Can We Restore Immunocompetence in CLL?

1. Introduction

Immunodeficiency is a hallmark of CLL and the cause of much morbidity and mortality. As modern treatments increasingly provide long-term survival, the question how one might restore immune function is taking center stage. Here we first review disease and treatment related factors that contribute to immunodeficiency and then address strategies that may boost immune function. Encouragingly, novel therapies are often less immunosuppressive than prior approaches using chemotherapy. At the same time, the advent of the coronavirus disease 2019 (COVID-19) pandemic heightens the urgency of developing effective strategies to protect patients with CLL from infection. Hopefully the past 10 years of progress in treating CLL can be the harbinger of forthcoming progress in restoring immunocompetence for patients.

2. Disease-Related Immunodeficiency

2.1. Adaptive Immunity

Hypogammaglobulinemia

Hypogammaglobulinemia is a common contributor to immunosuppression in patients with advanced CLL (Figure 1).¹ Immunoglobulin G (IgG) and its subclasses, IgG1, IgG2, IgG3, and IgG4, as well as IgA and IgM may be deficient.² The severity of hypogammaglobulinemia is correlated with stage, duration of disease, and susceptibility to severe and recurrent infections.^1,3 Both malignant and non-malignant immune cells appear to suppress the normal antibody response. Co-culture experiments have shown that Fas/Fas ligand interactions between tumor cells and bone marrow plasma cells inhibit antibody production.⁴ T and natural killer cells from CLL patients decrease antibody secretion by activated B cells from healthy donors.^5–7 CD30⁺ T cells, which are frequently expanded in CLL, inhibit isotype switching to IgG and IgA in nonclonal B cells.⁸ In addition, there are fewer newly produced B cells, and consequently a smaller pool of antibody-producing cells, in CLL patients compared to healthy controls.⁹

Figure 1. Components of immunodeficiency in CLL.

Patients with CLL have abnormal innate and adaptive immunity. Innate immune defects include reduced levels of complement, neutropenia related to treatment or less commonly, bone marrow infiltration of CLL, and increased MDSCs, which inhibit T-cell responses. Adaptive immune defects include hypogammaglobulinemia, Th2 polarization, T-cell expression of inhibitory receptors such as PD-1 and CTLA-4, and loss of immune synapse formation between T cells and target cells.

Cell-Mediated Immunity

The T-cell compartment in patients with CLL is simultaneously immunosuppressive and tumor supportive. CD8⁺ T cells highly express inhibitory receptors and have diminished proliferative capacity (Figure 1).¹⁰ Abnormalities in granzyme packaging, degranulation, and immune synapse formation reduce the cytolytic activity of CD8⁺ T cells (Figure 1).^10,11 CD4⁺ T cells are polarized toward an immunosuppressive Th2 phenotype.^12,13

In the tumor microenvironment, T cells interact directly with CLL cells via CD40L-CD40 and secrete soluble factors, such as interleukin-4 (IL-4) and interferon-gamma (IFN- γ), which promote tumor survival and proliferation.^14–16 Autologous CD4⁺ T cells have also been shown to facilitate engraftment and clonal expansion of CLL cells in patient-derived xenografts.¹⁷

2.2. Innate Immunity

Clearance of pathogens, in particular of encapsulated bacteria, requires opsonization by the complement system.¹⁸ Complement deficiency is frequently observed in patients with CLL and affects components of the classical, alternative, and terminal pathways (Figure 1).¹⁹ Patients deficient in one or more complement components are more susceptible to infection and have shorter overall survival.^19,20 In addition, low levels of complement have been shown to limit complement-dependent cytotoxicity of anti-CD20 monoclonal antibodies against primary CLL cells.²¹

Neutropenia caused by bone marrow infiltration of CLL cells, albeit less common than anemia and thrombocytopenia, can be a complication of active disease and an indication for treatment (Figure 1).²² More often, neutropenia is a treatment related toxicity. Grade ≥3 neutropenia affects approximately one-third of patients treated with chemoimmunotherapy,²³ half of patients treated with venetoclax and anti-CD20 mAb, and 10% of patient treated with ibrutinib monotherapy.²⁴ Qualitative defects in neutrophil function have also been reported.^25,26

