Version May 2024
INTRODUCTION — Infections have a major impact on the clinical course of patients with chronic lymphocytic leukemia (CLL). Patients with CLL have underlying abnormalities in immune function related to the primary disease process in addition to immune defects related to the specific antileukemic therapies administered. The spectrum of infections in CLL patients has evolved with the introduction of therapies such as the purine analogs and newer targeted therapies (phosphatidylinositol 3-kinase and Bruton tyrosine kinase inhibitors).
The immune defects related to CLL and its therapy as well as the spectrum of infectious complications will be reviewed here. The approach to infection prevention in patients with CLL is reviewed separately. The management and complications of CLL are also discussed separately. (See "Prevention of infections in patients with chronic lymphocytic leukemia" and "Overview of the treatment of chronic lymphocytic leukemia" and "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma" and "Treatment of relapsed or refractory chronic lymphocytic leukemia" and "Overview of the complications of chronic lymphocytic leukemia".)
The immune defects caused by the drugs and biologics used for CLL and other diseases is also reviewed separately. (See "Secondary immunodeficiency induced by biologic therapies".)
IMMUNE DEFECTS — Patients with chronic lymphocytic leukemia (CLL) have inherent immune defects in humoral and cell-mediated immunity that are related to the primary disease process, including hypogammaglobulinemia, abnormalities in T cell subsets, and defects in complement activity and neutrophil/monocyte function [1,2]. Therapy-related immunosuppression has further impact on immune function [3].
Humoral immunity — Hypogammaglobulinemia is the most predominant inherent immune defect in CLL patients, with subtypes immunoglobulin (Ig)G3 and IgG4 particularly affected. Hypogammaglobulinemia is related to defective functioning of T cells and non-clonal CD5-negative B cells. Hypogammaglobulinemia becomes more pronounced with longer disease duration and advanced-stage disease. There is generally no reversal in this defect, even with response to therapy. However, in one report, ibrutinib therapy resulted in partial reconstitution of humoral immunity, with an increase in IgA levels [4]. Although an association between hypogammaglobulinemia and infection frequency and survival has been demonstrated, there is no consistent correlation between a specific immunoglobulin class deficiency and infection risk [1,5,6].
The immunoglobulin heavy chain variable region (IgVH) gene may be mutated or unmutated in patients with CLL. Patients with unmutated IgVH genes tend to have a poorer prognosis than those with mutated IgVH genes. The impact of IgVH mutational status on humoral immunity and infections has been evaluated, with conflicting results [7,8]. In a study that included 33 patients with CLL, there were no significant differences in the levels of immunoglobulins or mannose-binding lectin, immune response to Haemophilus influenzae type b vaccination, or infection rate among patients with mutated versus unmutated IgVH gene status [7]. In contrast, in a retrospective review of 280 patients with CLL, those with unmutated IgVH genes had a significantly shorter time to first infection (31 versus 62 months) and significantly higher infection-related mortality than patients with mutated IgVH genes, although immunoglobulin levels were comparable [8]. Patients with p53 abnormalities, as well as CD38 positivity, had a significantly shorter time to first infection; zeta-chain-associated protein kinase 70 (ZAP-70) levels had no impact on occurrence.
The most common site of infection in CLL patients is the respiratory tract, which may be related to serum IgA and IgG4 deficiencies and possibly to mucosal immune defects [6]. It is not clear if mucosal immunity is regulated independently of systemic immunity or if mucosal B cells are part of the malignant B cell clone. The integrity of mucosal immune function and the relationship between systemic and mucosal immune dysfunction are not well delineated. In a report of serum and mucosal (salivary) immunoglobulin levels measurement in CLL patients, salivary IgM levels were profoundly decreased in hypogammaglobulinemic CLL patients, but no differences were found in salivary IgG or IgA levels among CLL patients versus controls [6]. However, no correlation between salivary immunoglobulin levels and infection occurrence was found.
Cell-mediated immunity — Although CLL patients have inherent defects in various parameters of cell-mediated immunity and complement activity, their impact on infection risk has not been examined. These defects may be related to transforming growth factor beta (TGF-beta) secretion by CLL B cells, which inhibits B cell proliferation, as well as release of circulating interleukin (IL-)2 receptor, which binds endogenous IL-2, resulting in down-regulation of T cell function.
