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 expanded with the 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), phosphatidylinositol 3-kinase inhibitors (eg, idelalisib, duvelisib), 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 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 associated 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), lenalidomide, 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 several 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 a purine analog in combination with cyclophosphamide with or without an anti-CD20 monoclonal antibody, 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 ibrutinib, idelalisib, or duvelisib. Pneumocystis prophylaxis is recommended with idelalisib and duvelisib therapy, and pre-emptive monitoring for CMV reactivation or infection is recommended when feasible. At present, there are no standard recommendations for antimicrobial prophylaxis with ibrutinib use. (See 'Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors' below.)

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 [6-8].

Purine analog therapy

Single-agent therapy — Antiviral and Pneumocystis prophylaxis is advocated by some experts for patients receiving single-agent purine analog therapy [5,9]. In the guidelines for patients with non-Hodgkin lymphomas, the NCCN has recommended Pneumocystis prophylaxis for patients receiving a purine analog [5]. In contrast, in the guidelines for prevention and treatment of cancer-related infections, the NCCN has suggested that Pneumocystis prophylaxis be considered only in those receiving a purine analog in combination with another T cell-depleting agent until the CD4 count is >200 cells/microL [10]. Pneumocystis prophylaxis has been advocated by some for use in older adult patients receiving a purine analog [11]. 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 patients receiving single-agent purine analog therapy [12]. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.)

Prophylaxis against HSV and VZV has also been recommended by the NCCN for neutropenic patients receiving single-agent purine analog therapy [10]. We also suggest antiviral prophylaxis in such patients based upon findings from a large prospective oncology cooperative group CLL treatment trial [12].

Although the NCCN suggests that fluoroquinolone prophylaxis be considered in patients receiving purine analog therapy, findings from oncology cooperative group CLL trials do not support the need for this [10,12]; thus, we do not routinely use fluoroquinolone prophylaxis for patients receiving single-agent purine analog therapy. (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'.)

Purine analog-anti-CD20 monoclonal antibody combination therapy — Based upon findings from oncology cooperative group clinical trials, the addition of rituximab to fludarabine does not increase the risk of infectious complications [13,14]. In patients receiving this regimen, we use antiviral (HSV, VZV) prophylaxis during therapy and for 6 to 12 months after completion of therapy. We generally do not use Pneumocystis prophylaxis, although it may be considered on a case-by-case basis [13-15]. In contrast, the NCCN recommends both antiviral and Pneumocystis prophylaxis with any purine analog-based regimen [5].

For patients receiving pentostatin-rituximab, we give Pneumocystis and antiviral prophylaxis (against HSV and VZV) during therapy and for 6 to 12 months after completion of therapy [16]. We also give myeloid growth factor support with each cycle.

Purine analog-cyclophosphamide combination therapy — For patients receiving fludarabine-cyclophosphamide, we use antiviral (against HSV, VZV) and Pneumocystis prophylaxis during therapy and for 6 to 12 months after completion of therapy [17]. We also give myeloid growth factor support with each cycle.

Purine analog-cyclophosphamide-anti-CD20 monoclonal antibody combination therapy — In patients receiving three-drug combinations such as fludarabine-cyclophosphamide-rituximab and pentostatin-cyclophosphamide-rituximab, we use Pneumocystis and antiviral prophylaxis [18-20]. We give prophylaxis during therapy and for 6 to 12 months after completion of therapy [20]. We also give myeloid growth factor support with each cycle. With ofatumumab-fludarabine-cyclophosphamide therapy, we use myeloid growth factor support as well as Pneumocystis and antiviral prophylaxis [21]. For the fludarabine-cyclophosphamide-rituximab-lite regimen (low-dose fludarabine and cyclophosphamide, high-dose rituximab), which may be used in older adult or frail patients, we use myeloid growth factor support as well as Pneumocystis and antiviral prophylaxis during therapy and for six months after therapy discontinuation [22].

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 [23]. Likewise, when one of these agents is used in combination regimens with agents such as chlorambucil or cladribine, we do not use antimicrobial prophylaxis [24]. However, in patients receiving a combination of an anti-CD20 monoclonal antibody and high-dose methylprednisolone, we give Pneumocystis and herpesvirus (HSV, VZV) prophylaxis during therapy and for two months following treatment discontinuation [25]. Invasive fungal infections with obinutuzumab therapy have been reported anecdotally [26].

Another issue that arises with the use of these agents is the potential for hepatitis B or C reactivation. 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) [5,27]. 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'.)

Alemtuzumab — We use antibacterial prophylaxis with a fluoroquinolone during therapy with alemtuzumab [10,15,28-30]. In addition, we use Pneumocystis prophylaxis during alemtuzumab therapy as well as for two to six months after treatment discontinuation and for as long as the CD4 count is <200 cells/microL [10]. We also give herpes prophylaxis (against HSV, VZV) during alemtuzumab therapy and for a minimum of two months after treatment discontinuation and for as long as the CD4 count is <200 cells/microL [10,15,28-30]. Antifungal prophylaxis is not necessary with alemtuzumab alone but may be indicated for patients receiving combination therapy [10,31]. We also give myeloid growth factor support [10,32].

