Prevention of infections in patients with chronic lymphocytic leukemia

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 defects in immune function related to the specific antileukemic therapies administered. The spectrum of infections in CLL patients has evolved with use of therapies such as the alkylating agents (chlorambucil, cyclophosphamide, bendamustine), purine analogs (eg, fludarabine), monoclonal antibodies (eg, alemtuzumab), Bruton tyrosine kinase inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib), and the B cell leukemia/lymphoma 2 inhibitor, venetoclax.

The approach to infection prevention will be reviewed here. The immune defects related to CLL and its therapy as well as the spectrum of infectious complications are discussed separately. (See "Risk of infections in patients with chronic lymphocytic leukemia".)

The management and complications of CLL are discussed separately. (See "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".)

ANTIMICROBIAL PROPHYLAXIS

General approach — As the immune defects caused by specific chronic lymphocytic leukemia (CLL) therapies have significant impact on subsequent infectious complications, our prophylaxis recommendations vary depending upon the type of therapy used (table 1). Additional considerations that impact antimicrobial prophylaxis in individual patients are treatment status (treatment naïve versus heavily pretreated) and past history of infections. There are no unique prophylaxis recommendations for older versus younger patients [1].

There have been no randomized trials evaluating the use of prophylactic antimicrobials in patients with CLL, and there are no evidence-based guidelines for antimicrobial prophylaxis in this population. Most recommendations for antimicrobial prophylaxis have been extrapolated from prophylactic regimens used in treatment trials as well as from anecdotal reports.

The National Comprehensive Cancer Network (NCCN) and the International Workshop on Chronic Lymphocytic Leukemia have developed supportive care guidelines for CLL patients based upon expert consensus opinion [2-5]. Our recommended approach takes these recommendations into consideration but also provides more specific recommendations based upon prophylaxis recommendations used in CLL treatment trials and infectious complications observed in these trials.

Indications based on CLL therapy — The use of prophylactic antimicrobials in patients with CLL depends upon the treatment regimen and its related immune defects (table 1). Suggested prophylactic regimens (for those with an indication) are summarized in the following table (table 2).

●Antimicrobial prophylaxis is not advocated for patients with CLL who are not receiving active therapy or who are receiving an alkylating agent (eg, chlorambucil, bendamustine), or venetoclax. Instead, such patients are candidates for vigilant observation and early initiation of treatment if symptoms develop.

●Patients receiving a purine analog-based treatment regimen are at increased risk for opportunistic infections. We use antiviral prophylaxis (against herpes simplex virus [HSV] and varicella-zoster virus [VZV]) in all patients receiving a purine analog. In those receiving combination therapy with a purine analog, we also use Pneumocystis prophylaxis. (See 'Purine analog therapy' below.)

●Patients treated with alemtuzumab are at increased risk for multiple opportunistic infections, including cytomegalovirus (CMV) reactivation. We use antiviral prophylaxis (against HSV and VZV) and Pneumocystis prophylaxis routinely in such patients, and we monitor patients weekly for CMV reactivation. (See 'Alemtuzumab' below.)

●Pneumocystis pneumonia has occurred in some patients receiving Bruton tyrosine kinase inhibitors. At present, there are no standard recommendations for antimicrobial prophylaxis with use of these agents. (See 'Bruton tyrosine kinase inhibitors' below.)

Bruton tyrosine kinase inhibitors — In addition to the immune defects inherent to CLL, the pathogenesis of infection with use of Bruton tyrosine kinase inhibitors may also be related to inhibition of ITK, impairment in macrophages, and multiple functional defects in neutrophil function, including decreased reactive oxygen species production [6-8].

Infections are a common occurrence in patients receiving Bruton tyrosine kinase inhibitor therapy, irrespective of which specific Bruton tyrosine kinase inhibitor is utilized (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib) [9-12]. It has been estimated that 52 to 56 percent of patients receiving Bruton tyrosine kinase inhibitor therapy, either as a single agent or as part of combination therapy, will sustain an infectious complication during the course of therapy [9]. Lower respiratory tract infections are especially common. Despite this, discontinuation of therapy due to infectious complications has been estimated to occur only in approximately 10 percent of patients [13].

Although in small numbers, the occurrence of a variety of opportunistic infections in patients receiving these agents, including Aspergillus and Pneumocystis infections, have been reported both anecdotally and from larger series [14-16]. Clinicians should have a high index of suspicion for these infections in patients receiving these agents, and the diagnosis should be sought in those with compatible signs and symptoms.