CD8-positive T cells secrete IL-4, which induces bcl-2 protein expression, possibly contributing to CLL pathogenesis and disease progression. As with B cell defects, T cell defects are more pronounced with advanced-stage disease.
Complement — Decreased levels of at least one component of complement, especially properdin, are found in most patients with CLL [1]. Defects in complement activation and binding and reduced expression of the complement receptors, CR1 and CR2, on CLL B cells have also been found.
Innate immunity — Quantitative and qualitative neutrophil and monocyte defects are found in CLL patients. The absolute neutrophil count is normal to slightly decreased in untreated patients. Defects in neutrophil phagocytic and bactericidal activity, including decreased C5a-induced chemotaxis, have been demonstrated, as well as deficiencies in monocyte levels of b-glucuronidase, lysozyme, and myeloperoxidase [1].
SPECTRUM OF INFECTIONS — The spectrum of infections in CLL patients has changed over the past several decades with the introduction of CLL therapies that have specific effects on immune function, particularly on cell-mediated immunity. The infectious complications seen in these patients have evolved in relation to the specific agents used and will be discussed below in relation to the various classes of CLL therapy.
Treatment-naïve patients are at increased risk for bacterial infections caused by common pathogens, such as Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa [1]. Recurrent bacterial infections with a mucosal origin (respiratory tract, urinary tract) are also common.
Alkylating agents — For many years, standard therapy for CLL patients was chlorambucil (or alternatively, cyclophosphamide) given alone or in combination with glucocorticoids. As in treatment-naïve patients, the majority of infections in patients treated with an alkylating agent are bacterial, caused by common pathogens such those described above [1]. Recurrent bacterial infections with a mucosal origin (respiratory tract, urinary tract) are common. Fungal and viral infections occur infrequently. In more recent times, bendamustine is used in combination with rituximab. However, no specific spectrum of infectious complications has emerged with this therapeutic combination.
Purine analogs
Fludarabine — With the use of purine analogs (eg, fludarabine), which result in quantitative and qualitative T cell abnormalities, a wider spectrum of infectious complications has emerged [9-15]. Inhibition of cytokine-induced activation of STAT-1- and STAT-1-dependent gene transcription results in decreased peripheral blood T cell counts, which occurs early in treatment and persists for up to two years after discontinuation of therapy [16]. A greater impact is seen on CD4+ T cells than CD8+ T cells or NK cells. Decreased B cell and monocyte counts also occur.
In addition to common bacterial infections, opportunistic infections caused by organisms such as Listeria, mycobacteria, Nocardia, Candida, Aspergillus, Cryptococcus, Pneumocystis, and herpesviruses (herpes simplex virus [HSV], varicella-zoster virus [VZV], and cytomegalovirus [CMV]) have been reported [10-14]. The addition of glucocorticoids to fludarabine increases the risk of these opportunistic infections and is therefore generally avoided [10,13,15]. HSV and VZV infections, the majority being localized infections, are more common in patients receiving single-agent fludarabine than in those receiving chlorambucil [14].
Infections are most common during the first several cycles of therapy and are relatively uncommon after discontinuation of therapy in responding patients [10]. Risk factors for infection in patients receiving fludarabine include poor therapeutic response, advanced disease stage, receipt of prior CLL therapy, elevated lactic dehydrogenase (LDH), and renal insufficiency [10-12,15,17-19]. In a trial in which patients received initial CLL therapy with fludarabine, chlorambucil, or both agents, a low baseline IgG level was a risk factor for infection [14]. Advanced age and a decreased creatinine clearance were risk factors only in patients receiving both agents. No association between infection and response to therapy or advanced-stage disease was observed. In a large retrospective review, risk factors for major infections identified on multivariate analysis included the number of prior regimens (risk ratio [RR] 1.8, 95% CI 1.2-8.0) and hemoglobin <12 g/dL (RR 0.6, 95% CI 0.5-0.8) [18]. Age and renal function had no impact on infection risk.
The risk and spectrum of infection in patients treated with fludarabine compared with conventional regimens based on alkylating agents have been examined [14,20,21]. In one trial, patients receiving fludarabine and chlorambucil had significantly more infections than those receiving either agent alone [14]. Those receiving fludarabine alone had more major infections and herpesvirus infections compared with patients treated with chlorambucil alone. Only three Pneumocystis infections and no Aspergillus infections were observed. Similarly, in a meta-analysis of single-agent fludarabine or alkylating agent-based therapy trials, grade 3/4 (severe) infections were more common with fludarabine therapy [21].