Myeloid derived suppressor cells (MDSCs) expand regulatory T cells, inhibit T-cell activation, and thereby suppress immune surveillance.^27–29 These cells are present at increased frequency in CLL patients compared to healthy individuals and associated with more aggressive disease (Figure 1).³⁰ MDSCs differentiate to tumor associated macrophages (TAMs), also referred to as nurse-like cells, in the tumor microenvironment.²⁸ In co-culture experiments, TAMs have been shown to enhance CLL cell survival via direct contact and secretion of immunosuppressive cytokines.^31,32

2.3. Clinical Manifestations

Infections

Patients with CLL are at increased risk of infection-related morbidity and mortality.³³ In a retrospective study of 125 patients over a 10-year period, severe infections occurred in 26% of patients and accounted for 30% of deaths.³⁴ Among patients with treatment naïve CLL, bacterial pneumonia, involving Streptococcus pneumonia, Staphylococcus aureus, and Hemophilus influenza, is the most common serious infection.³⁵ Recurrent infections may evolve into chronic sinusitis and bronchiectasis.³⁶ Other sites of infection in order of frequency are the upper respiratory tract, genitourinary tract, blood, skin and soft tissue, gastrointestinal tract, and central nervous system.³⁷

The severity of hypogammaglobulinemia correlates with infection risk.³⁸ IgG levels <3 g/L confer a high risk of infections and depressed IgA was associated with inferior survival independent of disease stage.^39,40

Defective cell-mediated immunity increases the frequency and severity of herpes family virus infection and reactivation.⁴¹ Disseminated and atypical herpes simplex 1 or 2 and herpes zoster, such as that involving the eye or liver, have been described.^42,43 Cytomegalovirus (CMV) disease and Epstein-Barr associated lymphoproliferative disorders are rare in untreated patients with CLL.⁴⁴

In a retrospective cohort study of patients with hematologic malignancies, there were 5 cases of invasive fungal infections (IFIs) among 1,104 newly diagnosed CLL patients over a 5-year period.⁴⁵ All cases were caused by Aspergillus sp. and resulted in death in 4 of 5 patients.⁴⁵ Uncontrolled malignancy, severe lymphopenia, CMV disease, prolonged neutropenia, and recent history of IFIs have been identified as treatment-independent risk factors for IFIs.⁴⁶ Pneumocystis jirovecii pneumonia (PJP) is uncommonly reported in treatment-naïve patients and more frequent in patients treated with purine analogs or steroids.⁴⁷

Second Primary Malignancies

The incidence of second primary malignancies (SPMs) in patients with CLL is increased. Disease, host, environment, and treatment-related factors influence malignancy type and overall risk. Overall, non-melanoma skin cancers are most common, followed by solid tumors and second lymphoid malignancies, including Richter transformation. Richter transformation is variably considered a SPM and can be a leading second cancer diagnosis in patients treated with chemoimmunotherapy.^48,49 Myeloid neoplasms are overall less common but may develop as a complication of genotoxic therapy, accounting for up to 10–14% of all second cancers in patients treated with fludarabine, cyclophosphamide, with or without rituximab.^49,50 In recent series, standardized incidence ratios of SPM in CLL patients range from 1.19 to 2.2.^51–54

T-cell dysfunction is thought to contribute to increased incidence of SPMs in patients with CLL.^51,53 Epidemiological support for a role of immune dysfunction is the increased relative risk for SPMs in patients with CLL that are more common in immunosuppressed patients including melanoma, kidney cancer, Hodgkin Lymphoma and the virally induced Merkel cell carcinoma and Kaposi sarcoma.⁵³ A disease related contribution to cancer risk is also suggested by the observation that patients with CLL have an increased risk of lung cancer and melanoma but patients with DLBCL do not.⁵⁵ In Australia, a country with high levels of ultraviolet radiation exposure, the standardized incidence of melanoma in patients with CLL is 7.7.⁵⁴

Whether targeted therapy changes the risk of SPMs is unclear. Patients on BTKi have an increased incidence of SPMs compared to data in the Surveillance, Epidemiology, and End Results (SEER) Program.⁵¹ However, the majority of these patients had CLL for many years and were previously treated with alkylating agents or purine analogs; 44% had a smoking history. In the front-line CLL14 trial that compared venetoclax with obinutuzumab versus chlorambucil with obinutuzumab, the reported rate of SPMs was 13.7% versus 10.3% of patients, respectively.⁵⁶ Additional studies will be needed to estimate the impact of targeted therapy on the risk of SPMs.

