Delayed-onset peripheral blood cytopenia after rituximab: Frequency and risk factor assessment in a consecutive series of 77 treatments

Abstract

The occurrence of unexplained peripheral blood cytopenia, particularly neutropenia, has been recently reported after rituximab. Its prevalence may be underestimated since it may occur late after treatment. This study analysed all cases of unexplained delayed-onset peripheral blood cytopenia of WHO grade II - IV occurring in an unselected series of patients treated with rituximab in order to evaluate its prevalence and clinical significance. Seventy-seven courses of rituximab (corresponding to 317 rituximab infusions) given to 72 consecutive patients affected by non-Hodgkin's Lymphoma and treated at a single Center with rituximab, alone (nine cases), associated with chemotherapy (50) or with chemotherapy and autologous stem cell transplantation (18) were evaluated. Twenty-three cases of cytopenia (29.8%) were observed. Neutropenia developed in 21 cases (27.3%), thrombocytopenia in eight (10.4%), anemia in four (5.2%). Multiple cytopenias were observed in nine cases. Neutropenia developed after a median of 10 weeks, anemia of 5 weeks and thrombocytopenia of 4 weeks after the last rituximab dose. Severe infections occurred in four of 21 neutropenic patients (19%), compared to two of 56 controls (3.6%) (p = 0.043). Cytopenia eventually resolved in nine of 18 evaluable cases after a median of 10 weeks (range 1 - 23). Age, sex, histology, bone marrow infiltration, hypogammaglobulinemia, previous chemotherapy, autologous stem cell transplant, rituximab schedule and timing, rituximab doses were analysed as predictors for cytopenia; by multivariate analysis only a previous treatment with chemotherapy and more than four rituximab doses were significantly associated with a higher risk of post-rituximab delayed cytopenia. Delayed-onset cytopenia, particularly neutropenia, is a clinically significant complication of rituximab treatment, which merits further investigation.

Rituximab as Maintenance Therapy for Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

“…Although the incidence of LON in patients with hematologic malignancies has been estimated to be as high as 35% within 1 year of starting rituximab (32), it is believed to be significantly lower in patients with autoimmune diseases (33). However, one study correlates the number of doses with the development of LON, raising concern that repeated rituximab administration will lead to a higher incidence of this complication despite nononcologic indications (34). In our practice, we measure a complete blood count with differential in all patients receiving rituximab who develop a fever.…”

Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro)myelocyte stage of granulopoiesis

“…The erythropoiesis is left-shifted and shows megaloblastoid features. There is impaired maturation in the granulocytopoeisis with abundant promyelocytes (arrows), although some rods and mature neutrophils are seen duration from 1 week to 1 month in the literature [7][8][9][10][11][12][13][14]. This is much higher than post-marketing reporting rates of LON 0.02% [20].…”

“…Although rituximab is well tolerated and has a favorable hematological toxicity profile [6], late-onset neutropenia (LON) occurring at least 4 weeks after rituximab therapy has recently been reported and the incidence has been calculated to be 5.6-27.3% [7][8][9][10][11][12][13][14]. However, predisposing features and pathogenic mechanisms are still poorly defined.…”

Lymphocyte subpopulation imbalances, bone marrow hematopoiesis and histopathology in rituximab-treated lymphoma patients with late-onset neutropenia

“…[1][2][3][4][5] The incidence of LON varies between series; this might be explained, at least in part, by the failure to detect some neutropenic episodes due to their short duration, the relatively long time to onset and the usually uncomplicated course. However, there is a gradual increase in the frequency of rituximab-related LON probably due to the widespread use of rituximab in the standard treatment of lymphomas and also due to the ongoing awareness for this event.…”