Infections with fludarabine-cyclophosphamide combination therapy have also been evaluated [22-25]. In a randomized intergroup trial of initial CLL therapy with this combination plus myeloid growth factor support and antiviral prophylaxis or single-agent fludarabine, infection rates less than 10 percent were reported in both arms; all patients received Pneumocystis prophylaxis [23]. The German CLL Study Group studied first-line fludarabine-cyclophosphamide therapy in a phase II trial as well as in a randomized trial in younger CLL patients, comparing it with single-agent fludarabine [24,25]. In the latter trial, the occurrence of severe and opportunistic infections was comparable (fludarabine 33 percent; fludarabine-cyclophosphamide 40 percent) [26]. However, dose reductions due to myelosuppression were more common with the combination, which may have impacted the infection rate. In previously treated patients, 57 percent receiving fludarabine-cyclophosphamide had infections or fever of unknown origin, including 26 percent caused by herpesviruses and 7 percent caused by fungal pathogens [27]. The incidence of infection during the first three cycles of therapy was 74 percent. Epstein-Barr virus-associated lymphoproliferative disorders have been reported in patients who received fludarabine-cyclophosphamide followed by autologous stem cell transplant [28].
Other purine analogs — As with fludarabine, treatment with cladribine (2-chlorodeoxyadenosine) or pentostatin (deoxycoformycin) also results in quantitative T cell subset abnormalities that persist for up to one to two years after therapy discontinuation. Receipt of prior therapy was a significant risk factor for infection in younger patients receiving cladribine (45 versus 26 percent) [29]. In a series of older adult patients treated with cladribine, the infection rate was 16 percent [30]. In a phase II trial of cladribine therapy in fludarabine-refractory CLL patients, severe infections occurred in 43 percent [31]. Bacterial infections were most common, although cases of herpesvirus infection, toxoplasmosis, and candidal esophagitis were also reported. Opportunistic infections such as disseminated herpes zoster and pulmonary aspergillosis have also been reported in patients with refractory CLL receiving cladribine [32].
In a large series of CLL patients treated with cladribine alone or with prednisone, infections and fever of unknown origin occurred more often in previously treated patients than in treatment-naïve patients (49 versus 38 percent) [33]. Herpesvirus infections also occurred more often in previously treated patients (25 versus 20 percent). In a trial in which patients were randomly assigned to initial therapy with cladribine or chlorambucil plus prednisone, neutropenic fever or fever of unknown origin was more common with cladribine therapy (56 versus 40 percent) as were herpesvirus infections (21 versus 11 percent) [34]. In a phase II trial of pentostatin for both previously treated and treatment-naïve CLL patients, infections occurred in over 50 percent of patients, especially in heavily pretreated patients [35]. Opportunistic infections (herpesviruses, Candida, Pneumocystis) occurred in 26 percent of patients. The use of initial CLL therapy with pentostatin, chlorambucil, and prednisone resulted in grade 3 infections in 31 percent of patients, including herpes zoster in 20 percent of patients [36]. The administration of pentostatin, cyclophosphamide, and rituximab to previously treated CLL patients resulted in a 28 percent incidence of severe infections [37]. This incidence was only 10 percent in treatment-naïve patients [38].
Anti-CD20 monoclonal antibodies
●Rituximab – Rituximab, an anti-CD20 monoclonal antibody that causes a transient reduction in the B cell count, has been used as single-agent therapy for CLL but is more commonly used as part of combination therapy. Grade 3 or 4 (severe) infections and opportunistic infections are uncommon with rituximab monotherapy [39]. However, in a phase II trial of concurrent versus sequential fludarabine plus rituximab in 104 previously untreated CLL patients, the severe infection rate was 20 percent [40]. Opportunistic infections, mainly localized herpesvirus infections, occurred in 16 percent of patients receiving concurrent fludarabine-rituximab and 26 percent receiving sequential therapy. With these agents, only two cases of Pneumocystis pneumonia were seen. Rituximab has been associated with reactivation of hepatitis B among patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc) [41]. Rituximab has also been associated with progressive multifocal leukoencephalopathy (PML) [42].