3. Treatment-Related Immune Changes

3.1. Anti-CD20 Antibodies

Anti-CD20 antibody therapy depletes normal B cells for several months but does not directly impact plasma cells. Rituximab use has been associated with development or worsening of hypogammaglobulinemia, especially in patients receiving maintenance therapy.⁵⁷ A confounding factor is the frequent co-administration of chemotherapy. Overall, anti-CD20 antibodies are well tolerated. Of specific clinical importance is the risk of hepatitis B reactivation; all patients should be screened for past or active infection before the initiation of anti-CD20 antibody therapy.⁵⁸ Retrospective case series uncovered an increased incidence of progressive multifocal leukoencephalopathy (PML), which remains a rare occurrence.⁵⁹ As a consequence of B cell depletion lasting many months beyond the last infusion, anti-CD20 therapy is thought to interfere with humoral vaccine responses.^60–62 Interestingly, cellular vaccine response was not affected by B cell depletion.⁶¹

3.2. Chemotherapy and Chemoimmunotherapy

Purine analogs can profoundly impact immune function ranging from an increased risk of opportunistic infections to precipitation of autoimmune cytopenia. Use of purine analogs is associated with neutropenia and lymphopenia and CD4 counts can remain depressed for years after conclusion of treatment.⁶⁰ Chemoimmunotherapy was the mainstay of CLL therapy for many years and has been associated with increased incidence of neutropenic and opportunistic infections including PJP and herpes virus reactivations.⁶³

3.3. Phosphatidylinositol-3-Kinase Inhibitors

The phosphatidylinositol-3-kinase (PI3K) inhibitors idelalisib and duvelisib are approved in the United States for the treatment of relapsed CLL and follicular lymphoma.^64,65 Both drugs target the PI3K-δ isoform in CLL cells that participates in signal transduction downstream of the BCR.⁶⁶ Duvelisib also inhibits PI3K-γ expressed by non-malignant immune cells in the tumor microenvironment.^67,68

Treatment with idelalisib increases the risk of PJP and CMV disease.^69,70 Higher mortality from opportunistic and bacterial infections among patients treated with idelalisib-based combination therapies resulted in the early termination of six clinical trials for CLL and indolent non-Hodgkin lymphoma.^71,72 Despite consensus recommendations for PJP prophylaxis, a survey of Medicare beneficiaries found that less than 40% received prophylaxis during idelalisib therapy.⁷³

Hepatotoxicity, colitis, pneumonitis, and rash are immune-related toxicities associated with PI3K inhibitors.⁷⁴ Quantitative and qualitive reductions in regulatory T-cell (Treg) function have been implicated. Murine models of PI3Kδ loss have shown that impaired Treg function leads to a CD8⁺ T-cell response and fatal autoimmune colitis.^75–77 Patients experiencing immune-related toxicities have decreased circulating Treg cells and increased infiltrating CD8⁺ T cells in affected tissues.^78,79

3.4. BTK Inhibitors

Ibrutinib and acalabrutinib are oral irreversible inhibitors of Bruton tyrosine kinase (BTK) and widely used to treat CLL. The risk of infection is highest during the first 6 months, then improves with extended treatment.^80–82 This improvement correlates with an increase in IgA, which may be an indicator or surrogate of humoral immune reconstitution (Figure 2).^81,82 Compared to chemoimmunotherapy, neutropenia and febrile neutropenia are less common among patients receiving BTK inhibitor therapy.⁸³

Figure 2. Immunologic alterations during treatment with ibrutinib.

Ibrutinib increases the level of serum IgA, restores immune synapses between T cells and CLL cells, and inhibits Th17 differentiation. Ibrutinib also reduces the frequency of MDSCs as well as their secretion of immunosuppressive factors such as NO and TNFα and migration toward chemokines such as CCL3 and CXCL12. Many inflammatory cytokines in the serum decrease on ibrutinib, including IFN-χ, IL-17, IL-4, IL-6 and TNFα.