A small number of cases of PML also have been reported in patients receiving Bruton tyrosine kinase inhibitor therapy. Clinicians should consider diagnostic evaluation in patients who present with suggestive signs and/or symptoms of PML. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase inhibitors'.)

At present, there are no standard recommendations for routine antimicrobial prophylaxis with the use of Bruton tyrosine kinase inhibitors [16]. However, prophylaxis may be considered for those patients at higher risk of infection, such as heavily pretreated patients or those with prior opportunistic infections. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase inhibitors'.)

Venetoclax — Venetoclax is a B cell leukemia/lymphoma 2 (BCL-2) inhibitor that has been utilized as a component of combination therapy, with agents such as rituximab, obinutuzumab, and ibrutinib. Infections remain one of the most common grade 3/4 adverse events with such regimens [17]. In a large phase III trial, 17.5 percent of patients receiving frontline therapy with venetoclax plus obinutuzumab sustained grade 3/4 infectious complications [18]. In another series, 8 percent of patients who received frontline venetoclax plus ibrutinib had grade 3/4 infection [19]. As with the use of Bruton tyrosine kinase inhibitors, a small number of opportunistic infections have been reported [20]. As this agent has not been definitively associated with an increased risk of opportunistic infections, antimicrobial prophylaxis is not typically recommended. However, antiviral, antifungal, and/or Pneumocystis prophylaxis may be considered on a case-by-case basis in patients with history of prior opportunistic infections that could recrudesce and/or who have residual immune defects from prior CLL therapy. Because venetoclax is a cytochrome P450 substrate, there are multiple potential drug interactions; voriconazole is specifically contraindicated with venetoclax administration. Specific interactions with other medications may be determined using the drug interaction program included within UpToDate.

Anti-CD20 monoclonal antibodies — When an anti-CD20 monoclonal antibody (eg, rituximab, ofatumumab, obinutuzumab) is used as single-agent therapy, we do not use antimicrobial prophylaxis [21]. However, when used in combination with high-dose methylprednisolone, we give Pneumocystis and herpesvirus (HSV, VZV) prophylaxis during therapy and for two months following treatment discontinuation [22]. Invasive fungal infections with obinutuzumab therapy have been reported anecdotally [23].

There is the potential for hepatitis B or C reactivation with use of these agents. We suggest testing hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and hepatitis C antibody (HCAb) prior to initiation of anti-CD20 monoclonal antibody therapy. If either HBsAg or HBcAb is positive, a quantitative hepatitis B viral load should be checked using the polymerase chain reaction (PCR). Patients who are receiving intravenous immunoglobulin (IVIG) may be HBcAb positive due to passive transfer. In HBsAg-positive patients who are planning to receive anti-CD20 monoclonal antibody therapy, we give prophylactic antiviral therapy with activity against hepatitis B (eg, entecavir, tenofovir) [5,24]. For those who are HBcAb positive, we also use prophylactic antiviral therapy. While receiving therapy with these agents, hepatitis B viral load should be monitored monthly. Anti-hepatitis B prophylaxis should be continued for up to one year after discontinuation of anti-CD20 monoclonal antibody therapy [5]. For active hepatitis B infection, consultation with a hepatitis expert is recommended. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

The anti-CD20 monoclonal antibodies have been associated with progressive multifocal leukoencephalopathy (PML), but no prophylaxis exists. Clinicians should consider diagnostic evaluation in patients who present with suggestive signs and/or symptoms of PML. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Anti-CD20 monoclonal antibodies' and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Phosphatidylinositol 3-kinase inhibitors — Duvelisib is the sole phosphatidylinositol 3-kinase (PI3K) inhibitor commercially available, and is approved for salvage therapy. In some studies, almost 70 percent of patients sustained infections while on therapy with duvelisib [25]. There is limited evidence suggesting that use of this agent may be associated with Pneumocystis and CMV infections. Clinicians should have a high index of suspicion for these infections in patients receiving these agents, and the diagnosis should be sought in those with compatible signs and symptoms. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Phosphatidylinositol 3-kinase inhibitors'.)

Pneumocystis prophylaxis is recommended by the manufacturer, as well as us, in all patients receiving duvelisib [26]. Therapy with duvelisib should be suspended if Pneumocystis pneumonia is suspected, and permanently discontinued if the diagnosis is confirmed. Use of herpesvirus prophylaxis is also recommended by the NCCN guidelines [3].