CMV reactivation, which occurs in 4 to 29 percent of CLL patients receiving alemtuzumab, is a significant infectious risk with alemtuzumab [33]. Despite the substantial risk of CMV reactivation, CMV prophylaxis is not typically used given the bone marrow toxicity associated with valganciclovir. However, some experts give valganciclovir to prevent reactivation of CMV, or letermovir, a newer antiviral agent with less bone marrow toxicity [34,35]. Instead of giving CMV prophylaxis, we suggest a pre-emptive approach involving weekly quantitative CMV PCR monitoring during alemtuzumab administration and for two months following completion of therapy [10,31,36]. The frequency of CMV testing may be decreased after the second month of therapy [31]. CMV PCR should also be checked in the setting of fever of unknown origin.

The issue of whether to institute therapy for CMV if viremia is present or only if the CMV viral load is increasing is controversial [37]. This 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'.)

Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors — There is limited but increasing evidence suggesting that the Bruton tyrosine kinase inhibitor ibrutinib is associated with invasive fungal infections, including Pneumocystis pneumonia and invasive aspergillosis, and that the phosphatidylinositol 3-kinase (PI3K) inhibitors, idelalisib and duvelisib, are 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. At present, there are no standard recommendations for antimicrobial prophylaxis with ibrutinib or acalabrutinib use. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase inhibitors' and "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 idelalisib or duvelisib [38-40]. Idelalisib or duvelisib should be suspended if Pneumocystis pneumonia is suspected and permanently discontinued if the diagnosis is confirmed.

In patients with a history of CMV infection or positive CMV serology receiving idelalisib, the manufacturer recommends that regular clinical and laboratory monitoring for CMV infection be performed [38]. For patients who develop CMV infection while receiving idelalisib and in whom idelalisib is reinstituted, monitoring with CMV PCR or CMV antigenemia should be done at least monthly.

The manufacturer of duvelisib suggests that clinicians consider the use of prophylactic antivirals to prevent CMV infection and reactivation [40]. 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.

For patients receiving either idelalisib or 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. When prophylaxis is not given, we monitor patients with a history of CMV infection or positive CMV serology closely as outlined above.

Cases of PML have been reported in patients receiving ibrutinib or idelalisib, 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 'Bruton tyrosine kinase inhibitors' and "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'.)

Lenalidomide — At present, lenalidomide, an immunomodulatory agent, has no treatment indication for patients with CLL outside of clinical trials. When lenalidomide is used as a single agent or in combination with an anti-CD20 monoclonal antibody or corticosteroids (as dexamethasone), we recommend antiviral prophylaxis [41,42]. However, anti-Pneumocystis and antiviral prophylaxis is suggested for patients receiving lenalidomide in combination with fludarabine and rituximab [43,44].

Venetoclax — Venetoclax is a B cell leukemia/lymphoma 2 (BCL-2) inhibitor that has not been definitively associated with an increased risk of opportunistic infections. Antimicrobial prophylaxis is therefore not typically given with this agent. However, antiviral, antifungal, and/or Pneumocystis prophylaxis may be considered on a case-by-case basis in settings of prior opportunistic infections that could recrudesce and/or residual immune defects from prior CLL therapy. Because venetoclax is a cytochrome P450 substrate, there a multiple potential drug interactions; voriconazole is specifically contraindicated during the ramp-up phase of venetoclax initiation. Other azoles may also interact and consultation with specialists familiar with the use of these drugs when considering use (see "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Venetoclax'). Specific interactions with other medications may be determined using the drug interaction program included within UpToDate.

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 [45]. 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. 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 [4,46].

One large [47] and several small randomized trials and a meta-analysis have evaluated the use of prophylactic IVIG in patients with CLL [47-52]. 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 [47]. 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, and live vaccines may result in vaccine-derived infections. The following figure summarizes immunization recommendations (figure 1). 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".)

A fatal case of vaccine-derived disseminated varicella-zoster infection was reported in a 79-year-old man with CLL who received zoster vaccine six months after completing six cycles of fludarabine, cyclophosphamide, and rituximab; his remission status was not reported [53]. The long-lasting immune effects of fludarabine and rituximab therapy as well as his advanced age may have predisposed this patient to disseminated infection.

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 [54-56]. Most analyses have been small patient series. Superior responses may be obtained with protein and conjugated vaccines compared with polysaccharide vaccines in CLL patients [56].

A recombinant herpes zoster virus vaccine is approved for immunocompetent adults at least 50 years of age [57]. 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 [58,59]. (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.)

•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), lenalidomide, 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.)

•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.)

•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.)

•At present, there are no standard recommendations for antimicrobial prophylaxis with BTK inhibitor use. (See 'Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors' above.)

•We use Pneumocystis pneumonia prophylaxis in all patients receiving idelalisib or 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 idelalisib or 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 'Bruton tyrosine kinase and phosphatidylinositol 3-kinase inhibitors' 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.