Chronic lymphocytic leukemia (CLL) is the most common leukemia in North America and Europe, with approximately 18,740 new cases diagnosed annually in the United States.1 CLL primarily affects an aging population, with a median age at diagnosis of approximately 70 years. The disease is characterized by clonal expansion of B cells, exhibiting monoclonality with either kappa or lambda light chain restriction on the cell surface membrane. These abnormal cells accumulate in the peripheral blood, bone marrow, lymph nodes, liver, and spleen.2,3 The clinical course is highly variable. Currently, disease progression is the leading cause of mortality in CLL, followed by infectious complications.4 Over the past decade, several advancements in treatment have been made, including novel agents targeting B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) inhibition and promoting apoptosis through the inhibition of the antiapoptotic protein BCL-2. As a result, overall survival for patients with CLL appears to be improving.5 However, mortality from severe infections remains a significant concern.
Infectious complications in CLL arise due to underlying deficiencies in immune function, resulting from either the primary disease or the therapies used. CLL affects both the innate and adaptive immune systems, impairing the host’s ability to respond effectively to invading pathogens. The spectrum and severity of infections have changed over the years. Treatment approaches have shifted from inducing absolute lymphodepletion with either bendamustine or fludarabine-based chemotherapy to selectively targeting B-cell functioning by blocking BCR signaling. The COVID-19 pandemic further perturbated the intricate balance between watch-and-wait strategies and active treatment in CLL, presenting new challenges in determining optimal treatment regimens and vaccination strategies for patients living with CLL. Therefore, understanding the nature of immune defects in CLL and developing strategies to augment the impaired immune system are needed to keep pace with advancements in treatment approaches. This review article summarizes available data on immune dysfunctions, their clinical consequences, therapeutic implications, and current strategies to enhance immune function in patients with CLL.
Deciphering the Mechanisms: Understanding How CLL Cells Induce Immune Dysfunction
During CLL, from diagnosis to relapsed disease, there is progressive impairment of the immune system, leading to episodes of recurrent infections. Before the availability of newer diagnostic tools, frequent and severe infections from common pathogens were often the presenting symptom in patients.6 Although the spectrum of infections varies throughout the clinical course, common bacterial pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae—which cause lower respiratory tract infections and urinary tract infections—frequently contribute to increased morbidity and mortality. The increased incidence of infections is observed in both treatment-naïve and treatment-exposed patients, suggesting an underlying primary immune dysfunction that is further compromised by immunosuppressive antileukemia therapies.
CLL affects both the innate and adaptive immune systems, altering all aspects of a functioning immune system. Innate immunity, the initial response to invading pathogens, is compromised by qualitative and quantitative deficiencies in normal natural killer (NK) cells, neutrophils, monocytes/macrophages, and the complement system (Figure 1). Additionally, components of the adaptive response system that are dependent on humoral and cellular immunity are impaired due to ineffective antigen recognition and subsequent antibody responses. These dysfunctions result from bidirectional interactions between normal tumor microenvironment (TME) bystander cells and CLL cells, either through direct interactions or via cytokine secretion, which causes effects throughout the lymphoid system. With the treatment of CLL using targeted therapies such as BTK or BCL-2 inhibitors, there is an improvement in the functioning of the innate immune system, leading to a reduction in the severity and frequency of infections.7,8
Innate immune system. Inner circle (pretreatment): deficiencies in the quality and quantity of key innate immune cells, such as NK cells, neutrophils, monocytes/macrophages, and the complement system, weaken the body’s initial response to invading pathogens.67–72 Outer circle (prolonged BTK ± BTK inhibitor treatment): qualitative and quantitative changes among innate immune system components, reducing infection severity and frequency.7,38,39
Abbreviations: BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; mMDSC, monocytic myeloid-derived suppressor cells; NK, natural killer.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2024.7090
Replacement of Normal B Cells With Neoplastic Clonal B Cells
Because CLL is a clonal and neoplastic process, prosurvival signals are essential for the proliferation and survival of the malignant B cells. Normal B cells express BCRs composed of surface immunoglobulin with a cytoplasmic signaling domain, which is responsible for appropriate response to an antigenic epitope. In CLL, chronic tonic signaling occurs due to autoantigen-mediated BCR signaling of the stereotyped BCRs, resulting in the selection and proliferation of neoplastic B cells over normal B cells.9 Additionally, the CD5+ lymphocytes in CLL resist apoptosis through interactions with CD40L+ T cells in the TME, leading to their survival.10,11 These neoplastic cells slowly infiltrate primary and secondary lymphoid tissues, replacing functional, normal B cells. Because these neoplastic cells recognize only specific antigens, they cannot produce effective antibodies against external pathogens. However, despite its appealing simplicity, this model does not fully explain immune dysfunction during the early stages of CLL, when tumor burden is low, suggesting that alternative etiologies may contribute to B-cell impairment.
