Elsevier

Blood Reviews

Volume 32, Issue 6, November 2018, Pages 499-507
Blood Reviews

Review
Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies

https://doi.org/10.1016/j.blre.2018.04.007Get rights and content

Abstract

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia with infections a leading cause of morbidity and mortality. Recently there has been a paradigm shift from the use of chemo-immunotherapies to agents targeting specific B-lymphocyte pathways. These agents include ibrutinib, idelalisib and venetoclax. In this review, the risks and timing of infections associated with these agents are described, taking into account disease and treatment status. Treatment with ibrutinib as monotherapy or in combination with chemo-immunotherapies is not associated with additional risk for infection. In contrast, the use of idelalisib is associated with a 2-fold risk for severe infection and opportunistic infections. Venetoclax does not appear to be associated with additional infection risk. The evolving spectrum of pathogens responsible infections in CLL patients, especially those with relapsed and refractory disease are described, and prevention strategies (prophylaxis, monitoring and vaccination) are proposed.

Introduction

Chronic lymphocytic leukaemia (CLL) is a malignancy of mature B lymphocytes comprising nearly 30% of all leukaemias [1,2]. Infections are a leading cause of morbidity and mortality in patients with CLL, contributing to the cause of death in more than half of all patients [1,2].

Patients with CLL are at increased risk for infection due to patient, disease and treatment-related factors (Fig. 1) [[1], [2], [3], [4]]. Increased age of patients is a known risk factor for infection in patients with haematological malignancy [5,6]. The majority of patients with CLL are elderly, and patients aged 65 years and older account for over half of annual deaths attributable to CLL [5]. Disease-related risks for infection include deficiencies in multiple arms of the immune system [7,8]. In particular, patients with CLL have reported deficits in cell-mediated immunity with hypogammaglobulinaemia, down-regulation of T-cell function and defects in antibody dependent cellular cytotoxicity [[7], [8], [9], [10]]. In the innate arm of the immune system, defective function of neutrophils, natural killer (NK) cells and decreased complement activity have been reported [7,8]. In addition, stage and status of disease and response to treatment are important determinants of infection risk [4,9]. Therapy for relapsed disease is associated with increased risk compared to use of the same treatment as initial therapy for the treatment naïve [11].

Despite advances in treatment over several decades, CLL remains incurable with disease remission maintained through increasing lines of therapy [7]. Increasing lines of therapy are associated with increased risk for infection [4]. In the past the standard of care was purine analogues in combination with monoclonal antibodies [7]. These include regimens such as fludarabine, cyclophosphamide and rituximab (FCR), bendamustine and rituximab (BR) or a combination of an anti-CD20 monoclonal antibody such as ofatumumab or obinutuzumab with chlorambucil. The rates, risk and spectrum of infections with the use of these agents are well described and supported by clinical guidelines to minimise morbidity and mortality [1,2,11,12] (Fig. 2). However, the treatment of CLL has undergone a paradigm shift from the use of chemo-immunomodulatory drugs to targeted therapies, mostly for patients with relapsed disease [7].

These therapies target various aspects of the B cell receptor signalling pathway and proteins required for cellular survival and their impact on patterns and risks for infection remains poorly defined [[13], [14], [15]](Fig. 3). This review aims to describe the epidemiology of infections in patients with CLL managed with three new-generation targeted therapies (ibrutinib, idelalisib and venetoclax). Evaluation of infection risk associated with the use of these new agents will take into account use in treatment naïve vs. patients with relapsed disease, the disease response to treatment, its use as monotherapy, following or in combination with chemo-immunodulatory therapy.

Section snippets

Ibrutinib

Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk), a critical enzyme involved in development, activation, function and survival of B lymphocytes [13,14]. In contrast, T lymphocytes appear to be spared from Btk inhibition [13,14]. Ibrutinib-induced Btk inhibition results in disruption of cellular microenviroment and promotes the apoptosis and reduced survival of CLL cells [13]. Although activated B cells are absent with the use of ibrutinib, serum immunoglobulin levels are

Prevention of infection

Patients with CLL in the era of targeted therapies remain at significant risk for infection and up to 50% of patients with relapsed and refractory disease still experience severe infection [19,25]. Disease-related immune deficits such as hypogammaglobulinaemia progresses with increasing disease duration with immunoglobulin G levels continuing to decrease despite treatment with targeted therapies [16,63,64]. Comprehensive assessment for history of recurrent infections and measurement of serum

Conclusion

Overall, rates of infection reported in the setting of ibrutinib monotherapy for CLL are 10 to 15%, with rates of 30–50% for relapsed disease [22,23]. Compared to the use of alkylating drugs or monoclonal anti-CD20 antibodies, infection risks are not increased [19,20]. Further, the addition of ibrutinib to chemo-immunotherapy does not appear to confer additional risk [28]. Available trials data do not demonstrate the use of venetoclax to be associated with additional risk for infection in CLL

