Immune Dysfunction and Infection – Interaction between CLL and Treatment: A Reflection on Current Treatment Paradigms and Unmet Needs

Chronic lymphocytic leukemia (CLL) is a hematological malignancy characterized by immune dysfunction, which significantly contributes to increased morbidity and mortality due to infections [1, 2]. While advancements in therapeutic strategies have improved overall survival (OS) rates for CLL patients, the risk of infection remains a major concern. Treatment options, such as combination chemoimmunotherapy (CIT) and targeted treatments, have demonstrated efficacy in targeting leukemic cells [3]. However, these therapies can also interact with the tumor microenvironment and immune components, compromising their clinical effectiveness and increasing the susceptibility to infections [4, 5]. Considering the inherent immune dysfunction caused by CLL itself, treatment becomes a double-edged sword. To ensure optimal personalized strategies for CLL patients, it is crucial to understand how conventional therapies impact the disease-microenvironment-infection axis. In this context, a machine learning-based algorithm called CLL Treatment-Infection Model (CLL-TIM) has been developed to identify high-risk patients for serious infections [6]. This review aims to explore management strategies for immune dysfunction and infections in CLL, highlight the foundations of infectious risk in CLL, and discuss the impact of current treatment options on infection susceptibility. By addressing these issues, we can improve patient outcomes and enhance the quality of life for individuals living with CLL.

At the core of CLL, immune dysfunction is caused by a plethora of molecular factors, which enhance tumor cell proliferation and survival, while re-educating the surrounding tumor microenvironment into a less protective state [1, 3, 7]. In primis, CLL patients’ high risk of infections is due to the decreased immune surveillance caused by intrinsic disease features [8]. The alteration of the B-cell compartment – majorly skewed toward malignant CLL B lymphocytes [9] – weakens the adaptive immunity and, thus, the functions of other immune cells like T lymphocytes. Even decades before leukemia diagnosis, monoclonal B-cell lymphocytosis, a pre-CLL stage, shows an increased monoclonal B-cell population in the peripheral blood (PB; <5,000 monoclonal B cells/mL) [9, 10]. Lymphocytosis, given the slow but progressive accumulation of CLL cells in the PB, worsens with disease progression (>5,000 monoclonal B cells/mL), leading to invasion of lymphoid organs [11], a general immune surveillance impairment (e.g., hypogammaglobulinemia [12]), ultimately increasing the risk of infections in patients affected by CLL [2, 13]. Further impact on immune response coordination is given by the considerable alteration in the antigen-presenting cell compartment, due to reduction of the complement-activating glycoprotein properdin in PB [14], binding and expression of the complement receptors 1 and 2 (CR1 and CR2) [15, 16], and further reduction of the major histocompatibility complex-II on dendritic cells [17]. Moreover, CLL cells can directly affect effector immune cells (e.g., CD8⁺ T and natural killer cells [18]) through immune checkpoint interactions [19], soluble components (including extracellular vesicles) [20], and indirectly by regulating modulatory cells, such as Treg [19, 21]. In combination with an altered lymphoid compartment, myeloid cells, have been described to either directly support CLL cell survival, proliferation, and migration (e.g., neutrophils and monocyte-derived cells) [22‒24], or having an impaired phagocytic potential [25]. A schematic summary can be found in Table 1.