Tumor Microenvironment in CLL
The CLL TME consists of interactions between soluble components such as cytokines and chemokines and between CLL cells and bystander cells such as T cells.11–14 Patients undergoing expectant observation (“watch and wait”) continue to show signs of immune dysfunction, despite slow or no progression of CLL. This suggests that the presence of CLL cells in lymphoid tissues is sufficient to suppress the immune system naturally. They achieve this indirectly through the excess production of anti-inflammatory cytokines such as IL-10 and continuous secretion of proinflammatory cytokines such as IL-6. This leads to an eventual anti-inflammatory environment that limits the host’s ability to respond to pathogens and vaccines.15–18 Additionally, chemokines such as CCL17 and CCL22 secreted by CD5+ CLL cells chemo-attract CD4+ T cells, which express CD40L, aiding the neoplastic cells in resisting apoptosis.19,20
Bystander cells such as T cells, NK cells, mesenchymal stromal cells, and nurse-like cells (NLCs), which are tumor-associated macrophages/monocytes, play a critical role in the survival and chemoresistance of tumor cells and form a nourishing environment in lymphoid tissues. The bidirectional interaction between these neoplastic B cells and bystander cells drives tumor progression and recruitment of additional cells to the TME (Figure 2). There is a skewing of CD4+ helper T cells and CD8+ cytotoxic cells in CLL in favor of the latter at the expense of reduced naïve T cells, which are necessary for anti-CLL immunity.21 Despite an increase in the number of cytotoxic CD8+ T cells, their ability to exert cytotoxic effects is severely compromised. CLL cells express inhibitory surface molecules such as CD200, PD-L1, CD276, and CD270, affecting T-cell synapse formation and producing a T-cell exhausted phenotype.21,22 CD200 expressed on CLL cells impairs T-cell proliferation by inhibiting IL-2 and IFN-γ production by CD4+ T cells and promotes the differentiation of CD4+ T cells into CD4+/CD25high/FOXP3+ regulatory T cells (Tregs).23 These Treg cells secrete IL-4, which leads to overexpression of BCL-2, an antiapoptotic protein, in CLL cells, promoting their survival and increasing susceptibility to BCL-2 inhibitors such as venetoclax.24
Tumor microenvironment in CLL. CLL cells upregulate CD200, HVEM, and PD-1, impairing synapse formation in T cells. CD200 and IL-10 promote the differentiation of CD4+ T cells into CD4+/CD25high/FOXP3+ Tregs. These Tregs secrete IL-4, which upregulates BCL-2 expression in CLL cells, promoting prosurvival signaling. HVEM and PD-L1 interact with CD160 and PD-1 on T cells, leading to T-cell exhaustion.73 In vitro, NLCs differentiate following long-term culture with PBMCs from patients with CLL. These NLCs in the microenvironment support CLL cell survival via BAFF, CXCL12, and APRIL.74 Small-molecule inhibitors, such as BTK inhibitors and venetoclax, alter the tumor microenvironment by interacting with T cells and NLCs and reducing the CLL disease burden.75–78
Abbreviations: APRIL, A proliferation-inducing ligand; BAFF, B-cell activating factor; BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; CXCL12, C-X-C motif chemokine 12; HVEM, herpes virus entry mediator; NLC, nurse-like cell; PBMC, peripheral blood mononuclear cell; Treg, regulatory T cell.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2024.7090
Other cells in the TME include monocyte-derived cells (MDC), such as monocytes, macrophages, and dendritic cells. Increased levels of MDCs in the TME correlate with worse prognosis in CLL and are primarily involved in promoting CLL survival and migration through chemokine secretion.25 NLCs, which are derived from monocytes, support CLL survival by secreting factors such as B-cell activating factor (BAFF), C-X-C motif chemokine 12 (CXCL12), and A proliferation-inducing ligand (APRIL).26 Overall, CLL cells potentiate an anti-inflammatory milieu, causing migration of bystander cells into the TME, which further promotes CLL cell survival and proliferation, leading to a vicious cycle of immunosuppression and tumor proliferation.
