Preventing infectious complications in patients with chronic lymphocytic leukemia

One of the most common supportive care challenges faced by the chronic lymphocytic leukemia patient is infectious complications. The increased risk for infectious complications compared with other malignancies arises from disease- and treatment-related factors. Patients with CLL have defects in immune function due to the accumulation of a clonal, dysfunctional lymphocyte population. In addition, these patients will often develop hypogammaglobulinemia, most commonly seen in patients with advanced stages of CLL.

Treatment for CLL can be lymphocyte-depleting, leading to further defects in immune function. These patients frequently receive regimens containing purine analogs, corticosteroids and lymphocyte-depleting monoclonal antibodies. Many current treatments for CLL consist of the combination of one or more chemotherapy agents and immunotherapy, which can lead to neutropenia as well.

Purine analogs are one of the most common classes of chemotherapy used in the initial treatment of CLL. Fludarabine and pentostatin are the most frequently used agents. These drugs result in the depletion of T-lymphocytes, which occurs early during treatment, and recovery may take months to years. Depletion of T-lymphocytes puts patients at higher risk of opportunistic infections. Infections of particular concern include opportunistic bacteria (eg, Nocardia, Listeria, Mycobacteria), Pneumocystis, fungal and viral infections. The risk for these infections appears to be highest in patients with previously treated and advanced stages of CLL receiving combination therapy.

Some of these opportunistic infections can be easily prevented. The National Comprehensive Cancer Network (NCCN) guidelines on prevention and treatment of cancer-related infections consider CLL patients receiving purine analogs or alemtuzumab (Campath, Genzyme) at intermediate- or high-risk, respectively, for developing infections. The guidelines recommend that patients receiving purine analog and/or alemtuzumab-containing regimens should be given prophylactic medications against viral infections and Pneumocystis infections, at a minimum. However, Pneumocystis infection in previously untreated patients receiving single agent fludarabine or in combination with rituximab (Rituximab, Genentech/Biogen Idec) is rare; prophylaxis may not be necessary in these specific populations.

Possible infectious complications

Pneumocystis prophylaxis is usually achieved with oral trimethoprim/sulfamethoxazole (TMP/SMZ). Alternatives in patients with intolerance to TMP/SMZ include dapsone, aerosolized pentamidine (NebuPent, APP) or atovaquone (Mepron, GlaxoSmithKline). Antiviral prophylaxis against herpes simplex virus (HSV) and varicella zoster virus (VZV) reactivation can be achieved by acyclovir or the equivalent. Prophylaxis, if given, should continue for at least two months after completion of therapy or until the CD4 lymphocyte count is greater than 200 cells/mcL. Some authors advocate continuing prophylaxis for at least six months after completion of therapy. In addition, patients receiving aggressive, combination chemotherapy regimens, such as those commonly used to treat lymphomas, may also need prophylactic antibacterials and antifungals during periods of neutropenia.

Cytomegalovirus (CMV) reactivation occurs in up to 25% of patients receiving alemtuzumab. Reactivation typically occurs three to six weeks after initiating therapy. The rate appears to be lower in previously untreated patients receiving alemtuzumab. Although rarely fatal, CMV reactivation can occasionally lead to CMV infection and, more frequently, delays in planned therapy. Valganciclovir (Valcyte, Roche), an oral pro-drug of ganciclovir, has demonstrated efficacy in preventing CMV reactivation in patients receiving alemtuzumab. Compared with antiviral medications without activity against CMV (eg, acyclovir), valganciclovir is more expensive and has a higher incidence of myelosuppression.

Deborah Blamble

Patients receiving valganciclovir prophylaxis should still have biweekly CMV monitoring. In a patient receiving alemtuzumab as initial therapy for CLL at a facility with the capability of performing weekly CMV monitoring, close monitoring and pre-emptive therapy is an alternative option to prophylaxis. Surveillance, with or without prophylaxis, should continue for at least two months after completion of therapy or until the CD4 lymphocyte count is greater than 100 cells/mcL.

Another potential viral infection that could occur in the CLL patients is reactivation of hepatitis B virus infection. Cases of fatal hepatitis from hepatitis B have been reported after immunosuppressive therapy, including rituximab treatment. Rituximab and recently approved ofatumumab (Arzerra, GlaxoSmithKline) have warnings in their prescribing information regarding hepatitis B reactivation.

It is recommended that patients being considered for immunosuppressive therapy should be screened for hepatitis B, particularly if thought to be at high-risk of infection. Screening includes hepatitis B surface antigen (HBSAg) and hepatitis B core antibody (HBCAb). If either is positive, viral load should be obtained and a hepatologist consulted. Viral load will need to be monitored during and several months after CLL therapy. Data support the use of prophylactic antiviral therapy with lamivudine (Epivir, GlaxoSmithKline) during rituximab treatment to prevent hepatitis B reactivation in seropositive patients.

Vaccinations

Patients with CLL will frequently have suboptimal responses to vaccinations, particularly if recently treated or with advanced disease. Patients with CLL should receive the annual influenza vaccine, although complete immunity should not be assumed. Patients should also receive the pneumococcal vaccine every five years, attempting to time vaccination after recovery from any prior CLL therapy if possible. Full B-cell recovery may take several months after rituximab therapy. Live vaccines should be avoided in this patient population.

Hypogammaglobulinemia is frequently seen in more advanced stages of CLL. Although prophylactic administration of intravenous immunoglobulin has not demonstrated a survival advantage to date, it is an option for patients who experience recurrent moderate to severe infections who have low levels of immunoglobin G (< 500 mg/dL). The dose of IVIg used is 0.3 mg/kg to 0.5 mg/kg given intravenously once monthly. Dose and interval can be adjusted to maintain an immunoglobin G level (measured before next IVIg dose) between 500 mg/dL to 700 mg/dL.

Use IVIg products with caution in patients with pre-existing, or those who are at risk for, renal dysfunction. Sucrose-containing IVIg products, in particular, appear to be more likely to cause acute renal dysfunction.

One of the biggest challenges facing the CLL patient — after considering the challenge of finding a cure for this malignancy — is the morbidity and mortality of infectious complications. As chemotherapy regimens become increasingly myelosuppressive and immunosuppressive, appropriate prophylactic antimicrobials become necessary to help prevent infectious complications.

This frequently older patient population may be underinsured, particularly relating to coverage of outpatient prescription medications. Health care providers should promote the use of appropriate and affordable supportive care regimens needed during CLL treatment.

Deborah Blamble, PharmD, BCOP, is an Oncology Clinical Pharmacy Specialist at The University of Texas M.D. Anderson Cancer Center.

For more information:

• Morrison VA. Clin Lymphoma Myeloma. 2009;9:365-370.
• O’Brien SM. Clin Lymphoma Myeloma. 2006;7:125-130.
• O’Brien SM. Blood. 2008;111:1816-1819.
• Segal BH. NCCN clinical practice guidelines in oncology. V.2.2009. Available at http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf. Accessed Jan. 2, 2010.
• Zelenetz AD. NCCN clinical practice guidelines in oncology. V.1.2010. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed Jan. 4, 2010.
• Ziakas PD. Haematologica. 2009;94: 998-1005.