Microbiome research represents an increasingly studied area with a potential to indirectly influence immune system as well as efficacy of immunotherapies in cancers and hematological malignancies [26]. Interestingly, disease-associated immune dysfunction is not the only risk factor for infections in patients affected by CLL. Indeed, gut microbiome (GMB) pathological alterations, known as dysbiosis, have been implicated in human diseases, playing a critical role by influencing host immune response, protection against pathogen overgrowth, biosynthesis, and metabolism [27]. Short-chain fatty acids, end products of anaerobic intestinal bacteria-mediated fermentation of dietary fibers, have been shown to promote naive T-cell differentiation into T helper (Th)1, Th17, or Treg [28]. Furthermore, tumor-associated chronic inflammation sustained by altered cytokine levels have been shown to be correlated with dysbiosis [29]. Finally, we recently compared the GMB’s between patients with CLL and healthy control populations, observing a consistent dysbiosis in the CLL group, suggesting a link between gut dysbiosis and immune dysfunction in CLL pathogenesis [30]. Thus, given the GMB ability to influence the immune system components (e.g., macrophage, dendritic cells, and different T-cell subsets), its role in enhancing CLL-associated immune dysfunction warrants further investigation. The importance of addressing immune dysfunction in CLL is further emphasized by the increased risk of common bacterial infections like invasive pneumococci [31], COVID-19 infections [32], and even the increased need for antimicrobial prescriptions decades prior to diagnosis of CLL [33]. Despite the immune dysfunction of CLL leading to increased risk of infections, morbidity, worsened quality of life, and increased mortality, data on the interaction of CLL treatment with CLL immune dysfunction are currently lacking, while evidence for preventive measures are warranted.

In the last decades, CLL treatment options have improved specificity by targeting leukemic cells while reducing off-target effects. Despite these improvements, targeted treatment regimens still lead to immune suppression in CLL (Table 2) [4, 5].

In an era dominated by increasing use of targeted agents for CLL, CIT remains a fixed-duration treatment option for patients with mutated IGHV and no TP53 aberrations in the first-line setting, as well as the only treatment option for a number of health systems [34]. Fludarabine combined with cyclophosphamide and rituximab (FCR) are favored for patients <65 years of age due to achieving durable remissions, while bendamustine-rituximab is preferred for elderly fit patients due to lower risk of infections [35, 36]. In line with this, the phase 3 clinical trial GAIA/CLL13 (NCT02950051), assessed CIT versus targeted combinations based on venetoclax and CD20 antibodies for fit CLL patients. Superior efficacy in achieving undetectable minimal residual disease and improved progression-free survival (PFS) was demonstrated for venetoclax-obinutuzumab combinations [37, 38]. However, for mutated IGHV patients, comparable efficacy of CIT regimens was demonstrated, while triplet combinations with venetoclax-obinutuzumab-ibrutinib resulted in the highest frequency of infections (grade ≥3). Despite its efficacy, fludarabine-based regimes are associated with severe and opportunistic infections like Pneumocystis jirovecii, Listeria monocytogenes, mycobacteria, and cytomegalovirus (CMV) [39], likely related to, in addition to neutropenia, significant and sustained reduction, and/or dysfunction of CD4⁺ T-cells [40].

Importantly, high-grade infections (grade ≥3) are more often observed in previously treated patients [41‒43]. Indeed, in the CLL8 trial (NCT00281918), fungal and opportunistic infections were rare in treatment naïve (TN) patients receiving FCR despite grade 3–4 neutropenia observed in one third of patients [44], in the setting of pneumocystis prophylaxis implemented for most patients. Thus, while neutropenia and lymphopenia entail increased risk of infections, having received previous treatment, especially with an alkylating agent, significantly worsens the risk of severe and opportunistic infections upon fludarabine-based treatment. This can both be due to long-term impact of previous therapy, and due to the more severe immune dysfunction upon relapse of CLL. In line with this, risk of infections upon progression of CLL after first line therapy is emphasized by the increased mortality from infections after chlorambucil-obinutuzumab as compared to ibrutinib-venetoclax in the GLOW trial (NCT03462719), where most fatal infections occurred among patients off therapy after chlorambucil treatment [45, 46].

Worth of notice is that the CLL8 trial also demonstrated the impact of dysbiosis in posttreatment disease progression. Indeed, patients previously treated with anti-Gram-positive antibiotics achieved lower overall response rate and OS. Further analysis associated anti-Gram-positive antibiotic treatment with reduced PFS [47].

Hematological toxicities and related infections are fewer and less severe upon treatment with bendamustine and chlorambucil, hence the rationale for their use for fit, low-risk CLL patients >65, and frailer CLL patients, respectively [48]. With these regimes, common infections include Streptococcus pneumoniae, and Klebsiella pneumoniae, while fungal, viral, and opportunistic microbes are more uncommon [49]. Like fludarabine, bendamustine induces prolonged T-cell lymphopenia [50, 51]. However, the treatment-related immunosuppression is less severe. When comparing bendamustine + rituximab (BR) with FCR for fit TN CLL in the CLL10 trial (NCT00769522), BR demonstrated lower rates of high-grade neutropenia and infections compared with FCR. Importantly, infections in the FCR arm occurred primarily in patients >65, further highlighting the rationale for BR as the favored choice in this age group [48].