Hypogammaglobulinemia
An objective measure of humoral immunity in CLL is the assessment of serum levels of immunoglobulins IgA, IgG, and IgM. Hypogammaglobulinemia, particularly affecting the IgG3 and IgG4 subtypes, is a prominent defect in CLL, contributing to increased susceptibility to infections.27 Decreased IgA levels are observed in up to 68% of patients with CLL, leading to recurrent respiratory tract infections and serving as a positive predictor of shorter time to infection development, the need for treatment, and decreased survival.28–30 The etiology of reduced immunoglobulin secretion in CLL involves nonclonal B cells and T cells in the TME. The interactions between CD70 on clonal and nonclonal B cells and its ligand CD27 present on bystander T cells in the TME lead to decreased IgG production and plasma cell differentiation via PI3K and MEK signaling.31 CLL clonal B cells suppress plasma cell function and induce direct apoptosis of plasma cells via CD95L(FasL)/CD95(Fas) interactions between CLL cells and plasma cells, leading to hypogammaglobulinemia.32 Therefore, the overall consequence is reduced differentiation toward plasma cells and reduced production of all classes of immunoglobulins.
Clinical Ramifications of Immune Dysfunction in CLL
The intricate interplay between CLL and the immune system is complex and cannot be elucidated in a simplified model. However, its effects are routinely experienced by patients, affecting both their quality and quantity of life. These effects can be grouped into 3 major areas: increased susceptibility to infections, development of secondary primary malignancies, and the emergence of autoimmune disorders associated with CLL.
Infection Risk and Spectrum in CLL
Infections are the second most common cause of mortality in CLL, with their incidence increasing based on disease stage, serum IgG levels, mutations in CLL cells, and the treatments used.5,33 The 5-year risk of developing severe infections increases up to 68% from a baseline risk of 26% in patients with IgG levels <650 mg/dL and Rai stage C disease.34 The most frequent severe infections include pneumonia, followed by sepsis and urinary tract infections caused by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitides, as well as Staphylococcus aureus and Enterobacteriaceae.35 Viral agents, including herpes simplex virus (HSV) and varicella-zoster virus, become more prevalent during antileukemia treatment and occasionally require chronic suppressive therapy during the treatment course.
In 2019, the COVID-19 pandemic challenged health care systems and public policies worldwide, with a particularly severe impact on elderly patients and those with comorbidities or suppressed immune systems. SARS-CoV-2 infection has a variable clinical course but is associated with a high case fatality rate, approaching 33% in patients with CLL.16 This high fatality rate was observed in patients undergoing watch-and-wait observation as well as those undergoing treatment. A high CD8+ T-cell count is associated with lower mortality in SARS-CoV-2 infections. However, in CLL, the CD8+ T cells exhibit functional defects in proliferation and cytotoxicity, making them functionally incompetent.36,37 Prolonged viremia with SARS-CoV-2 is observed in patients with CLL with impaired ability to produce pathogen-specific antibodies, as seen in treatment-naïve patients and those receiving B-cell–depletion therapy with anti-CD20 monoclonal antibodies such as rituximab or obinutuzumab. This prolonged viremia contributes to increased hospital readmissions and higher mortality in patients with CLL and SARS-CoV-2 infection. Multiple resurgences of SARS-CoV-2 infection with newer strains have caused patients to experience crippling fear and anxiety about developing severe infection, often leading to prolonged periods of social isolation and increased rates of depression.
The challenges faced by patients with CLL during the COVID-19 pandemic, particularly the heightened risk of severe infection and mortality, underscore the critical need for therapeutic strategies that can bolster the immune system and reduce susceptibility to infections. Long-term treatment with venetoclax and ibrutinib has been shown to result in immune recovery.38,39 This recovery is dependent on the eradication of CLL cells and restoration of normal B cells, T-cell subtypes, monocytes, and dendritic cells.7 The effect of this immune system recovery on infection risk and mortality is currently being investigated in the PreVent-ACaLL phase II trial of acalabrutinib combined with venetoclax for high-risk CLL (ClinicalTrials.gov identifier: NCT03868722). These findings suggest that targeted therapies not only have the potential to induce remission but may also create an opportunity to enhance treatment responses with immunotherapy and reduce infection risk in this patient population.
