086/588660.

  22. Moreira J, Rabe KG, Cerhan JR, 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(1):136–41. doi: 10.1038/leu.2012.187.

  23. Morrison VA. Infectious complications of chronic lymphocytic leukaemia: pathogenesis, spectrum of infection, preventive approaches. Best Pract Res Clin Haematol. 2010;23(1):145–53. doi: 10.1016/j.beha.2009.12.004.

  24. Morrison VA, Rai KR, Peterson BL, et al. Impact of therapy With chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011. J Clin Oncol. 2001;19(16):3611–21. doi: 10.1200/jco.2001.19.16.3611.

  25. Anaissie EJ, Kontoyiannis DP, O’Brien S, et al. Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med. 1998;129(7):559–66. doi: 10.7326/0003-4819-129-7-199810010-00010.

  26. Hensel M, Kornacker M, Yammeni S, et al. 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(4):600–6. doi: 10.1046/j.1365-2141.2003.04497.x.

  27. Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011–9. doi: 10.1182/blood-2018-10-879429.

  28. Baden LR, Swaminathan S, Angarone M, et al. Prevention and Treatment of Cancer-Related Infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14(7):882–913. doi: 10.6004/jnccn.2016.0093.

  29. Varughese T, Taur Y, Cohen N, et al. Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer. Clin Infect Dis. 2018;67(5):687–92. doi: 10.1093/cid/ciy175.

  30. Jongstra-Bilen J, Cano AP, Hasija M, et al. Dual functions of Bruton’s tyrosine kinase and Tec kinase during Fcgamma receptor-induced signaling and phagocytosis. J Immunol. 2008;181(1):288–98. doi: 10.4049/jimmunol.181.1.288.

  31. Strijbis K, Tafesse F, Fairn GD, et al. Bruton’s Tyrosine Kinase (BTK) and Vav1 contribute to Dectin1-dependent phagocytosis of Candida albicans in macrophages. PLoS Pathog. 2013;9(6):e1003446. doi: 10.1371/journal.ppat.1003446.

  32. Wierda WG, Byrd JC, Abramson JS, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 5.2019 – May 23, 2019. Available from: (accessed 5.07.2019).

Taxonomic Structure and Antibiotic Resistance of Bloodstream Infection Pathogens in Oncohematological Patients

NS Bagirova

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Natal’ya Sergeevna Bagirova, DSci, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-18-60; e-mail:

For citation: Bagirova NS. Taxonomic Structure and Antibiotic Resistance of Bloodstream Infection Pathogens in Oncohematological Patients. Clinical oncohematology. 2015;8(2):191–200 (In Russ).


Background & Aims. In oncohematology, infections are one of main causes of morbidity and mortality in patients with hematological malignancies. Changing epidemiological patterns of infections in patients with hematological malignancies are characterized not only by the appearance of new pathogens of bloodstream infections, but also by the growth of pathogens resistant to antimicrobial drugs. It is important to conduct constant monitoring of taxonomic structure of bloodstream infections pathogens and their antimicrobial resistance in order to ensure adequate and timely treatment of severe infections. The aim of the study is the following: analysis of the taxonomic structure of pathogens isolated while diagnosing bacteremia in adult cancer patients using modern devices taking into account efficacy of the therapy of severe infections.

Methods. A microbiological study of blood samples of adult patients with hematological malignancies was carried out over the period from 2005 till 2013, if sepsis and other severe infections were suspected. Bacteremia was diagnosed using hematological analyzer/incubator Bactec FX400 (Becton Dickinson, USA) and Bact/Alert (BioMerieux, France), identification of strains was done using mass-spectrometer MALDI-TOF Microflex LT (Biotyper, Bruker Daltonics, Germany). Antimicrobial susceptibility was determined using automatic analyzers Microscan Walk Away 40/96+ (Siemens, Germany) and Vitek 2 (BioMerieux, France). Comparative data of foreign researchers are presented.

Results. 3794 blood cultures were obtained, 600 of which (15.8 %) demonstrated growth. Of 392 strains, only 210 (53.6 %) strains were considered true causative agents of bacteremia. No statistically significant differences in the frequency of isolation of Gram-positive cocci (47.6 %) and Gram-negative rods (39.5 %) were found. Fungi were significantly less common than Gram-positive cocci and Gram-negative rods (9 %; < 0.0001). Other microorganisms constituted 3.8 %.

Conclusion. Therapy and prevention of infectious complications in adult patients with hematological malignancies are accompanied by development of growing antibiotic resistance of pathogens. Changes in taxonomic structure of pathogens of bloodstream infections should be taken into account when prescribing the empirical and etiotropic treatment.

Keywords: infections, cancer, bloodstream infections, bacteriemia, antimicrobial resistance, oncohematological disorders, antimicrobial therapy.