For CIT-combinations, it is thus important to carefully balance between a rapid and durable treatment effect (undetectable minimal residual disease) and increase in infection risk due to the chosen therapeutic regime. CIT may also impair the gut-blood barrier leading to more gut-derived blood stream infections and thus a different landscape of infections as compared to TN CLL patients with infections [52].

Targeted therapy has gradually replaced CIT as treatment of choice over the past decade. Currently, Bruton’s tyrosine kinase inhibitors (BTKi) ibrutinib, acalabrutinib, and zanubrutinib as monotherapy, B-cell lymphoma-2 inhibitor (BCL-2i) venetoclax alone or combined with anti-CD20 antibody, as well as in rare incidences (due to risk of infections and autoimmune complications), phosphoinositide 3-kinases-δ inhibitors (PI3Kδi) idelalisib and duvelisib combined with an anti-CD20 antibody, are options in first- and later line treatment [53].

Infectious risk upon treatment with ibrutinib is proposed to be related to off-target inhibition of other TEC family tyrosine kinases such as inducible T-cell kinase as well as BTK in other immune cells such as T-cells, NK cells, and macrophages [54‒56]. In particular, suppressed macrophage function has been shown to increase susceptibility to fungal infections, as seen more often on BTKi treatment [57, 58]. Infectious risk upon treatment with 2nd generation BTKi acalabrutinib and zanubrutinib is similar to the risk with ibrutinib, despite increased BTK selectivity (e.g., ELEVATE-RR, NCT02477696; ALPINE, NCT03734016) [59‒62]. Thus, off-target kinase inhibition does not alone explain treatment-associated infections with BTKi. Real-world data have shown that infections, especially in the airways and urinary tract, upon ibrutinib are most frequent in the first 6 months, after which rates decline [63]. This is in accordance with Sun et al. [64], where a transient increase in immunoglobulin (Ig)M and a sustained increase in IgA could explain the post-six-month immune reconstitution in those patients. The importance of the interplay between CLL disease and treatment is emphasized by the CLL12 trial (NCT02863718) testing preemptive ibrutinib for high-risk CLL without treatment need; here, similar rates of infections are seen between the ibrutinib and placebo arm [65]. This may suggest immunosuppression correlating with dynamics of the CLL tumor burden in PB, with initial BTKi-induced lymphocytosis in the first months followed by subsequent lymphocyte decrease.

For the BCL-2i venetoclax, neutropenia constitutes a frequent adverse event, likely due to the dependency of BCL-2 in granulopoiesis [66]. However, neutropenic fever is less frequent on venetoclax treatment combined with a CD20 antibody as compared to CIT, while the infectious burden increases to the same or even higher levels than on CIT for triple combinations with venetoclax [67]. Early studies of venetoclax for patients with relapsed/refractory (RR) CLL receiving monotherapy demonstrated grade 3–4 neutropenia in approximately 40%, and reported infections were predominately upper respiratory tract infections (URTIs) and pneumonia (NCT01889186) [68, 69].

Idelalisib is a PI3Kδi primarily used in combination with the anti-CD20 antibody rituximab in RR CLL, or occasionally in TN patients with TP53 mutation or del(17)p [53]. Although demonstrating effective clinical responses, idelalisib treatment is associated with autoimmune-related toxicities and URTIs including increased susceptibility to Pneumococcus pneumonia [70‒73]. Furthermore, idelalisib treatment has also been associated with complications, including febrile neutropenia and neutropenia, with a 70% infection increase in the single-arm treatment [71]. Infection-related deaths in this study were due to pneumonia, sepsis, and septic shock [71]. Idelalisib-associated toxicities are likely linked to inhibition of PI3Kδ in T-cell receptor signaling, impairing CD8⁺ T-cell cytotoxicity but also inhibiting Treg, resulting in impaired immune tolerance [74]. Furthermore, increased susceptibility to bacterial infections is likely related to neutropenia and impaired neutrophil function [75]. The PI3Kγ/δ dual inhibitor duvelisib has been previously tested alone (DUO; NCT02004522) or in combination with anti-CD20 (NCT01871675). Generally, treatment with duvelisib was associated with neutropenia, leading to pneumonia (18%) and URTIs (16%), as well as pneumonitis and hepatitis [70, 71, 76].

