Rituximab Likely Well-Tolerated In Pediatric Patients, But Infections Are Common

Rituximab seemed to be well tolerated in children and adolescents in a retrospective study, but infections were common, and B cell count recovery could take more than a year, researchers say.

"Practice among doctors measuring B cell recovery and immune function was highly variable," Dr. Casey McAtee of Baylor College of Medicine in Houston told Reuters Health by email. "Most children underwent testing within the first two months, a period in which patients had universal B cell depletion. Results from this study support delaying such investigation following a dose to capture the extended time period of potential immune reconstitution."

"Fortunately, most (infections) were mild, and incidence trended downwards as B cells recovered," he said. "But 18% of children had infections requiring hospitalization."

"We were surprised to find that infections were particularly high in the patients who received immune supplementation with intravenous immunoglobulin (IVIG)," he noted, "suggesting that IVIG as prescribed in our cohort of patients is insufficient to prevent infections in a high-risk subset of these patients."

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"It is also possible that patients receiving IVIG were a higher risk population for infections," he said. "Future studies should focus on strategies - IVIG or other approaches - to reduce infections in the period of immunosuppression following rituximab."

As reported in JAMA Network Open, Dr. McAtee and colleagues studied records of 468 patients receiving at least one dose of rituximab infusion from October 2010 through 2017. The median age at first dose was 14.3; 63% were women and 45%, self-reported White Hispanic. Follow-up was 11,713 person months.

Rituximab-associated adverse events occurred in 72 patients (15.4%), and anaphylaxis in 17 (3.6%).

No long-term adverse events, such as prolonged neutropenia and leukoencephalopathy, were reported.

Infections occurred in almost half (47.9%) of patients; 18% had severe infections and three (0.6%) died. Concurrent use of intravenous chemotherapy, systemic lupus erythematosus treatment, neutropenia, and intravenous immunoglobulin use were associated with increased risk of infection.

Close to a third of patients (28.8%) were followed to B cell count recovery; CD19+ or CD20+ cell numbers normalized in a median of 9 months following rituximab, whereas 51% had low-for-age B cell counts for more than a year.

CD27+ memory B cell number recovery occurred in a median of 15.7 months.

About a quarter (23.2%) of patients with normal baseline values developed low immunoglobulin G (IgG) levels and 40.8% developed low IgM levels; among evaluated beyond 12 months from rituximab, 13.7% had persistently low IgG and 33.9% had persistently low IgM.

Dr. Joseph Rosenthal, director of pediatric hematology-oncology at City of Hope, in Duarte, California, commented in an email to Reuters Health, "The importance of this report is in solidifying pieces of data known from previous smaller reports by using a very large group of subjects."

"Subjects treated with rituximab in the study suffered from a wide spectrum of disorders — most are associated with a state of immunocompromise, either because of the primary diagnosis or the treatment thereof," he said.

"The authors make a strong point that rituximab affects the immune system by reducing the number of B cells and therefore decrease the levels of immunoglobulins," he noted. "However, that adverse impact on the immune system cannot be differentiated from the contribution of other origins. Improved management of infectious diseases is needed for the underlying conditions and their therapies with or without rituximab."

Dr. Carli Beall, Clinical Pharmacy Manager, Pediatric Transplantation and Cellular Therapy, at the Montefiore Health System in New York City, also commented by email, "The majority of patients in this study had non-oncologic indications for rituximab, therefore making it less generalizable to pediatric patients with hematologic malignancies."

"Since the highest risk of infection is within one month of rituximab, it would be interesting to look at the use of bacterial prophylaxis during this time," she said. "I agree that it is important to further explore the relationship between IVIG administration and infections after rituximab."

"It would have been useful to report if all patients were screened for hepatitis B infection prior to receiving rituximab and if patients received prophylaxis, if indicated," she added. "Although only nine patients experienced herpes simplex virus infection, five of these did require hospitalization. It would be beneficial to explore the use of HSV prophylaxis and if it would prevent these infections without causing additional adverse events."

The study was funded by an investigator-initiated research grant to one coauthor from Bristol/Myers Squibb.

—Marilynn Larkin

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