The manufacturer of duvelisib suggests that clinicians consider the use of prophylactic antivirals to prevent CMV infection and reactivation [26,27]. For patients who develop CMV infection, duvelisib should be withheld until infection resolves. If duvelisib is resumed after CMV infection, monitoring with CMV PCR or CMV antigenemia should be done at least monthly.

Cases of PML have been reported in patients receiving duvelisib, but no prophylaxis exists. Clinicians should consider diagnostic evaluation in patients who present with suggestive signs and/or symptoms of PML. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Phosphatidylinositol 3-kinase inhibitors' and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

CAR T-cell therapy — Lisocabtagene maraleucel, a CD-19 CAR-T product, has recently been approved for patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two prior lines of therapy, including a Bruton tyrosine kinase inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor [28,29]. In clinical trials, an infection rate of 35 percent was reported, with grade 3/4 infections occurring in 16 percent of patients. Screening for hepatitis B and C, as well as HIV, is recommended prior to administration and antimicrobial prophylaxis is advised as per each institution's guidelines.  

Alkylating agents — The most frequent infections occurring in patients receiving chlorambucil or cyclophosphamide, as a single agent or with prednisone, are common bacterial infections. We do not use antimicrobial prophylaxis when these agents are used to treat CLL. Antimicrobial prophylaxis is also not recommended for patients receiving bendamustine as a single agent or in combination with rituximab, chlorambucil, or mitoxantrone [30-32].

Purine analog therapy

Single-agent therapy — Pneumocystis and antiviral prophylaxis is advocated by some experts for patients receiving purine analog-based therapy [5,33-36]. Pneumocystis prophylaxis has been recommended for patients receiving such therapy in the NCCN guidelines for patients with non-Hodgkin lymphomas, as well as in the NCCN guidelines for prevention and treatment of cancer-related infections. However, based upon data from large prospective oncology cooperative group CLL treatment trials in which Pneumocystis pneumonia occurred rarely, we do not suggest routine Pneumocystis prophylaxis for these patients [37]. Prophylaxis against HSV and VZV has also been recommended by the NCCN for neutropenic patients receiving purine analog-based therapy [38]. We also suggest antiviral prophylaxis in such patients based upon findings from a large prospective oncology cooperative group CLL treatment trial [37]. Antiviral and Pneumocystis prophylaxis should be administered during therapy and for 6 to 12 months after completion of therapy [39]. Although the NCCN suggests that fluoroquinolone prophylaxis be considered in patients receiving purine analog-based therapy, findings from oncology cooperative group CLL trials do not support the need for this [37,38]; thus, we do not routinely use fluoroquinolone prophylaxis for patients receiving single-agent purine analog therapy. Myeloid growth factor should also be used with each treatment cycle. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults", section on 'Guidelines' and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults", section on 'Intermediate-risk patients' and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.)

Alemtuzumab — We use antibacterial prophylaxis with a fluoroquinolone as well as herpesvirus prophylaxis (against HSV, VZV) and Pneumocystis prophylaxis during therapy with alemtuzumab [38,40-43]. Antiviral and Pneumocystis prophylaxis should be continued for two to six months after treatment discontinuation and for as long as the CD4 count is <200 cells/microL. Antifungal prophylaxis should also be considered [38,44]. We also give myeloid growth factor support [38,45].

CMV reactivation occurs in 4 to 29 percent of CLL patients receiving alemtuzumab [46]. CMV prophylaxis with agents such as valganciclovir or letermovir is recommended by some experts [47,48]. Alternatively, a pre-emptive approach involving weekly quantitative CMV PCR monitoring during alemtuzumab administration and for two months following completion of therapy may be utilized [38,44,49]. The variance in approach to CMV prophylaxis is largely due to the fact that no cutoff viral load associated with CMV disease has been established. (See "Approach to the diagnosis of cytomegalovirus infection", section on 'Predictive role'.)

Hematopoietic cell transplantation — Patients with CLL who undergo hematopoietic cell transplantation (HCT) should receive antimicrobial prophylaxis regimens recommended for HCT recipients. Recommendations for such patients are provided separately. (See "Prevention of infections in hematopoietic cell transplant recipients" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Prevention of viral infections in hematopoietic cell transplant recipients".)

