Late-onset Neutropenia Following Rituximab Therapy

Abstract and Introduction

Abstract

Late-onset neutropenia (LON) is emerging as a common adverse effect to rituximab therapy owing to widespread use of this drug in the treatment of B-cell lymphomas and autoimmune diseases. However, the true incidence and mechanisms are not fully understood. LON has been reported in 5–27% of rituximab-treated lymphoma patients. Similar figures apply for autoimmune patients but they appear to have more infections during the neutropenic period. Recent reports imply that host factors may play an intriguing role for development of LON, for example, polymorphisms in FCGR3. Pronounced B-lymphocyte depletion and lower serum IgM, as reported in LON patients during the period of neutropenia compared with matched controls, may play a role for understanding the mechanisms and risk stratification for emergence of LON.

Introduction

Rituximab is a chimeric IgG-1 human/mouse monoclonal antibody directed against the CD20 antigen on normal and neoplastic B lymphocytes, originally developed for treatment of CD20-positive non-Hodgkin lymphoma.^[1,2] It is also used in the treatment of patients with autoimmune disorders.^[3] Rituximab causes a rapid depletion of CD20⁺ B lymphocytes by means of an antibody- and complement-dependent cell-mediated cytotoxicity, or direct induction of apoptosis, but the mechanisms are not fully understood.^[4] B lymphocytes return to the peripheral blood (PB) at a mean of approximately 8 months (range: 5–12 months) later, initially with the emergence of immature naive B lymphocytes.^[1,5]

Although rituximab is well tolerated and has an acceptable hematological toxicity, certain delayed adverse effects are noted.^[6] One is late-onset neutropenia (LON), occurring at least 4 weeks after rituximab therapy in patients with no signs of preexisting chronic neutropenia and who have recovered from chemotherapy-induced neutropenias. LON is defined as an unexplained absolute neutrophil count (ANC) of ≤1.5 × 10⁹/l (corresponding to neutropenia of grade 2–4 according to National Cancer Institute Common Toxicity Criteria) starting from 4 weeks after termination of rituximab therapy, until end of follow-up. The follow-up period for detection of LON has varied from 6–12 months after the last rituximab infusion.

Late-onset neutropenia has been reported in lymphoma patients by a number of groups,^[7–16] and recent case reports suggest that LON also occurs in rituximab-treated patients with autoimmune disease.^[17–20] The validation of LON as a distinct entity is well established by reevaluating data from randomized trials on lymphoma patients where no LON episodes were reported in the historical control group, consisting of patients who had been treated with non-rituximab-containing regimens.^[7,9,10] The true incidence, predisposing factors and mechanisms of LON are still poorly defined. In this review, we discuss the current literature on possible mechanisms of LON and its clinical features. However, until recently there was no published information on the incidence, risk factors and mechanisms of LON in autoimmune diseases^[21] and, hence, our discussions are mainly derived from studies on lymphoma patients. We will focus on some novel mechanisms that might be taken into future consideration in LON studies for patients treated with rituximab for lymphoma and autoimmune diseases, but not give a comprehensive review of all discussed phenomena.

Expert Rev Hematol. 2011;4(6):619-625. © 2011 Expert Reviews Ltd.

Cite this: Late-onset Neutropenia Following Rituximab Therapy - Medscape - Dec 01, 2011.