●Ofatumumab – Ofatumumab is another anti-CD20 monoclonal antibody utilized for CLL therapy, and its profile of infectious complications are similar to that seen with rituximab [43]. Hepatitis B reactivation and PML may occur [44,45]. Infections in patients receiving ofatumumab are usually grade 1 or 2; among grade 3 or 4 infections, pneumonia and other respiratory tract infections are most common [46,47]. As an example, in a trial comparing ofatumumab and ibrutinib in relapsed/refractory CLL patients, overall infection rates were lower in the ofatumumab group (54 percent versus 70 percent) but severe infection rates were similar (22 percent versus 24 percent) [48]. In another study of ofatumumab, 189 infections occurred in 92 patients, including 13 fatal infections, with one episode of Fusarium infection and one of PML [46].
●Obinutuzumab – Obinutuzumab is a type 2 anti-CD20 monoclonal antibody that is approved in combination with either acalabrutinib or venetoclax for CLL therapy [49]. Its profile of infectious complications are similar to that seen with rituximab [43]. In preliminary data, most infections occurring with obinutuzumab were bacterial in origin, with opportunistic infections being uncommon [49,50]. Grade 3 to 5 infection rates range from 5 to 19 percent.
●Fludarabine-cyclophosphamide-rituximab combination – The fludarabine-cyclophosphamide-rituximab regimen has been used as initial and salvage CLL therapy, generally with antiviral and Pneumocystis prophylaxis [51,52]. In a large series of treatment-naïve patients, although one-third had at least one infection and 10 percent had fever of unknown origin, only 3 percent had major infections [51]. Reactivation of herpes simplex or varicella-zoster virus occurred in 5 percent of patients, but no cases occurred in those receiving antiviral prophylaxis. A small number of opportunistic infections (Pneumocystis, Aspergillus, Candida glabrata, CMV) occurred. With fludarabine-cyclophosphamide-rituximab therapy in the setting of relapsed or refractory disease, major infections (including one case of CMV pneumonitis) occurred in 16 percent of patients and minor infections occurred in 18 percent [52]. Major infection incidence was comparable in fludarabine-sensitive and fludarabine-refractory patients.
Alemtuzumab — Therapy with alemtuzumab, an anti-CD52 monoclonal antibody, is associated with profound defects in cell-mediated immunity as well as neutropenia [53-63]. Reductions in B, T, and NK cells occur early in treatment and persist for four to nine months after discontinuation of therapy. There is no correlation between the severity or duration of immunosuppression and the alemtuzumab cumulative dose or route of administration, although nonresponders are at greater risk of infection [53,58,59,64]. Alemtuzumab has been associated with a wide range of infections, including bacterial, viral, fungal, and protozoal infections [56,60]. CMV reactivation/disease is the most significant infectious complication occurring with alemtuzumab. The incidence of symptomatic CMV infection with alemtuzumab therapy ranges from 4 to 29 percent, with a peak onset four to six weeks after initiation of therapy [65]. CMV infections are more common in patients who have received previous treatment for CLL and are uncommon after discontinuation of therapy. Although alemtuzumab in combination with rituximab is approved as salvage therapy for CLL patients, use of this drug is limited because of these serious and common infectious complications [57,61,63,65-69], as well as the availability of newer targeted agents, such as Bruton tyrosine kinase (BKI) inhibitors, with better adverse effect profiles.
Bruton tyrosine kinase inhibitors
●Ibrutinib – Ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved for therapy of CLL. This agent causes hypogammaglobulinemia and inhibition of B cell signaling [70]. The most common infections are infections of the upper respiratory tract, with the majority being grade 1 or 2 infections [66,71]. Other less common infections include sinusitis, cellulitis, and urinary tract infections, also mostly grade 1 or 2 infections.
Serious infections occur in around 10 to 20 percent of patients receiving ibrutinib. In one large series, the use of ibrutinib salvage therapy was complicated by more major infections than previous chemoimmunotherapy, and these infections required either hospitalization or intravenous antimicrobial therapy [68]. In another study, a 17 percent rate of grade 3 or 4 pneumonia was reported in a series of relapsed/refractory CLL patients receiving therapy with ibrutinib plus ofatumumab [67]. In a retrospective study of 378 patients receiving ibrutinib for CLL or non-Hodgkin lymphoma, serious infections developed in 43 (11.4 percent), primarily during the first year of therapy [72]. Of those with serious infections, 23 (53.5 percent) developed serious bacterial infections, 16 (37.2 percent) developed invasive fungal infections, and 4 (9.3 percent) developed viral infections.