IFIs, predominantly involving aspergillus, have been reported in patients receiving ibrutinib.^84,85 Most patients who develop IFIs have predisposing factors including neutropenia, corticosteroid use, and antecedent chemotherapy.⁸⁴ Nevertheless, susceptibility to invasive aspergillosis has been demonstrated in BTK knockout mice.⁸⁵ In addition, patients treated with single-agent ibrutinib can develop PJP, mostly presenting with mild symptoms or radiographic changes only.⁸⁶

Ibrutinib reverses some aspects of T-cell dysfunction in CLL. Downregulation of inhibitory receptors, restoration of immune synapses, and suppression of Th2 differentiation are among the favorable changes observed (Figure 2).^87–89 These changes appear to benefit patients treated with T-cell directed immunotherapy. For example, expansion of autologous anti-CD19 chimeric antigen receptor (CAR) T-cells is enhanced by antecedent treatment with ibrutinib.⁹⁰ Concurrent ibrutinib reduces the severity of cytokine release syndrome during CAR T-cell therapy.⁹¹ Bispecific antibodies engage T cells and CLL cells simultaneously to facilitate cell-mediated lysis of tumor cells. Prior therapy with ibrutinib increases CLL cell killing by autologous T cells in response to a bispecific antibody targeting CD3 and CD19 in vitro and in vivo.⁹² Interestingly, the benefit of ongoing therapy with ibrutinib was still maintained in patients with early progressive disease and mutations in BTK or PLCG2 that have been associated with ibrutinib resistance.⁹² Others have observed increased efficacy of a ROR1 targeting BITE in PBMCs from ibrutinib-treated patients.⁹³ While the mechanism for improved T cell cytotoxicity still requires additional studies, improved immune synapse formation between T cells and CLL cells in ibrutinib-treated patients may be partially responsible.^93,94 Preclinical testing suggests that coadministration of acalabrutinib could also enhance T cell cytotoxic functions.⁹⁵

3.5. Venetoclax

Venetoclax is effective in relapsed refractory and frontline settings.^22,56 Venetoclax has been combined with anti-CD20 antibodies,^22,56 and investigated in combination with ibrutinib.⁹⁶ Tolerability of these regimens has generally been good. Neutropenia is a common adverse event on venetoclax. The rate of neutropenia in patients treated with venetoclax and obinutuzumab or chlorambucil and obtinutuzumab was comparable, as was the rate of febrile neutropenia at 5.2% versus 3.7%,respectively.⁵⁶ Little is known about the impact of venetoclax on specific immune responses. Combined treatment with venetoclax and obinutuzumab reduced healthy B cells, T cells and NK cells.⁹⁷ The CD4/CD8 ratio and differentiation state of T cells did not change during therapy.

3.6. Lenalidomide

Lenalidomide, an analog of thalidomide and commonly used agent in patients with multiple myeloma, has been extensively studied in CLL.⁹⁸ Although lenalidomide has considerable anti-CLL activity, its adoption has been hampered by concerns about toxicity, predominantly with regard to infections and SPMs.^99,100 Paradoxically, lenalidomide exerts multiple and potentially beneficial immunologic effects in patients with CLL.¹⁰¹ Lenalidomide upregulates costimulatory molecules on tumor cells, improves T-cell immune synapse formation, and enhances cytotoxic effector functions.^11,102 At treatment initiation, activation of T cells results in tumor flare reactions with release of inflammatory cytokines, which often manifests clinically as painful swelling of lymphoid tissues, fever, and malaise.^102,103 The degree of this tumor flare reaction has been correlated with improved treatment response and superior progression-free survival.^104,105 In paired lymph node biopsies obtained from patients with CLL pre-treatment and on day 8 of lenalidomide therapy, we observed increased tumor infiltration by T cells and a shift towards Th1 polarization that positively correlated with anti-tumor response.¹⁰⁶ Maintenance therapy with lenalidomide after chemoimmunotherapy has been shown to lead to sustained improvements in T-cell responses and to delay disease progression.^107–109

Lenalidomide stimulates the production of immunoglobulins by normal B cells. During treatment with lenalidomide, IgG, IgA, and IgM increase, albeit with considerable interpatient variability.^104,110 There was no correlation between serum Ig levels and the rate of infections in a small cohort of patients.¹⁰⁴ Mechanistically, class switching and increased antibody secretion from normal B cells depends on lenalidomide mediated upregulation of CD154, the ligand of CD40, on CLL cells. Further studies will hopefully reveal how to harness the beneficial effects and avoid concerning toxicities of this class of agents.