Monoclonal antibodies targeting CD20 have been explored as monotherapy and in various combinations. Considerable reduction in side effects, moderate neutropenia, and infections (e.g., pneumonia) for rituximab, have been achieved with later generations (ofatumumab and obinutuzumab) due to different CD20 targeted epitopes [77]. Nevertheless, immune impairment due to anti-CD20 monotherapy persists also with later generation drugs, including myelosuppression and neutropenia in patients treated with ofatumumab [78]. In clinical practice, venetoclax is commonly combined with rituximab (Ven+R; MURANO, NCT02005471) or obinutuzumab (Ven+O; CLL14, NCT02242942) after clinical trials have demonstrated high efficacy in both TN and RR disease [79‒81], although grade 3–4 neutropenia rates close to 60% have been reported. Combination therapy has never been compared to monotherapy in a trial setting; however, in a real-world study of patients with RR CLL, rates of neutropenia were much lower (34%) and similar to monotherapy (40%) [82]. Interestingly, another real-world study on venetoclax+anti-CD20 showed similar rates of neutropenia between TN and RR patients (19 and 17%, respectively), while infection rates were significantly higher in the RR group [83], thus reflecting the interplay between treatment, CLL disease and impact of previous treatment for immune dysfunction. Ven+O and Ven+R combination in the GAIA/CLL13 trial demonstrated slightly higher frequency of grade 3–4 neutropenia (45% vs. 40%) and pneumonia (5% vs. 2%) with Ven+O versus Ven+R, while the risk was significantly higher upon addition of ibrutinib as a triple combination [37]. Acalabrutinib as monotherapy or combined with obinutuzumab in TN CLL was recently investigated in the ELEVATE-TN clinical trial (NCT02475681) [60]. Here, the combination entailed considerably higher rates of grade 3–4 neutropenia (30 vs. 10%) and respiratory tract infections (grade 3–4 pneumonia, 5 vs. 2.2%) compared to monotherapy.

Combining ibrutinib with venetoclax (Ven+Ibr) constitutes another approach aiming to deepen remissions based on drug synergy and enable fixed-duration treatment. Generally, neutropenia and infection rates with Ven+Ibr are similar in TN and RR CLL (GLOW; CLARITY, NCT02267590; HOVON141/VISION, NCT03226301) [45, 84, 85]. Grade 3–4 neutropenia is more frequent with Ven+Ibr (around 35%) [45, 84, 85] than with ibrutinib alone (10–25%) [62, 86], likely due to the additional BCL-2i impact on myelopoiesis, but less frequently than observed for venetoclax +/− anti-CD20 [68, 69]. Despite this, infection rates with Ven+Ibr [45] are similar or slightly higher than with venetoclax +/− anti-CD20, while higher than observed with chlorambucil-based CIT [37, 45, 79, 81, 87], although cross-trial comparisons should be cautiously considered with all the potential biases. The higher infection rate with Ven+Ibr may in part be due to suppressive off-target effects of ibrutinib on T cell and innate immune function, or due to differences in patient age and fitness. In line with this, infections appear to be less frequent with Ven+Ibr than what is observed for ibrutinib alone [59, 62, 86]. Here, additional mechanism could be the rapid elimination of CLL cells by venetoclax, thus eradicating CLL-mediated immune suppression faster. Triplet combination therapy with a BTKi, BCL-2i, and anti-CD20 antibody is also a strategy currently being explored. Recent data from acalabrutinib combined with venetoclax and obinutuzumab (AVO; NCT03580928) in TN CLL patients reported 37% grade 3–4 neutropenia, thus similar to other venetoclax-based regimes and acalabrutinib+obinutuzumab, while infections grade 3 or higher were observed in only 6% [88]. Meanwhile, in the GAIA/CLL13 trial, ibrutinib combined with venetoclax and obinutuzumab (IVO) in TN CLL led to grade 3–4 neutropenia in around 50% of patients, with grade 3–4 infections in 21% of patients, similar or higher rates than seen on CIT [37]. In a phase 2 study of IVO in both RR and TN CLL, grade 3–4 neutropenia was unsurprisingly higher in the RR patients (76% vs. 56%), while grade 3–4 of any reported infections were rare in both RR and TN patients [89]. Chemotherapy-free triplet combination therapy may be particularly relevant for patients with del(17)p or TP53 mutation, given the inferior prognosis of this patient group regardless of treatment choice. The CLL2-GIVE trial (NCT02758665) investigated IVO in TN CLL patients with del(17)p and/or TP53 mutation. Here, 40% of patients had grade 3–4 neutropenia during the induction phase, which declined throughout consolidation and maintenance treatment. Additionally, grade 3–4 infections which were mainly respiratory and urinary tract infections, only occurred in 5% of patients. It is still premature to conclude whether this treatment strategy will improve long-term depth and duration of remissions in this high-risk patient group. However, treatment-related infectious risk with triple combination therapy was, importantly, not elevated in this setting [90].