Ibrutinib is also associated with serious opportunistic infections, with one large retrospective study reporting an incidence of four percent [69,73]. Invasive aspergillus in particular is one of the most common opportunistic infections seen in this patient population [74-78].
Aspergillosis is the most common invasive fungal infection that occurs in patients with CLL taking ibrutinib [72,73,77,79]. In a retrospective study of 566 patients who received ibrutinib for the treatment of a hematologic malignancy, 23 (4.1 percent) patients developed infection, 12 of whom had invasive aspergillosis [73]. In another retrospective study of 378 patients receiving ibrutinib for CLL or non-Hodgkin lymphoma where 43 (11.4 percent) patients developed infections, there were eight cases of proven or probable aspergillosis [72]. Two involved the brain in addition to the lungs, one involved the pleura, and five were limited to the lungs. Infection resulted in death in 6 of the 43 patients (14 percent). Risk factors for invasive fungal infections among patients who received ibrutinib included receipt of ≥3 prior anti-tumor regimens and receipt of glucocorticoids at any time during the course of ibrutinib. However, the majority of patients who developed invasive fungal infections while receiving ibrutinib (62.5 percent) lacked typical risk factors (eg, neutropenia, lymphopenia, receipt of glucocorticoids). In a small retrospective study of 33 patients with relapsed or refractory chronic lymphocytic leukemia, mantle cell lymphoma, or Waldenström's macroglobulinemia treated with ibrutinib (as a single agent or in combination) who developed invasive fungal infection, median time from initiation of therapy to fungal infection diagnosis was 3 (range, 1 to 30) months [79].
In a series of 96 patients receiving ibrutinib as the sole agent for CLL, five were reported to have Pneumocystis pneumonia [80]. Four of the five patients had not been treated previously for CLL and all had a CD4 count >500/mm3and an IgG level >500 mg/dL. All five had a positive polymerase chain reaction (PCR) assay from bronchoalveolar lavage fluid and one also had a positive direct fluorescence antibody stain. Gomori-methenamine silver staining was negative in all patients. A limitation of the study is that positive PCR results can be due to either Pneumocystis infection or colonization. All of the infections were grade ≤2 and resolved with oral therapy with trimethoprim-sulfamethoxazole. The approach to Pneumocystis prophylaxis is presented separately. (See "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors'.)
Other reported opportunistic infections include disseminated cryptococcosis, histoplasmosis, blastomycosis, fusariosis, hepatitis B virus reactivation, Staphylococcus aureus meningitis, miliary tuberculosis, mucormycosis, amebic encephalitis, cutaneous Mycobacterium chelonae infection, progressive multifocal leukoencephalopathy, and disseminated VZV infection [69,72,75,78-95].
●Pirtobrutinib – Pirtobrutinib has very recently been approved for salvage therapy of chronic lymphocytic leukemia, after receipt of at least two lines of therapy, including a BKI and BCL-2 inhibitor. It was initially approved for salvage therapy of mantle cell lymphoma [96]. In the mantle cell lymphoma trial, grade ≥3 infections occurred in 28 (17.1 percent) patients, with the most common infection of any grade observed being pneumonia (10.4 percent, n = 17) and COVID-19–related pneumonia (3 percent, n = 5).
Phosphatidylinositol 3-kinase inhibitors — Idelalisib targets the B cell receptor signaling pathway, specifically as an inhibitor of the delta isoform of PI3K. This agent can alter CD4+ regulatory T cell function and reduce chemokine production [70,97]. It has been studied in combination with rituximab in patients with relapsed CLL and as a single agent in patients with relapsed indolent lymphoma [98-101]. In a trial of idelalisib for CLL, pneumonia occurred in 6 percent of patients, febrile neutropenia in 5 percent, Pneumocystis pneumonia in 3 percent, and neutropenia in 3 percent, with all being grade 1 or 2 toxicities [98]. In a trial of idelalisib for indolent lymphomas, neutropenia was seen in 56 percent of patients (grade ≥3 in 27 percent), pneumonia in 11 percent (grade ≥3 in 7 percent), and upper respiratory tract infections in 14 percent (all grade 1 or 2) [99]. Grade 3 or 4 pneumonia rates have approached 20 percent in some series [100,101]. No antimicrobial prophylaxis was mandated in clinical trials.