4. Strategies to Boost Immunity

4.1. Vaccinations

Patients with CLL have consistently demonstrated a weakened and less durable response to immunizations (Figure 3). Patient factors associated with blunted vaccine responses include advanced disease, older age, and hypogammaglobulinemia.^111–113 Conversely, patients with monoclonal B lymphocytosis, a precursor state of CLL, mount a better response to influenza vaccination than patients with CLL.¹¹⁴ From a safety perspective, live attenuated vaccines carry a risk of virus replication and disease in immunocompromised individuals. Patients with CLL have died from disseminated varicella zoster virus (VZV) infection after administration of live attenuated zoster vaccine.^115,116 Subunit, recombinant, polysaccharide, conjugate, or mRNA vaccines and those comprised of inactivated virus, and toxins do not have this risk. Taken together, patients with CLL should receive non-live vaccinations at diagnosis when immunity is least suppressed by disease and subsequent therapies (Figure 3).

Figure 3. Vaccination overview in CLL.

(A) Vaccine efficacy diminishes as patients progress from MBL to CLL to active disease requiring treatment. (B) The antibody response to a vaccine depends on treatment history and whether the vaccine antigen induces a primary or secondary adaptive immune response. Patients with CLL have an impaired response to immunization compared to the general population. Treatment with a BTK inhibitor further suppresses this response, particularly against novel vaccine antigens such as hepatis B. (C) Potential strategies to improve vaccine response include vaccination early in diagnosis, administration of booster doses, modification of vaccine type, and addition of adjuvants to increase immunogenicity.

Vaccine types have evolved with the aim of eliciting better responses with variable success for patients with CLL (Figure 3). For example, conjugation of polysaccharide to a carrier generates a T-cell dependent humoral response and improves immunological memory compared to polysaccharide only vaccine.¹¹⁷ A randomized study of the 13-valent pneumococcal conjugate vaccine (PCV13) versus the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in 128 patients with treatment naïve CLL found higher antibody titers against 10 of 12 serotypes one month after PCV13.¹¹⁸ Nevertheless, only 58.3% of patients with treatment naïve CLL develop an adequate antibody response to PCV13 compared to 100% in healthy subjects.¹¹⁹

Other potential strategies to enhance vaccine response in patients with CLL are coadministration of drugs and booster doses (Figure 3). Lenalidomide modulates multiple facets of the immune system as described above. While concomitant lenalidomide increased serum immunoglobulins in patients with CLL, it did not improve the response to PCV13.¹²⁰ Ranitidine has been investigated for its antagonistic effect on histamine, which inhibits antibody responses in mice.¹²¹ Ranitidine given concurrently with the Hemophilus influenza type B conjugated vaccine increased post-vaccination titers compared to controls.^122,123 These published series are small, the benefit was limited to conjugated vaccines, and the concept was not further tested in larger studies. Vaccine type may determine the efficacy of booster vaccination. A booster dose of PCV13 administered 2 months after the initial vaccine resulted in seroconversion to at least 1 serotype in all participants.¹²⁰ However, repeated vaccination with inactivated subunit influenza vaccine 3 weeks apart did not increase the rate of seroprotection or hemagglutinin inhibition titers.¹²⁴

Due to its mechanism of action, BTK inhibitors have the potential to inhibit or abrogate the humoral immune response to vaccines. Early immunization studies in ibrutinib-treated patients tested the antibody response to influenza vaccination.^125,126 This response depends on preexisting memory B cells from prior immunization or infection.^127,128 Seroconversion was observed in 7% to 26% of patients, with a lower rate among patients who had received prior lines of therapy.^125,126 Treatment with ibrutinib significantly reduced the antibody response to influenza vaccination and PCV13 compared to patients with untreated CLL (Figure 3).¹²⁹