Combining targeted agents may constitute a strategy to improve efficacy, reduce toxicity, and overcome resistance. Paradoxically, while aiming for drug synergy, disadvantageous immunosuppressive effects on the microenvironment may also increase along with the risk of infection (Table 3). It should still be emphasized, that differences in toxicity and risk of infections between the different treatment regimens in clinical trials are also due to differences in patient populations, treatment follow-up time, use of supportive care, and how data are reported and presented. This makes it especially important to evaluate benefits versus risks for the individual patient or patient risk group in a daily clinical setting.

Overall, the gain in treatment efficacy when choosing one regiment over another should be carefully weighed against the infectious risk associated with treatment-, CLL-, and patient-related risk factors. Here, improved strategies to identify which patients will benefit the most from a given treatment with the least risk of adverse events including infections are indeed warranted.

Currently, vaccination and prophylaxis represent conventional strategies against infections, a topic extensively discussed in our recent review [4] and summarized in Figure 1.

Despite immunological impairment in CLL, vaccines can be effective and constitute an important tool in protection against infections. In particular, it is important to consider a preventing vaccination strategy before CLL requires treatment, including revaccination if there is the suspect of a reduced efficacy of previous vaccines. However, due to the immune dysfunction, it is important to be aware of which vaccines are likely to be effective versus potentially harmful, and why. Impaired humoral response is inherent to CLL [91] and is further attenuated by B-cell targeted treatments like BTKi and anti-CD20 antibodies (including cases of hepatitis B reactivation), as well as ongoing or previous chemotherapy [92‒95]. As a consequence, vaccines relying solely on antibody-dependent immunization are less effective in CLL. One strategy to overcome this is the use of conjugated vaccines that, in addition to boosting the humoral response [96], also elicits a T-cell response [97] providing an additional level of immune protection. Similarly, mRNA vaccines against COVID-19 provide T-cell memory in addition to humoral response [98]. Other strategies to exacerbate the response to vaccines constitute use of adjuvants [99] as well as booster vaccines [100]. Due to the weakened immune system, live attenuated vaccines should generally be avoided in CLL due to the risk of opportunistic infections and severe systemic reactions [101]. Finally, effective vaccination of close family and contacts could provide an additional protection for patients with CLL from infection. With this in mind, we here briefly summarize current practice recommendations for CLL.

