More than a feeling: new approach required for assessing immunosuppression

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Despite advances in treatment and survival seen in the past decade, infective complications are a significant cause of morbidity and mortality in patients with CLL, with infection related mortality ranging from 30 to 50% [1]. This stems from multiple disease and treatment related factors. Disease related impairment of the immune system is well known, and involves multiple arms of the immune system including hypogammaglobulinemia and numerical and functional deficits of T lymphocytes, monocytes and neutrophils, compounded by defects in the level and activity of complement [2,3]. Infection risk increases with duration and stage of disease. Unsurprisingly, the pattern of infections seen with or without treatment with alkylating agents consists mainly of infections with encapsulated bacteria [2].

The introduction of various treatment regimens has added to the pre-existing disease related immunosuppression. Although purine analogs have led to significantly improved disease response rates, they have also resulted in a change in the incidence and spectrum of infections through selective depletion of CD4 T lymphocytes for as long as 2 years [3]. In addition to bacterial infections, previously unseen opportunistic infections such as Pneumocystis jirovecii and Listeria monocytogenes and reactivation of latent viral infections have been increasingly detected in this patient group [4]. It should be noted that with successful disease treatment and remission, the risk of severe and opportunistic infections declines with increasing length of remission [5].

Purine analogs such as fludarabine are now used in combination with cyclophosphamide and rituximab (FCR) as first-line therapy. While the addition of rituximab to fludarabine and cyclophosphamide has not led to an overall increased incidence of infections, rare and often fatal viral infections such as JC virus-associated progressive multifocal leukoencephalopathy have been associated with rituximab use [2]. In this issue, Appleby et al. describe two patients with CLL managed with FCR who presented with febrile episodes in association with high detectable BK viral loads in urine [6]. BK virus belongs to the same polyomavirus family as JC virus. High BK viral load was associated with hemorrhagic cystitis in one of the cases, while the other had symptoms of cystitis. Although not heavily pretreated, both cases had significant burden of disease. BK virus related hemorrhagic cystitis is uncommonly seen outside of transplant recipients, and is a marker of severe and profound immunosuppression.

Purine analogs used in combination therapy for salvage treatment are associated with a further increased risk of infection compared to first-line therapy, highlighting refractory disease and multiple treatment courses as risk factors for infection [2,7]. Cumulative immunosuppression results from a contribution of progressive or refractory disease and treatment related factors, but this is often difficult to assess. Lessons learnt from past studies have resulted in the use of prophylaxis such as trimethoprim–sulfamethoxazole against Pneumocystis and Listeria, and the use of acyclovir against reactivation of herpes viruses for patients managed with fludarabine or monoclonal antibodies such as alemtuzumab [3,8]. For some infections such as the cases presented by Appleby et al., prophylaxis has not proven feasible. Although prophylaxis reduces the rates of some infective complications such as Pneumocystis or herpes viruses, the duration of prophylaxis required has remained largely undefined. There is some evidence that the commonly practiced duration of prophylaxis of several months after ceasing treatment may not be adequate, due to longer than expected persistence of immunosuppression [9].

In patients with CLL, there is interplay between disease, treatment related immunological deficits and consequent risk and patterns of infection [2,3]. However, it is not always clear why some develop more serious and rare infections than others. This provides an opportunity for the use of immunological profiling to determine depth of immunosuppression and thus predict infective risk. Purine analogs, the current standard treatment for CLL, are known to deplete T lymphocytes. This depletion of T lymphocytes is thought to contribute to the range of opportunistic infections seen [4,5]. Correlation between CD4 cell counts and opportunistic infection risk and type has been long established in the human immunodeficiency virus (HIV) positive patient population [10]. While this correlation is not as well described in the hematology population, there is evidence, when CD4 counts are reported, that opportunistic infections such as P. jirovecii occur in association with CD4 counts < 200 cells/μL in patients managed with FCR [9]. Future studies of opportunistic infective complications should consider reporting CD4 cell counts where available, to help define this association.

Improved survival afforded by therapies for CLL will result in a large group of patients maintained by multiple lines of treatment with cumulative immunosuppression. In our opinion, monitoring of CD4 cell counts in patients with CLL managed with purine analogs and/or alemtuzumab may aid the identification of “at risk” patients and help guide commencement and duration of prophylaxis. The management of infective complications in HIV-positive patients has shown that CD4 guided prophylaxis management is practical and effective [10]. However, the utility of this approach in the hematology population, as well as the incorporation of more complex immunological profiling such as quantification of T cell responses to pathogenic antigens, will require further study, correlation with epidemiological studies of infective complications and clinical validation, before it can be considered standard practice.

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