Rituximab is usually well tolerated, and toxicities are generally mild.12,24,58
Common side effects include pruritus, nausea, vomiting, dizziness, headaches, fevers, and rigors. A major concern is the potential for an infusion-related reaction, such as rigors, chills, anaphylactic reactions potentially leading to myocardial infarction and cardiogenic shock. These reactions occur most commonly during the first administration of rituximab. Although infusion reactions are rarely fatal, predisposing cardiac conditions can increase the risk of death. Pre medication with acetaminophen and antihistamines is recommended prior to infusion. Reactions usually abate if the infusion is discontinued and can then be restarted at a slower rate. The benefit of premedication with glucocorticoids is not entirely clear, but they are useful if a reaction occurs. Mucocutaneous reactions, including Stevens–Johnson syndrome, have also been reported within one to 13 weeks following rituximab exposure.
Tumor lysis syndrome has also occurred in patients with bulky lymphoma. Hepatitis B reactivation with fulminant hepatitis, hepatic failure, and death have been reported in patients with previous hepatitis B infection who have been treated with rituximab. Consultation with a hepatologist and administration of antiviral therapy should be considered if hepatitis B antigen is detectable. The risk of reactivation of hepatitis C is not well defined. The use of live vaccines, including those against herpes zoster, is not recommended during rituximab therapy secondary to the risk of causing an active infection. Rituximab-treated patients are also at risk for other viral infections, including cytomegalovirus, herpes simplex, parvovirus B19, and West Nile virus.
Late-onset neutropenia has been described as a possible complication of adding rituximab to chemotherapy.59
In a retrospective review, patients who received chemotherapy plus rituximab for CD20+, B-cell NHL had a higher rate of late-onset neutropenia compared with historical controls receiving chemotherapy alone.
A study published in 2009 reported 57 cases of progressive multifocal leukoencephalopathy (PML) following the administration of rituximab, usually with additional therapy, in HIV-negative patients.60
PML, a viral infection that affects the white matter of the brain, is usually fatal. This cohort of patients was treated with a median of six doses of rituximab. The median time from last rituximab dose to PML diagnosis was 5.5 months, and median survival after the diagnosis of PML was two months. In accordance with these data, the FDA issued a boxed (black-box) warning.
Reversible posterior leukoencephalopathy (RPLE), a subacute neurological syndrome manifested as headaches, cortical blindness, and seizures with a characteristic appearance on magnetic resonance imaging (MRI), has also been described in rare cases.61,62
It is not clear whether these events are directly related to rituximab, because most of these patients have received multiple therapies, but RPLE has also been reported after other antibody and small-molecule therapeutics. Cardiac arrhythmias, renal toxicity, and bowel obstruction with perforation have also been reported.57
Rituximab induces B-cell depletion, which may compromise the immune system; however, recovery of the normal B-cell population usually occurs six to nine months after discontinuation of therapy.15
Despite this depletion, rituximab has not been definitively shown to cause a significant decrease in circulating immunoglobulin levels, although this may occur with more prolonged maintenance strategies. Stable immunoglobulin levels are likely to reflect that plasma cells are long-lived and do not express CD20.
In a prospective study, van der Kolk et al. investigated the effect of rituximab on the humoral immune response to two primary antigens and two recall antigens.63
After rituximab treatment, the humoral immune response to the recall antigens was significantly decreased when compared with the response before treatment.