In 2016, seven clinical trials of idelalisib used in combination with other agents for CLL or indolent non-Hodgkin lymphoma were halted due to an increase in serious adverse events and fatalities in patients receiving idelalisib [102]. The majority of adverse events were infections, including sepsis and pneumonia. In particular, an increase in cases of Pneumocystis pneumonia and CMV infection was observed in both treatment-naïve and previously treated patients enrolled in three clinical trials of idelalisib used in combination with other agents [103,104]. In a retrospective analysis describing 2198 patients with CLL or indolent non-Hodgkin lymphoma across eight studies, the overall incidence of Pneumocystis pneumonia was 2.5 percent in patients receiving an idelalisib-containing regimen (idelalisib alone or in combination with an anti-CD20 monoclonal antibody or bendamustine + rituximab) versus 0.2 percent in those in a regimen without idelalisib (an anti-CD20 monoclonal antibody +/- bendamustine) [105]. The median time to Pneumocystis pneumonia was 141 days after initiation of therapy.
Therapy with idelalisib plus ofatumumab in previously treated patients with chronic lymphocytic leukemia was associated with grade 3 to 4 neutropenia in 34 percent of patients and grade 3 to 4 pneumonia in 14 percent of patients, compared to 16 percent and 8 percent, respectively, in patients receiving single agent ofatumumab alone [104]. Serious infections were more common with combination therapy than with single agent ofatumumab, including sepsis (11 percent versus 1 percent), Pneumocystis infections (5 percent versus 1 percent), urinary tract infections (4 percent versus 0 percent), and cytomegalovirus infection (2 percent versus 0 percent). Pneumonia is one of the most common infectious complications associated with idelalisib use, with a reported incidence of approximately 20 percent; the majority of cases are grade ≥3 [106]. Other opportunistic infections, including cases of PML (255) and disseminated herpes zoster infection, have been reported in patients with CLL receiving idelalisib [87]. At present, idelalisib is approved only for the therapy of relapsed chronic lymphocytic leukemia, in combination with rituximab. Recommendations for prophylaxis and monitoring are presented separately(See "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors'.)
A small number of cases of PML in patients receiving idelalisib and rituximab have occurred. Although rituximab is known to be associated with PML, the number of cases reported may be greater than expected from rituximab; this raises concern that idelalisib might increase the risk of PML. However, using the US Food and Drug Administration's Adverse Event Reporting System (FAERS) database, no increase in the risk of PML was observed with idelalisib. Further study is necessary to assess whether idelalisib itself increases the risk of PML. (See 'Anti-CD20 monoclonal antibodies' above.)
Duvelisib — Duvelisib is an inhibitor of PI3K delta and gamma isoforms that has been approved by the US Food and Drug Administration as a single agent for the treatment of patients with relapsed CLL/small lymphocytic leukemia who have received at least two prior therapies [107]. In the manufacturer's safety analysis, serious infections occurred in 137 of 442 patients (31 percent) receiving duvelisib, including 18 fatal infections (4 percent). The most common serious infections were pneumonia and sepsis. Serious, including fatal, Pneumocystis infection and CMV reactivation or infection each occurred in 1 percent of patients. Median time to onset of infection of any grade was three months, with 75 percent of cases occurring within six months of starting the drug. In one review, infections were reported in 70 percent of patients with relapsed/refractory CLL receiving duvelisib, including pneumonia in 18 percent and upper respiratory infections in 16 percent [108]. Reported respiratory tract infections included aspergillosis, pseudomonal pneumonia, and Pneumocystis pneumonia, the last occurring in patients not receiving appropriate prophylaxis. (See "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors'.)
Lenalidomide — Lenalidomide, an immunomodulatory agent, has been used in the treatment of patients with multiple myeloma, certain subtypes of non-Hodgkin lymphoma such as mantle cell lymphoma, and CLL, the last as part of clinical trials. Based upon review of the trial data, it appears that lenalidomide therapy causes no specific immune dysfunction that would increase the risk of opportunistic infections in these patients [109]. As such, no routine antimicrobial prophylaxis is generally given to patients receiving this agent. However, this agent is not approved for therapy of CLL patients outside of clinical trials.
Venetoclax — Venetoclax is a B cell leukemia/lymphoma 2 (BCL-2) inhibitor that is approved for therapy of treatment-naïve CLL patients in combination with either obinutuzumab or ibrutinib, and in previously treated CLL patients as a single agent, or in combination with either rituximab or ibrutinib [110-113].