To test the humoral immune response against novel antigens, hepatitis B vaccination was administered to treatment naïve CLL patients and patients on ibrutinib or acalabrutinib.¹³⁰ All patients had undetectable anti-HBs antibodies prior to vaccination and no history of hepatitis B infection or vaccination.¹³⁰ While treatment naïve patients had an inferior response of 28.1% compared to >95% in healthy subjects, response was nearly absent (one responder, 3.8%) in patients treated with BTK inhibitor (Figure 3).¹³⁰ In contrast, 59.1% of treatment-naïve patients and 41.5% of patients on a BTK inhibitor responded to varicella zoster vaccination, which induces a recall immune response. Consistent with relatively preserved recall responses, B-cell repertoire analysis of patients on ibrutinib have shown partial preservation of non-malignant antigen-experienced B cells during treatment.¹³¹

Vaccination prevents, and in some instances have eradicated, infections in the general population. Unfortunately, vaccine efficacy is diminished in patients with CLL who are particularly vulnerable to infectious complications. Studies to enhance vaccine response in CLL are urgently needed.

4.2. Immunoglobulin Replacement

Few treatments have been associated with improvements in Ig levels: lenalidomide has been found to increase IgG, IgA, and IgM, and BTK inhibitor therapy increases IgA levels in many patients. Thus the mainstay of improving hypogammaglobulinemia is exogenous administration of purified IgG pooled from donors. Immunoglobulin replacement therapy (IgRT) can reduce frequency of infections, rates of hospital admissions, and antibiotic usage. However, there is no demonstrated impact on (short-term) mortality and some question the cost-effectiveness of (routine) IgRT. However, others make the case that IgRT is the standard of care to prevent infections in patients with primary immunodeficiency disorders who share an increased susceptibility to the same infections and advanced hypogammaglobulinemia as patients with CLL.¹³²

Randomized trials of IgRT in patients with CLL have used different inclusion criteria, dosage and frequency of administration (reviewed in ¹³²). Overall, IgRT should be considered for patients with bacterial infections and IgG levels <4 g/L.¹³² While the risk of infection may increase at IgG levels <6g/L, one study reported 2/3 of infections in 1/4 of patients having IgG <3g/L.³⁹ Immunoglobulin preparations dosed at 100–800mg/kg given intravenously every 3–5 weeks have been investigated. One study comparing 100mg/kg, 400mg/kg and 800mg/kg dose levels concluded 400mg/kg given every 3 weeks for 4 doses followed by maintenance every 5 weeks was optimal.¹³³ Notably, this dose is lower than what may be required in patients with MM who have a more rapid clearance of immunoglobulins. One study reported that 50% of patients with breakthrough infections became infection-free when the dose was increased from 18 g to 24 g every 3 weeks, lending support to strategies that individualize dosing based on clinical outcomes.³⁹ IgRT can be achieved with intravenous or subcutaneous administration. Subcutaneous administration of 75mg/kg weekly compared to intravenous 300mg/kg every 4 weeks achieved higher IgG trough levels and was associated with lower incidence of infections and less antibiotics usage. Subcutaneous obviates the need for intravenous access and offers the possibility of self-administration at home.

IgRT is typically well tolerated with minor systemic reactions after infusion or local irritation at the injection site with subcutaneous administration. Infrequent anaphylactoid reactions and an increased risk of thromboembolic events have been associated with intravenous administration.¹³⁴ For a detailed discussion and proposed treatment algorithm for the use of IgRT we refer to the review by Lachance and colleagues.¹³²

A variation of IgRT is convalescent plasma from donors who have recovered from COVID-19. Immunosuppressed patients may not be able to mount an antibody response leading to protracted COVID-19 infection.^135,136 In this setting, administration of convalescent plasma containing high-titer neutralizing antibodies to a patient with CLL has been reported to resolve the infection.¹³⁵ However, the titer of neutralizing antibodies in donor plasma can be highly variable and may be critical for success.^135,137 Engineered monoclonal SARS-CoV-2-neutralizing antibodies have also been developed and could contribute to humoral anti-viral defense.¹³⁸