Incidence of Second Primary Malignancies in CLL
The risk of developing subsequent primary malignancies (SPMs) in patients with CLL is 3 times higher compared with age- and sex-matched controls.40,41 Among SPMs, the highest risk is observed for nonmelanoma skin cancers, with up to an 8-fold increase, followed by a 2-fold increase in other solid tumors, such as malignant melanoma, soft tissue sarcomas, and lung cancer.42,43 The incidence of these SPMs matches that seen in renal transplant recipients, suggesting immunodeficiency as a primary etiology. High-count monoclonal B-cell lymphocytosis, a precursor to CLL, is also associated with an increased risk of nonhematologic cancers compared with healthy individuals, suggesting that the immune dysfunction contributing to the development of SPMs occurs early in the course of CLL.44 The risk of SPMs further increases in patients who receive chemotherapy compared with those who remain untreated, suggesting a model of baseline immune dysfunction in CLL that is further aggravated by subsequent therapies. Even with newer targeted therapies, such as BTK inhibitors and BCL-2 inhibitors, the risk of SPM is as high as 9%.41,45–47 Furthermore, the presence of preexisting CLL in patients with SPMs is associated with inferior overall survival and cancer-specific survival, indicating a general state of impaired cancer immunosurveillance in CLL.48
Autoimmune Diseases in CLL
Autoimmunity is a relatively common complication in CLL, with 20% to 25% of patients developing hematologic or nonhematologic autoimmunity over the disease course.49 Autoimmune hemolytic anemia (AIHA) is the most common autoimmune manifestation, followed by immune thrombocytopenia, pure red cell aplasia, and autoimmune neutropenia. Nonhematologic autoimmune disorders, such as paraneoplastic pemphigus, angioedema, and paraneoplastic glomerular disease with proteinuria, occur less frequently and are often observed in patients with stable CLL.50,51 The pathogenesis of paraneoplastic and autoimmune disorders in CLL is complex. It is thought to result from a combination of abnormal antigen presentation by CLL cells during their interactions with helper T cells, which misidentify self-antigens as foreign, and the failure of Tregs to regulate an autoimmune response to self-antigens.52 In the past, treatment with purine analogs such as chlorambucil or fludarabine also led to an increased incidence of AIHA, possibly due to their lymphodepleting effects on Tregs.53 Autoimmune cytopenias (AICs) have also been reported with novel agents, occurring in 9% of patients, typically within the first 6 months of treatment.53 The German CLL Study Group reported AIC incidences of 8% with venetoclax, 2% with BTK inhibitors, and 15% with venetoclax in combination with BTK inhibitor. Regardless of the underlying etiology, the treatment of autoimmune disorders in CLL requires both suppression of interactions between autoantigens and the innate immune system using corticosteroids and, in some cases, eradication of malignant B-cell clones through antileukemia therapies.25
Navigating Implications of Immune Challenges in CLL
In navigating the complex landscape of immune dysfunction and its clinical consequences in CLL, specific strategies have been explored to minimize the effects of a suppressed immune system and even use immunotherapy to develop newer antileukemia treatments. Current approaches include reducing infectious complications through vaccination against preventable infections, repleting protective antibodies using donor-derived antibodies from pooled plasma of healthy donors, and using chronic suppressive anti-infective therapy during antileukemia treatment. Although these strategies show promise, each comes with its own limitations.
Vaccinations in CLL
The potential to enhance adaptive immunity in CLL through vaccinations against pathogens such as pneumococcal, Haemophilus influenzae type b, tetanus, varicella, and SARS-CoV-2 has been extensively investigated.54 However, due to defective antigen presentation and reduced antibody production in CLL, seroconversion rates are poor. Furthermore, patients with advanced disease or low IgG levels have suboptimal responses to immunization, indicating the need to vaccinate early at diagnosis.55 Anti-CD20 monoclonal antibodies and BTK inhibitor therapy further decrease rates of seroconversion.56,57 With SARS-CoV-2 mRNA vaccines, treatment-naïve patients and those receiving B-cell–directed therapy, including BTK and BCL-2 inhibitors, demonstrate poor seroconversion rates, decreased neutralizing antibodies against SARS-CoV-2 spike proteins, and diminished CD4 T-cell responses.58,59 However, no studies have shown that vaccinations cause harm by worsening disease or triggering new, untoward adverse events. Therefore, vaccinations should be discussed at diagnosis and administered ≥2 weeks before treatment initiation.60 Influenza, SARS-CoV-2, pneumococcal, and respiratory syncytial virus vaccines are recommended for all patients. Additionally, recombinant zoster vaccines are indicated for those receiving a BTK inhibitor.61 Live virus vaccines should be avoided.