MYELOID GROWTH FACTORS — The use of myeloid growth factors, such as granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF), in patients with CLL who are expected to have neutropenia should follow established guidelines for the management of infections in such patients. The Infectious Diseases Society of America guidelines suggest that the prophylactic use of myeloid growth factors be considered for afebrile patients receiving a treatment regimen for which the anticipated risk of fever and neutropenia is ≥20 percent [50]. This is discussed in greater detail separately. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

Our approach to the use of myeloid growth factors depends upon the CLL regimen used and is discussed above. (See 'Indications based on CLL therapy' above.)

IMMUNOGLOBULIN REPLACEMENT — The majority of patients with CLL either have or will develop hypogammaglobulinemia at some point in the course of their disease (see "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Humoral immunity'). The use of prophylactic intravenous immune globulin (IVIG) to restore immunoglobulin (Ig)G levels is controversial, but we generally reserve IVIG for selected patients who have recurrent serious infections.  

●For most patients with CLL, prophylactic IVIG is not recommended.

●For patients with CLL who have had recurrent infections requiring intravenous (IV) antibiotics or hospitalization and who also have a serum IgG <500 mg/dL, we suggest the administration of IVIG. The usual dose is 200 to 400 mg/kg by IV infusion, given as a single dose at three- to four-week intervals. We aim at maintaining the trough serum IgG in treated patients above 500 to 700 mg/dL as a general guideline. If there is a substantial decrease in the incidence of infections, treatment at gradually extended intervals may be considered. There is no good endpoint for when such therapy can be discontinued. This is discussed in more detail separately. (See "Immune globulin therapy in inborn errors of immunity", section on 'Administration and dosing' and "Overview of intravenous immune globulin (IVIG) therapy".)

Similarly, the routine use of prophylactic IVIG is not recommended by the European Society of Medical Oncology or the International Workshop on Chronic Lymphocytic Leukemia clinical practice guidelines for CLL [4].

One large [26] and several small randomized trials and a meta-analysis have evaluated the use of prophylactic IVIG in patients with CLL [26,51-55]. IVIG has not been directly compared with the use of prophylactic antimicrobials. The randomized trials of prophylactic IVIG found that patients who receive IVIG have a decreased incidence of minor and moderate, but not major, bacterial infections. However, IVIG does not appear to increase quality of life or survival.

The largest study evaluating the role of IVIG was a multicenter randomized trial in 84 patients with CLL who were at increased risk of bacterial infection due to hypogammaglobulinemia, a history of infection, or both [26]. Patients received IVIG (400 mg/kg) or placebo, each administered every three weeks for one year. Although minor or moderate bacterial infections were significantly less common in patients receiving IVIG, there was no impact on the incidence of major infections, mortality, or nonbacterial infections. It was found that routine IVIG therapy was not cost-effective.

Potential toxicities related to IVIG include anaphylaxis, fever, chills, "flu-like" symptoms, and headache. In addition, potentially severe hemolytic reactions may be seen. (See "Intravenous immune globulin: Adverse effects".)

The optimal dose, schedule, and subset of patients who would benefit from prophylactic IVIG are not clear. Another important aspect of IVIG therapy is that it replaces neither IgM nor IgA.

IMMUNIZATIONS — Vaccines are important for patients with CLL, but generally they should not be given during periods of immunosuppression from chemotherapy or immunotherapy because, at such times, they may not be effective. Live vaccines may result in vaccine-derived infections and should be avoided. The following figure summarizes immunization recommendations (figure 1). Vaccines that should be given to patients include the annual influenza vaccine (avoiding the live attenuated vaccine), pneumococcal vaccine, zoster recombinant vaccine, and COVID-19 vaccine. Immunizations in patients with cancer (including recommendations regarding the appropriate timing of vaccinations) are discussed in greater detail separately, as are coronavirus disease 2019 vaccination recommendations for patients with cancer. (See "Immunizations in adults with cancer".)

Although a variety of immunizations have been studied in CLL patients, these have shown suboptimal responses due to impaired antibody production and defects in antigen presentation [56-58]. Most analyses have been small patient series. Superior responses may be obtained with protein and conjugated vaccines compared with polysaccharide vaccines in CLL patients [58].

A recombinant herpes zoster virus vaccine is approved for immunocompetent adults at least 50 years of age [59]. Efficacy and safety of this vaccine has been studied in cancer patients, including those with CLL, to ascertain efficacy as well as adverse effects. Recommendations for use of this vaccine in immunocompromised patients from the United States Centers for Disease Control and Prevention are now available [60,61]. (See "Vaccination for the prevention of shingles (herpes zoster)", section on 'Immunocompromised persons' and "Immunizations in adults with cancer", section on 'Zoster vaccine'.)