5. Discussion

While the clinical sequelae of immunodeficiency in CLL are readily apparent, the mechanistic aspects of how CLL cells interfere with normal immune function still need to be better understood. BTK and PI3K kinase inhibitors have shown both beneficial and deterimental effects on humoral and cellular immune responses. There is still much to learn about how to best harness these properties for the treatment of CLL and to reverse or even prevent disease-related immunodeficiency in patients with CLL. At present, the best approaches may be to avoid immunosuppressive therapies, boost specific immune responses by vaccinating early in the diseae course, and to take appropriate supportive measures for patients with recurrent infections and severe hypogammaglobulinemia.

Early intervention trials have failed to show a survival benefit and observation in the absence of active disease remains the recommended approach to patients with CLL. Most endpoints in early intervention trials incorporate traditional response criteria especially PFS, exposing the trials to possible criticism that the outcome of comparing an active treatment regimen versus placebo is a forgone conclusion.¹³⁹ It is tempting to speculate that early intervention could forestall the immunodeficiency that seems unvavoidable if the disease is left to run its course. On the other hand, early intervention, depending on the regimen chosen, could worsen immunodeficiency or expose patients unnecessarily to the risk of serious adverse events. Ideally, assessment of immune status would be incorporated as an objective for all clinical trials in CLL akin to safety and efficacy endpoints.

Notable among ongoing early interevention trials is the PreVent-ACaLL study that uses a recently developed scoring system to identify patients with untreated CLL who do not meet criteria for treatment initiation but are predicted to have a high risk of infection and/or need of CLL treatment within 2 years of diagnosis.¹⁴⁰ Patients are randomized to observation versus 12 weeks of therapy with acalabrutinib and venetoclax. The primary endpoint is the rate of grade ≥3 infection-free, CLL treatment-free survival at 24 weeks.¹⁴¹ A possible extension of the observation period to 2 years from enrollment is considered. An emphasis on systematically testing immunorestorative interventions is required to build upon the significant therapeutic advancements that have already been made toward the outcome of patients with CLL.

6. Clinical Care Points

• Patient with CLL are at increased risk for Infections and second primary malignancies due to their underlying immunodeficiency.

• Vaccinations should be administered early in the disease course to improve the likelihood of an immune response.

• Non-live virus vaccines are generally safe in patients with CLL and, while response rates tend to be lower than in the general population, are an important component of preventing infections.

• Patients with IgG levels < 4g/L and history of bacterial infections may benefit from immunoglobulin replacement therapy to reduce the rate of infections and hospitalizations.

• Patients should be counseled about the benefit of cancer screening, especially skin exams.

Key Points:

• Immunodeficiency in CLL is caused by disease intrinsic and treatment related factors that impair adaptive and innate immunity.

• Available treatments have differing impact on immune function in CLL: chemoimmunotherapy is associated with opportunistic infections and increased risk of myeloid malignancies; anti-CD20 antibody therapy and BTK inhibitors increase the risk of hepatitis B reactivation; neutropenia, but not neutropenic fever, is a frequent adverse event on venetoclax; oppoportunistic infections and autoimmune complications are increased on idelalisib.

• Hypogamaglobulinemia generally worsens over the course of the disease and low levels of IgG are associated with an increased risk of infections.

• BTK inhibitor therapy can improve aspects of T-cell function and promote a moderate increase in IgA that is associated with lower rates of infection.

Synopsis.

Reversing or preventing immunodeficiency in patients with chronic lymphocytic leukemia (CLL) is of the highest priority. The past decade of research has met the challenge of treating CLL for most patients. However, patients continue to struggle with infections and second primary malignancies related to immunodeficiency. Strategies addressing this need are currently limited to vaccinations, with suboptimal efficacy, and immunoglobulin replacement. Correlative studies have provided insights into immunologic alterations on treatment. Understanding vulnerabilities in the immune system may help identify potential interventions to boost immunity. An emphasis on systematically testing such interventions is required to restore immunocompetence in patients with CLL.