Conjugated antipneumococcal vaccination is highly recommended, particularly with PCV13 (Prevenar 13-peptide vaccine) followed by PPSV23 (Pneumovax 23-polysaccharide vaccine) 2 months later [96]. Nevertheless, vaccine serologic response requires examination at least 4–6 weeks afterward, to evaluate the necessity of a possible revaccination [102, 103]. Preventive vaccination against varicella-zoster virus (recombinant), hepatitis B (entecavir or tenofovir) and Clostridium tetani, Corynebacterium diphtheriae, and Bordetella pertussis or B. Parapertussis (Tdap) is also highly recommended [102, 103]. Recombinant vaccines use recombinant proteins or non-replicating plasmids inserted in viral, bacterial, or mammalian vectors, inducing strong long-term cellular immune responses [104]. On the other hand, nasal vaccine and other live attenuated vaccines including measles/mumps/rubella/yellow fewer viruses are discouraged for patients with CLL due to the risk of later disease severe manifestations [102‒104]. Given the higher mortality associated with COVID-19 infection for CLL patients [105, 106], vaccination against COVID-19 is highly recommended. Despite the compromised seroconversion and new COVID-19 variants of concern, 2-dose scheduled vaccination (ChAdOx1, mRNA BNT162b, and mRNA1273) followed by booster vaccination shows efficacy for a third of CLL patients, with probably more patients achieving a T-cell response and increased response upon several booster vaccinations, which are recommended for patients with CLL [107, 108].

In order to justify prophylaxis in CLL, which is generally not recommended, it is important to consider infection history for each patient, as well as current or planned treatments. Indeed, knowledge of previous opportunistic infections may guide prophylactic strategies, for instance against infection caused by Mycobacterium tuberculosis, CMV, and herpes virus (e.g., Acyclovir 400 mg bid) [53, 109]. Environmental risk, based on regional or local microbiological recommendations (e.g., malaria and yellow fever areas), should also be considered. In these circumstances, mosquito repellents are highly recommended for CLL patients, while novel mRNA-based vaccines can be expected in the coming years. On the other hand, treatment-based prophylaxis should also be evaluated in particular instances like prophylaxis against Pneumocystis jirovecii pneumonia (PJP) for purine analogs or Pi3Kδi treatment [110], while it is not recommended during BTKi treatment due to low PJP infection risk [109, 111]. Despite some prior recommendations, PJP prophylaxis is not generally recommended in R/R BTKi-treated CLL patients [109, 110]. To prevent CMV infections during idelalisib monotherapy or in combination with rituximab, seronegative patients should receive CMV-negative or purified blood products while, for confirmed presence of CMV, use of ganciclovir or valganciclovir in combination with idelalisib discontinuation is highly recommended [112, 113]. Interactions between specific antimicrobials and specific CLL treatments should be considered when prophylaxis or antimicrobial strategy is chosen [4]. Finally, granulocyte colony stimulating factor (G-CSF) should be implemented for CLL patients affected by neutropenia-associated complications [114]. Despite we currently have minimal information regarding efficacy and survival benefit, it is important to mention that Ig replacement is a viable option for CLL patient affected by recurrent infections and hypogammaglobulinemia [53, 115].

Concerning COVID-19, prophylaxis through passive immunization using tixagevimab and cilgavimab, depending on antibody availability, appears to be effective for CLL patients [116]. Beyond this, recently, secondary prophylaxis treatment efficacy using nirmatrelvir plus ritonavir was also demonstrated, suggesting how current guidelines should be now supplemented with similar preemptive treatments [117, 118].

Given vaccination and prophylaxis cannot always be applied and may not prevent a number of severe infections in CLL, and that currents treatments can result in sustained immune dysfunction, leading to increased morbidity and mortality due to infections, it is essential to define strategies aiming to identify risk factors prior to treatment to test novel interventions and inform treatment choice from the perspective of risk of immune dysfunction.

Such preventive strategies could aim at improving immune function in early-stage CLL based on preemptive treatment strategies for early disease control. Currently, this is tested in the CLL12 and EVOLVE (NCT04269902) clinical trials. With the hypothesis that an early intervention using ibrutinib would minimize toxicity and increase disease control, CLL12 demonstrated an improvement in PFS and low toxicity. Despite this, infections of any grade were similar between ibrutinib (63.9% patients) and placebo (71% patients) groups [65]. The EVOLVE trial, currently recruiting, aims at improving OS by preemptive Ven+O combination for high-risk patients [119].