Vaccinations for coronavirus disease 2019 (COVID-19) are reviewed separately. (See "COVID-19: Vaccines".)

SUMMARY AND RECOMMENDATIONS

●Broad immune deficits − 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 "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Introduction' and "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Immune defects'.)

●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 "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Spectrum of infections'.)

●Prophylaxis varies by therapeutic regimen − Since the immune defects rendered by specific CLL therapies have significant impact on subsequent infectious complications, our approach to prophylaxis varies depending upon the type of therapy used. We suggest the approach to therapy outlined in this table (table 1) and in the text above (Grade 2C). Dosing for prophylactic antimicrobial regimens are summarized in this table (table 2). (See 'Antimicrobial prophylaxis' above.)

•BTK inhibitors and venetoclax – At present, there are no standard recommendations for antimicrobial prophylaxis with BTK inhibitor or venetoclax use. (See 'Bruton tyrosine kinase inhibitors' above and 'Venetoclax' above.)

•CD-20 monoclonal antibodies – When an anti-CD20 monoclonal antibody (eg, rituximab, ofatumumab, obinutuzumab) is used as single-agent therapy, we do not use antimicrobial prophylaxis. However, when used in combination with high-dose methylprednisolone, we give Pneumocystis and herpesvirus (HSV, VZV) prophylaxis during therapy and for two months following treatment discontinuation.

•PI3K inhibitors – We use Pneumocystis pneumonia prophylaxis in all patients receiving duvelisib. In patients with a history of CMV infection or positive CMV serology receiving idelalisib or duvelisib, regular clinical and laboratory monitoring for CMV infection should be performed. Such monitoring should also be considered in all patients receiving these agents, if feasible. For patients who develop CMV infection while receiving either agent and in whom the drug is reinstituted, monitoring with CMV polymerase chain reaction or CMV antigenemia should be performed at least monthly. An alternative to close monitoring is CMV prophylaxis; for patients receiving duvelisib, we determine the appropriateness of CMV prophylaxis on a case-by-case basis, balancing the risk of CMV reactivation with the risk of toxicity from CMV prophylaxis. (See 'Phosphatidylinositol 3-kinase inhibitors' above.)

•Alkylating agents – Antimicrobial prophylaxis is not advocated for patients with CLL who are not receiving active therapy or who are receiving an alkylating agent (eg, chlorambucil, bendamustine) or venetoclax. Instead, such patients are candidates for vigilant observation and early initiation of treatment if symptoms develop. (See 'Indications based on CLL therapy' above and 'Alkylating agents' above.)

•Purine analog therapy – Patients receiving a purine analog-based treatment regimen are at increased risk for several opportunistic infections. We use antiviral prophylaxis (against herpes simplex virus and varicella-zoster virus) in all patients receiving a purine analog. In those receiving a purine analog in combination with cyclophosphamide with or without an anti-CD20 monoclonal antibody, we also use Pneumocystis prophylaxis. (See 'Purine analog therapy' above.)

•Alemtuzumab – Patients treated with alemtuzumab are at increased risk for multiple opportunistic infections, including cytomegalovirus (CMV) reactivation. We use antiviral prophylaxis (against herpes simplex virus and varicella-zoster virus) and Pneumocystis prophylaxis routinely in such patients, and we monitor patients weekly for CMV reactivation. (See 'Alemtuzumab' above.)

●Myeloid growth factors − The use of myeloid growth factors, such as granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF), in patients with CLL who are expected to have neutropenia should follow established guidelines for the management of infections in such patients. These are discussed in detail separately. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

●IVIG for recurrent infections − The use of prophylactic intravenous immune globulin (IVIG) to restore immunoglobulin (Ig)G levels is controversial. We generally reserve IVIG for selected patients who have recurrent serious infections. (See 'Immunoglobulin replacement' above.)

●Importance of vaccination and its timing − Vaccines are important for patients with CLL, but they should not be given during periods of immunosuppression from chemotherapy or immunotherapy because, at such times, they may not be effective and live vaccines may result in vaccine-derived infections. The following figure summarizes immunization recommendations (figure 1). (See 'Immunizations' above and "Immunizations in adults with cancer".)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Elias Anaissie, MD, and Kieren A Marr, MD, who contributed to earlier versions of this topic review.