Delayed Onset Adverse Effects Associated with Rituximab Treatment in Patients with Non-Hodgkin's Lymphoma – A Single Center Experience

Rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, has now become a cornerstone in the treatment of many CD20 positive B cell lymphomas. RTX induces a rapid depletion of normal CD20 expressing B-cells in the peripheral blood, and their level remains low for 2–6 months before returning to pretreatment levels, generally within 12 months. Some patients develop late side effects such as neutropenia and hypogammaglobulinemia regardless of the level of B cells; these patients are more vulnerable to life-threatening infections. In addition, treatment with RTX is a risk factor for HBV and HCV reactivation in occult and chronic carriers.

The goal of the study was to identify the clinical and laboratory indices that serve as predictors of risk for developing late side effects in patients with non- Hodgkin's lymphoma (NHL) treated with RTX in a single medical center. Statistical correlation between these variables and occurrence of infectious complications secondary to late hematologic adverse effects such as neutropenia and hypogammaglobulinemia was performed. Clinical outcome of patients with infectious complications was evaluated.

We conducted a retrospective study of 120 patients who were diagnosed with B cell NHL and were followed in the Institute of Hematology of Carmel Medical Center in Haifa between 2000–2008. Each patient received RTX as a monotherapy or in combination with chemotherapy. All the patients in the study were RTX naive. The study was approved by the local Helsinki committee. For the purpose of the study, the follow-up period was defined from the time of termination until a period of 24 months from the last therapeutic dose of RTX. Late side effects were defined as side effects that appeared 6 months after the last therapeutic dose of RTX or continued beyond the 6 month period. For each variable we evaluated retrospectively the proportion of patients who developed late side effects. In an attempt to characterize the risk factors such as age, sex, status of lymphoma, type of chemotherapy, number of treatments and the interval between the treatments, comparison was made between the patients who developed side effects and those who did not.

Twenty two of the 120 surveyed patients (18.3%) developed infections. Hematologic side effects observed were anemia (28.3%), thrombocytopenia (7.5%) and neutropenia (3.28%). We found that age ≥70 years and recurrence of the disease were significant risk factors for developing side effects. Laboratory indexes that were found to be significant predicting factors for the risk of infection were: PMN<2.0×10⁹/mm³, LDH≥480u/l, SGOT≥44u/l. An active disease and grade 3–4 neutropenia were both variables that contributed to the risk of infection. There was no correlation between gender of patients, the histological type and stage of lymphoma, type of chemotherapy, or number of therapeutic courses with RTX and increased risk of infection. We did not find any association between hypogammaglobulinemia and the risk of infection. Regarding viral infections, only 2 HCV carriers were detected in the study; none of them had reactivation during the follow up. Reactivation of HBV occurred in 1 of the 6 occult carriers (16.7%).

In recent years RTX has become an essential component in the therapy of B cell NHL. Late side effects of this drug are now beginning to emerge and require new risk assessment for safety. Twenty two patients (18.33%) in our study developed infectious complications. This rate is lower than the one reported in the literature (30%). In contrast, mortality following infection was 7% as compared to 2% reported in the literature. These data can be explained by the fact that our study examined hospitalized patients who had more severe infections. Our study supports the previous observation that hypogammaglobulinemia does not present a risk factor for infection. In contrary to the reports in literature, we found no correlation between the number of therapeutic courses with RTX and the risk of infection. In conclusion, we suggest that RTX should be used with caution in patients over age 70 and in patients with recurrent disease. In order to confirm our findings, further assessment of late adverse effects on the larger population of patients treated with rituximab is warranted.

No relevant conflicts of interest to declare.