Received: January 12, 2015

Accepted: January 30, 2015

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  1. European Centre for Disease Prevention and Control (ECDC). Annual epidemiological report on communicable diseases in Europe 2008. Stockholm: ECDC; 2008.
  2. Pien BC, Sundaram P, Raoof N, et al. The clinical and prognostic importance of positive blood cultures in adults. Am J Med. 2010;123(9):819–28. doi: 10.1016/j.amjmed.2010.03.021.
  3. Dreyer AW. Blood Culture Systems: From Patient to Result. In: Azevedo L, ed. Sepsis – An Ongoing and Significant Challenge. InTech; 2012. pp. 287–310. doi: 10.5772/2958.
  4. Dellinger RP, Carlet JM, Masur H, et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32(3):858–73. doi: 10.1097/01.ccm.0000117317.18092.e4.
  5. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589–96. doi: 10.1097/01.ccm.0000217961.75225.e9.
  6. Girmenia C, Menichetti F. Current Epidemiology and Prevention of Infectious Complications in Cancer Patients. Eur Oncol Haematol. 2011;7(4):270–7. doi: 10.17925/eoh.2011.07.04.270.
  7. Baron EJ, Miller JM, Weinstein MP, et al. A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM)a. Clin Infect Dis. 2013;57(4): e22–e121. doi: 10.1093/cid/cit278.
  8. Багирова Н.С. Микробиологическая диагностика и рациональные подходы к терапии сепсиса у онкогематологических больных: Автореф. ¼ д-ра мед. наук. М., 2003. 274 с.
    [Bagirova NS. Mikrobiologicheskaya diagnostika i ratsional’nye podkhody k terapii sepsisa u onkogematologicheskikh bol’nykh. (Microbiological diagnosing and rational approaches to therapy of sepsis in oncohematological patients.) [dissertation] Moscow; 2003. 274 p. (In Russ)]
  9. Багирова Н.С., Дмитриева Н.В. Микробиологическая диагностика бактериемии. Пособие для врачей. М.: Министерство здравоохранения Российской Федерации, 2004. 35 с.
    [Bagirova NS, Dmitrieva NV. Mikrobiologicheskaya diagnostika bakteriemii. Posobie dlya vrachei. (Microbiological diagnosing of bacteriemia. Manual for physicians.) Moscow: Ministerstvo zdravookhraneniya Rossiiskoi Federatsii Publ.; 2004. 35 p. (In Russ)]
  10. Багирова Н.С. Современное состояние диагностики бактериемии. Сопроводительная терапия в онкологии. 2006;3:23–38.
    [Bagirova NS. State-of-the-art diagnostics of bacteriemia. Soprovoditel’naya terapiya v onkologii. 2006;3:23–38. (In Russ)]
  11. Laupland KB, Deirdre CL. Population-Based Epidemiology and Microbiology of сommunity-Onset Bloodstream Infections. Clin Microbiol Rev. 2014;27(4):647–64. doi: 10.1128/cmr.00002-14.
  12. Molnar Z, Fogas J. Timing IgM treatment in sepsis: is procalcitonin the answer? In: Vincent J-L, ed. Annual update in intensive care and emergency medicine 2012. Springer; 2012. pp. 109–15.
  13. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America (IDSA Guidelines). Clin Infect Dis. 2011;52(4):e56–e93. doi: 10.1093/cid/cir073.
  14. European Centre for Disease Prevention and Control (ECDC). Annual epidemiological report on communicable diseases in Europe 2009. Stockholm, European Centre for Disease Prevention and Control (Surveillance Report – 2.6 Antimicrobial resistance and healthcare-associated infections); 2010. рр. 167–78.
  15. Bagirova N, Dmitrieva N. Bacteriemia in patients with hematological malignancies. J Clin Microbiol Infect Dis. 2005;11(Suppl 2):678.
  16. Bal AM, Garau J, Gould IM, et al. Vancomycin in the treatment of meticillin-resistant Staphylococcus auseus (MRSA) infection: End or an era? J Glob Antimic Resist. 2013;1(1):23–30. doi: 10.1016/j.jgar.2013.01.002.
  17. Peel T, Cheng AC, Spelman T, et al. Differing risk factor for vancomycin-resistant and vancomycin-sensitive enterococcal bacteraemia. J Clin Microbiol Infect Dis. 2011;18(4):388–94. doi: 10.1111/j.1469-0691.2011.03591.x.
  18. Kim YJ, Kim SI, Hong KW, et al. Carbapenem-resistant Acinetobacter baumannii: diversity of resistant mechanism and risk factor for infection. Epidemiol Infect. 2012;140(1):137–45. doi: 10.1017/s0950268811000744.
  19. Vila J, Pachon J. Acinetobacter baumannii resistant to everything: what should we do? J Clin Microbiol Infect Dis. 2011;17(7):955–6. doi: 10.1111/j.1469-0691.2011.03566.x.
  20. Villa-Fares X, Garcia de La Maria C, Lopez-Rojas R, et al. In vitro activity of several antimicrobial peptides against colistin-susceptible and colistin-resistant Acinetobacter baumannii. J Clin Microbiol Infect Dis. 2011;18(4):383–7. doi: 10.1111/j.1469-0691.2011.03581.x.
  21. Bagirova NS, Dmitrieva NV, Blokhin NN. Yeasts in patients (PTS) with hematologic malignancies (HM). Intern J Infect Dis. 2002;6(Suppl 2):S45. doi: 10.1016/s1201-9712(02)90273-0.
  22. Pfaller MA, Diekema DJ. Progress in antifungal susceptibility testing of Candida spp. by use of Clinical and Laboratory Standards Institute broth microdilution methods, 2010 to 2012. J Clin Microbiol. 2012;50(9):2846–56. doi: 10.1128/jcm.00937-12.
  23. Ranque S, Lachaud L, Gari-Toussaint M, et al. Interlaboratory reproducibility of Etest amphotericin B and caspofungin yeast susceptibility testing and comparison with the CLSI method. J Clin Microbiol. 2012;50(7):2305–9. doi: 10.1128/jcm.00490-12.
  24. Rangaraj G, Granwehr BP, Jiang Y, et al. Perils of quinolone exposure in cancer patients: breakthrough bacteremia with multidrug-resistant organisms. Cancer. 2010;116(4):967–73. doi: 10.1002/cncr.24812.