LATE-ONSET NEUTROPENIA AFTER RITUXIMAB TREATMENT IN B-CELL LYMPHOMA: A SINGLE CENTRE EXPERIENCE

Background Recent studies have reported the occurrence of late onset neutropenia (LON) in 3%-27% of patients (pts) treated with Rituximab-based therapies. LON is defined as grade 3-4 neutropenia developing several weeks after Rituximab infusion; the aetiology is not completely understood. Several hypotheses have been proposed to explain this occurrence: infections, the production of antineutrophil antibodies, expansion of large granular lymphocyte (LGL) populations that may induce neutrophil apoptosis through Fas and Fas-ligand interactions. According to anther hypothesis, the interaction between B-cell recovery and stroma-derived factor-1 (SDF-1) inhibits neutrophil egress from the bone marrow. Immunoglobulin G Fc receptor polymorphism has also been suggested in the aetiology of LON. In addition, purine analogues, high dose therapy, AIDS are considered to increase the risk of LON. Aims The aim of our study was to evaluate the incidence and clinical relevance of WHO grade 3/4 LON in pts treated with Rituximab-based therapy. Methods We examined 238 B-cell lymphoma pts treated with Rituximab in our institution between 2008 and 2011; 124 (53%) of them had an indolent lymphoma. In9 pts(4%) the neutrophil count fell below 0.5 x 10e9/L a few weeks after the last Rituximab infusion. Pts median age was 63 years (range 19-92). Histology was Follicular Lymphoma in 3 cases (33%), Marginal Zone lymphoma in 3 (33%), SLL in 2 (23%) and DLBCL in 1 (11%). Seven (78%) pts had bone marrow involvement. Four pts(44%) developed LON after first line therapy that was RCHOP in 3 (33%) and RFC in 1 (11%); 5 (55%) pts, in relapse, had received previous chemotherapy (containing fludarabine in three cases, 60%) when LON occurred. Results LON appeared after a median of 103 days (range 40-140) from the last Rituximab infusion and median duration was 57 (14-236) days. When LON occurred 7 (78%) pts were EBV positive with high IgG levels, while no viral reactivation or autoimmune disorder was documented. Bone marrow examination revealed hypocellularity and maturation arrest of the myeloid series in 7 (78%) cases and normal cellularity in 2 (23%). Four pts (44%) had decreased immunoglobulin concentrations. Only 2 (23%) episodes of pulmonary pseudomonas infection were documented during the neutropenia period. Three pts (33%) had fever. All pts received corticosteroids and5 pts(55%) had GCSF treatment, but the clinical course of LON was not affected by these treatments, being always self-limiting with complete resolution of marrow impairment. Conclusions In our experience an indolent histology, bone marrow involvement and high EBV IgG levels seem to be related to the onset of delayed neutropenia. A transitory myelosuppressive effect of Rituximab could have a role in the pathogenesis of LON in our cohort of pts. The treatment of LON is not well defined. A watchful waiting approach is appropriate in the majority of patients. Further biological and prospective studies are needed to better clarify the pathogenesis, clinical impact and treatment of LON.