Practice points

  • Patients with CLL remain at risk for infection due to disease and treatment-related factors despite advances in therapy

  • Infection risk is associated with disease status with higher risk associated with relapsed and refractory disease and risk reduction seen with immune recovery from effective targeted therapy

  • Ibrutinib does not appear to be associated with increased risk when used as monotherapy or in combination with chemoimmunotherapy compared to alkylating drugs, monoclonal anti-CD20

Research agenda

  • Dedicated studies of the patterns, outcomes and risk factors for infection to identify high-risk periods and patients treated with targeted therapies are required

  • Pharmaco-surveillance studies ensure early detection of the emergence of other opportunistic infections or reactivation of latent viruses with current and future targeted therapies

  • Evaluation of preventative approaches such as prophylaxis and optimal duration require further study

Conflict of interest

B.W.T has received speaker fees from Merck Sharpe and Dohme. C.S.T has received research funding and honorarium from Janssen and Abbvie and honorarium from Gilead. S·H has received an honorarium from Gilead and educational grant from Abbvie. M.A.S has received research funding and honorarium from Merck Sharpe and Dohme and Gilead.

Acknowledgements

Dr. Benjamin W Teh is a Peter MacCallum Cancer Centre clinical research fellow and is a National Health and Medical Research Council (NHMRC) early career fellow. Prof. Monica Slavin is director of NHMRC funded National Centre for Infections in Cancer.

References (80)

  • J.A. Burger et al.

    Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study

    Lancet Oncol

    (2014)
  • S.M. Jaglowski et al.

    Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study

    Blood

    (2015)
  • A. Chanan-Khan 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)
  • B. Arthurs et al.

    Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia

    Respir Med Case Rep

    (2017)
  • I.E. Ahn et al.

    Atypical pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib

    Blood

    (2016)
  • P. Jain et al.

    Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib

    Blood

    (2015)
  • A.R. Mato et al.

    Ibrutinib-induced pneumonitis in patients with chronic lymphocytic leukemia

    Blood

    (2016)
  • M.D. Blunt et al.

    Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

    Leuk Res Rep

    (2015)
  • A.D. Zelenetz et al.

    Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial

    Lancet Oncol

    (2017)
  • J.R. Brown et al.

    Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia

    Blood

    (2014)
  • S.M. O'Brien et al.

    A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia

    Blood

    (2015)
  • B.L.K.H.T. Lampson et al.

    Efficacy results of a phase 2 trial evaluating Idelalisib plus Ofatumumab in patients with previously untreated chronic lymphocytic leukemia

    Blood

    (2017)
  • M.A. Anderson et al.

    The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism

    Blood

    (2016)
  • S. Coutre et al.

    Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy

    Blood

    (2018)
  • J.A. Jones et al.

    Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial

    Lancet Oncol

    (2018)
  • S. Stilgenbauer et al.

    Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study

    Lancet Oncol

    (2016)
  • J.F. Seymour et al.

    Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study

    Lancet Oncol

    (2017)
  • E.E. Perez et al.

    Update on the use of immunoglobulin in human disease: a review of evidence

    J Allergy Clin Immunol

    (2017)
  • S.K. Agarwal et al.

    Management of venetoclax-posaconazole interaction in acute myeloid leukemia patients: evaluation of dose adjustments

    Clin Ther

    (2017)
  • C.O. Morrissey et al.

    Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial

    Lancet Infect Dis

    (2013)
  • M.Z. Farooqui et al.

    Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial

    Lancet Oncol

    (2015)
  • V.A. Morrison

    Management of infectious complications in patients with chronic lymphocytic leukemia

    Hematology Am Soc Hematol Educ Program

    (2007)
  • A. Molteni et al.

    Multiple lines of chemotherapy are the main risk factor for severe infections in patients with chronic lymphocytic leukemia with febrile episodes

    Haematologica

    (2005)
  • M. Hensel 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)
  • L. Balducci et al.

    Chronic lymphocytic leukemia in the elderly: epidemiology and proposed patient-related approach

    Cancer Control

    (2015)
  • A.D. Zelenetz et al.

    Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015

    J Natl Compr Canc Netw

    (2015)
  • K.A. Thursky et al.

    Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab*

    Br J Haematol

    (2006)
  • L.J. Worth et al.

    An analysis of the utilisation of chemoprophylaxis against pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer hospital

    Br J Cancer

    (2005)
  • V. Kaur et al.

    Ibrutinib in CLL: a focus on adverse events, resistance, and novel approaches beyond ibrutinib

    Ann Hematol

    (2017)
  • R.H. Advani et al.

    Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies

    J Clin Oncol

    (2013)
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