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
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
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
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 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
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
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
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.
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