Immunoglobulin Replacement Therapy
As mentioned previously, hypogammaglobulinemia is a common occurrence in patients with CLL, present either at diagnosis or as a result of B-cell–directed therapy. The use of prophylactic intravenous immunoglobin (IVIG) replacement therapy has been extensively studied and is used in selected patients at risk for severe infections. In a randomized placebo-controlled trial involving patients with CLL and ≥3 sinus infections or 1 episode of pneumonia and low IgG serum levels, administration of 400 mg/kg IVIG every 3 weeks for at least 1 year reduced the incidence of minor to moderate bacterial infections but had no effect on severe infections or mortality rates.62 Similarly, a more recent trial of subcutaneous immunoglobulin replacement therapy showed improved serum IgG levels specific to Streptococcus pneumoniae.63 Other studies continue to show minor benefits without effect on quality of life or increase in overall survival. Clinical studies suggest that lower IgA levels, rather than IgG, are a better predictor of infection risk, raising further questions about the value of IgG replacement therapy.29,30 Therefore, the use of IVIG is controversial and recommended only in cases of recurrent infections with low serum IgG levels.61
Antimicrobial Prophylaxis
Antimicrobial prophylaxis should be individualized based on patient history and risk factors. In general, primary prophylaxis is not indicated for patients receiving BTK or BCL-2 inhibitors, although prophylaxis for Pneumocystis jiroveci pneumonia (PJP) and HSV can be considered for select patients.61 Treatment with BTK inhibitors may increase the risk of invasive fungal infections, such as aspergillosis; however, this risk is low and does not warrant antifungal prophylaxis for all patients. If a patient receiving a BTK inhibitor develops respiratory decompensation or other symptoms suggestive of a fungal infection, testing for serum galactomannan and a chest CT scan should be considered as part of the diagnostic workup. Because venetoclax is associated with significant neutropenia, typically within the first few months of initiation, we recommend early use of granulocyte colony-stimulating factor (G-CSF) and, for patients with prolonged neutropenia (>7 days), consideration of fluoroquinolone and fungal prophylaxis. Entecavir prophylaxis and close monitoring of hepatitis B viral load by quantitative RT-PCR are recommended for patients at high risk for reactivation (eg, hepatitis B surface antigen–positive or hepatitis B core antibody–positive). Although less frequently used in CLL, current or prior treatment with chemoimmunotherapy (purine analogs or bendamustine), phosphoinositide 3-kinase (PI3K) inhibitors, or alemtuzumab warrants HSV and PJP prophylaxis. Additionally, patients receiving PI3K inhibitors or alemtuzumab have a high risk of cytomegalovirus reactivation and should be monitored closely; ganciclovir and consultation with infectious disease specialists may be indicated for managing viremia.
Infection Management
BTK inhibitors and venetoclax-based regimens can typically be continued during the treatment of low-grade infections, with the caveat that antimicrobial therapies should be checked for potential drug–drug interactions. Therapy interruption should be considered for patients who develop severe infections (grade ≥3), with resumption once clinical improvement is evident.64–66 The timing of resumption is individualized, depending on the patient and the type of infection. Caution should be taken with patients receiving a BTK inhibitor, particularly early in their course, as dose interruptions may lead to disease progression. The development of multiple significant infections may warrant a dose reduction. In addition to appropriate antimicrobial therapy, other supportive measures such as G-CSF or IVIG may be considered if supported by the patient’s laboratory values and clinical history.
Conclusions
CLL presents significant challenges due to its impact on the immune system, leading to increased susceptibility to infections, a higher risk of secondary malignancies, and the development of autoimmune disorders. Despite advancements in treatment, mortality from infections remains a prominent concern, especially in the context of the COVID-19 pandemic. The intricate interactions between CLL cells, the immune system, and the TME contribute to immune dysfunction, affecting both innate and adaptive immunity. The clinical consequences of these dysfunctions underscore the importance of comprehensively addressing immune challenges in CLL. Strategies such as vaccinations, immunoglobulin replacement therapy, and antimicrobial prophylaxis have been explored to mitigate infectious complications, but their efficacy is variable. Navigating the implications of immune challenges in CLL requires a nuanced understanding of the disease’s immune dynamics and ongoing research to develop more effective therapeutic approaches. Despite the complexities involved, efforts to enhance immune function and minimize associated risks remain crucial for improving the quality of life and clinical outcomes for individuals living with CLL.
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