This agent impacts immune function, causing depletion of dendritic cells and reduction in interferon-alpha production (in animal models) as well as reductions in the absolute lymphocyte count [70]. Grade 3 or higher neutropenia occurs in 40 to 50 percent of patients [114]. In the manufacturer's integrated safety analysis of 330 patients enrolled in phase I or II trials, 70 percent of patients had infections, most commonly upper respiratory tract infections (23 percent), pneumonia (11 percent), and nasopharyngitis (10 percent) [70]. Opportunistic infections occurred in 3.6 percent of patients and included invasive aspergillosis, Pneumocystis infection, oral/esophageal candidiasis, ocular toxoplasmosis, nocardiosis, herpes pharyngitis, and multidermatomal herpes zoster. When given in combination with rituximab, the incidence of neutropenic fever was 12 percent [110].
SUMMARY
●Immune defects – Infections have a major impact on the clinical course of patients with chronic lymphocytic leukemia (CLL). Patients with CLL have inherent immune defects in humoral and cell-mediated immunity that are related to the primary disease process, including hypogammaglobulinemia, abnormalities in T cell subsets, and defects in complement activity and neutrophil/monocyte function. Therapy-related immunosuppression has further impact on immune function in these patients. (See "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Introduction' and 'Immune defects' above.)
●Spectrum of infections – The spectrum of infections in CLL patients has changed over the past several decades with the introduction of CLL therapies that have specific effects on immune function, particularly on cell-mediated immunity. The infectious complications seen in these patients have evolved in relation to specific agents used. (See 'Spectrum of infections' above.)
•Alkylating agents – Treatment-naïve patients and patients treated with alkylating agents are at increased risk for bacterial infections caused by common pathogens, such as Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Recurrent bacterial infections with a mucosal origin (respiratory tract, urinary tract) are common. (See 'Spectrum of infections' above and 'Alkylating agents' above.)
•Purine analogs – With the use of purine analogs (eg, fludarabine), which result in quantitative and qualitative T cell abnormalities, a wider spectrum of infectious complications has emerged compared with what has been seen with alkylating agents. In patients receiving a purine analog, in addition to common bacterial infections, opportunistic infections caused by organisms such as Listeria, mycobacteria, Nocardia, Candida, Aspergillus, Cryptococcus, Pneumocystis, and herpesviruses (herpes simplex virus, varicella-zoster virus, and cytomegalovirus [CMV]), have been reported. (See 'Purine analogs' above.)
•Anti-CD20 monoclonal antibodies – Rituximab, ofatumumab, and obinutuzumab are anti-CD20 monoclonal antibodies that cause a transient reduction in the B cell count. Grade 3 or 4 (severe) infections and opportunistic infections are uncommon with anti-CD20 monotherapy. However, hepatitis B reactivation may occur among patients positive for hepatitis B surface antigen (HbsAg) or hepatitis B core antibody (anti-HBc). Progressive multifocal leukoencephalopathy has also been reported in patients receiving an anti-CD20 monoclonal antibody. (See 'Anti-CD20 monoclonal antibodies' above.)
•Alemtuzumab – Therapy with alemtuzumab, an anti-CD52 monoclonal antibody, is associated with profound defects in cell-mediated immunity as well as neutropenia. Alemtuzumab has been associated with a wide range of infections, including bacterial, viral, fungal, and protozoal infections. Severe infections have included Aspergillus, Mucorales, Candida, Listeria, Pneumocystis, and CMV. CMV reactivation/disease is the most significant infectious complication occurring with this agent. (See 'Alemtuzumab' above.)
•Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors – There is limited but increasing evidence suggesting that ibrutinib is associated with invasive fungal infections, including Pneumocystis pneumonia, invasive aspergillosis, and cryptococcosis, and idelalisib and duvelisib are associated with Pneumocystis and CMV infections. (See 'Bruton tyrosine kinase inhibitors' above and 'Phosphatidylinositol 3-kinase inhibitors' above.)
•Lenalidomide and venetoclax – Therapy with lenalidomide or venetoclax has not been associated with opportunistic infections. (See 'Lenalidomide' above and 'Venetoclax' above.)
●Prevention of infections – The approach to prevention of infections in patients with CLL is reviewed separately. (See "Prevention of infections in patients with chronic lymphocytic leukemia".)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Elias Anaissie, MD, and Kieren A Marr, MD, who contributed to earlier versions of this topic review.
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