Delayed‐onset neutropenia associated with rituximab therapy

Abstract

Summary. The characteristics of severe neutropenia with a delayed onset following administration of rituximab have been evaluated in 53 consecutively treated patients. All but one patient received rituximab for the treatment of non‐Hodgkin's lymphoma. Eight episodes of grade 4 neutropenia were detected between 1 and 5 months after rituximab, when administered alone on five occasions, and on three occasions in combination with chemotherapy, where neutrophil counts had recovered prior to the development of neutropenia. In three episodes, the patients presented with sepsis. Development of neutropenia did not correlate with either the presence of detectable disease or the administration of further treatment. Neutropenia was associated with selective depletion of neutrophil precursors in all but one episode, where it was associated with generalized bone marrow hypoplasia. All episodes developed after a period of either normal or mildly depressed neutrophil counts following treatment with rituximab, and persisted for between several days and several months, before undergoing spontaneous recovery in four instances, and after administration of filgrastim in the remainder. Episodes of neutropenia were associated with disordered immune status manifested by lymphopenia and hypogammaglobulinaemia, raising the possibility that either disturbance of the balance of lymphocyte subsets or an immune dyscrasia induced by rituximab resulted in the development of this type of neutropenia.

Rituximab does not compromise the mobilization and engraftment of autologous peripheral blood stem cells in diffuse-large B-cell lymphoma

“…14 Proteolytic enzymes such as neutrophil elastase, cathepsin G and matrix metalloproteinase-9 released from the activated neutrophils and monocytes can degrade and/or inactivate adhesion molecules such as VCAM-1/VLA-4, chemokines such as stromal-derived factor (SDF)-1/CXCR-4 and soluble Kit ligand, resulting in the disruption of contact between stem/progenitor cells and the bone marrow microenvironment, and then stem/progenitor cells would be released to migrate into peripheral blood. 14,15 However, recently late-onset neutropenia has been reported following rituximab-based chemotherapy, 22,23 and Dunleavy et al 24 have suggested that rituximab may induce perturbations of SDF-1/CXCR-4 interaction, which could retard the egress of neutrophils from bone marrow. Therefore, we investigated expression levels of adhesion molecules on PBSC in the two groups.…”

Rituximab-related late-onset neutropenia after autologous stem cell transplantation for aggressive non-Hodgkin's lymphoma

“…1 Recently, several cases of late-onset neutropenia have been described in relation to its utilisation. 3,4 Reversible rituximab-related late-onset neutropenia tends to occur 2-6 months after rituximab therapy and can be associated with infectious complications. 4 In the postmarketing phase, the rate of lateonset neutropenia reported by Genentech (manufacturer of rituximab) was less than 0.02%.…”

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

“…[1][2][3]6 However, published data are mainly based on small series and are often contradictory, perhaps due to the selective evaluation of isolated parameters. Our previous studies suggesting that LON in rituximab-treated lymphoma patients may be associated with T-cell large granular lymphocytic (T-LGL) proliferation [1][2] alluded to the possibility of altered T-cell responses associated with B-cell depletion induced by rituximab.…”

“…1 For example, we previously showed that SAHA induces growth arrest and apoptosis of human mantle cell lymphoma cells in association with induction of histone acetylation of the p21 waf1 promoter region, resulting in upregulation of the p21 waf1 protein. 3 This study found that MS-275 induces growth arrest of human acute myelogenous leukemia (AML) HL-60 and NB4 cells, as well as freshly isolated leukemia cells from individuals with AML with concentration that induced 50% inhibition (IC 50 ) values less than 1 mM on day 2 of culture, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and thymidine uptake, respectively ( Figure 1a, Table 1). Western blot analyses showed that exposure of these cells to MS-275 downregulated levels of antiapoptotic molecules Bcl-2 and…”

“…[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.…”