ReviewInfections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies
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
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Patients with CLL remain at risk for infection due to disease and treatment-related factors despite advances in therapy
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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
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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
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Dedicated studies of the patterns, outcomes and risk factors for infection to identify high-risk periods and patients treated with targeted therapies are required
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Pharmaco-surveillance studies ensure early detection of the emergence of other opportunistic infections or reactivation of latent viruses with current and future targeted therapies
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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.
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