Another approach to improve immune dysfunction could be selection of treatment type and even time of treatment aiming at reducing the risk of infections. To this end, the CLL12 trial has tested whether treatment with ibrutinib monotherapy for high-risk CLL close to diagnosis, prior to iwCLL criteria for treatment [120], could improve outcome [121]. Unfortunately, early ibrutinib did not reduce risk of infection nor improved OS. In terms of selection of treatment type, the mainstay has been that CIT caused more immune dysfunction than targeted therapy. However, the GAIA/CLL13 trial demonstrated that 1st-line treatment with the triplet of obinutuzumab-venetoclax-ibrutinib led to at least as high infection rates as CIT with FCR or R-bendamustine, while obinutuzumab-venetoclax led to lower rates of infection [38]. Thus, the triplet could not be generally recommended. At time of progression after 1st-line treatment, recent data from the GLOW trial indicates that fatal infections occurred upon progression after obinutuzumab-chlorambucil treatment prior to patients meeting iwCLL criteria for next line of treatment [45]. A similar trend for increased fatal infections was not seen in the VISION/HO141 trial, testing MRD-guided reinitiation of ibrutinib-venetoclax upon molecular relapse [85, 122].

A different approach to improve outcome from preemptive treatment in CLL, would be to identify patients in the watch and wait setting with high-risk of infections, as their 30-day mortality upon the first serious infection is 10% [2]. We previously demonstrated that assessment of each CLL patient’s comorbid conditions can correlate with increased infection and mortality [123]. In line with the necessity to test new strategies for identifying high-risk patients, we developed the machine learning-based algorithm CLL-TIM), identifying patients with a 70% risk of serious infection and/or CLL treatment within 2 years from diagnosis [124]. In the PreVent-ACaLL trial (NCT03868722), we selected high-risk patients based on the CLL-TIM algorithm for randomization between standard of care (watch and wait) or short term (3 cycles) treatment with acalabrutinib and venetoclax [6]. The aim of the PreVent-ACaLL study is to improve infection-free, treatment-free survival for such high-risk CLL patients, without jeopardizing their health by prolonged treatment leading to risk of infections and other adverse events. Despite studies highlighting the correlation between recurrent CLL mutations and high infection risk [125, 126], including extensive OMICS data on top of the routine data included for the CLL-TIM algorithm did not improve predictive performance [127].

Current guidelines for management of CLL do not recommend general preventive strategies against infections but restrict recommendations to vaccine recommendations and very specific cases of prophylaxis. Nevertheless, infections are still the major cause of death for patients with CLL. In particular, despite novel therapeutic strategies, mortality and morbidity due to infection showed no improvement over the last decades [4, 13, 63, 128]. Thus, the lack of more general preventive strategies against infections in CLL reveals an unmet need. Cross-trial comparisons, with all the limitations of such comparisons, indicate that obinutuzumab-chlorambucil- and venetoclax- or ibrutinib-based treatment leads to similar immunosuppression, while FCR and R-bendamustine treatment causes more immunosuppression than BTK- or BCL-2 inhibitor-based treatment, except for the triplet combinations of obinutuzumab-venetoclax-ibrutinib leading to the highest infection counts. Early targeted treatment prior to iwCLL criteria for treatment initiation did not reduce risk of infections, while progression after 1st-line treatment may lead to increased risk of infections prior to meeting iwCLL criteria for next line of treatment. We encourage the research community to use these examples as an incitement to thoroughly explore real-world data and clinical trial data to develop and test strategies to improve immune function and reduce morbidity and mortality from infections in CLL, challenging the current paradigm for management of CLL.

CUN received research funding and/or consultancy fees outside this work from AbbVie, AstraZeneca, Octapharma, Janssen, CSL Behring, BeiGene, Genmab, Eli Lilly, MSD, and Takeda. All the other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

This work was supported by grants from the Danish National Research Foundation (DNRF; DNRF126) to E.G. R.S.T. received funding from the Danish Cancer Society. C.U.N. received funding from the Danish Cancer Society and the EU-funded ERA PerMED program for this work.

E.G., R.S.T., T.F., and C.U.N. wrote the manuscript and created the figures and tables jointly. E.G. was responsible for the revision of the manuscript, the final version was approved by all authors.