Abstract
Rituximab has been given following autologous hematopoietic cell transplantation (HCT) for recurrent or refractory B cell lymphoma with the goal of eradicating minimal residual disease. Our recent study showed that this is a feasible strategy although transient grade 3 or 4 neutropenia was observed in 51% of patients (Blood 103:777, 2004). We also reported that two IgG Fc receptor (FcγR) polymorphisms, FcγRIIIa 158 V/V and FcγRIIa 131 H/H genotypes, predict response to rituximab therapy in patients with follicular lymphoma, probably due to their role in the antibody-dependent cellular cytotoxicity (ADCC) (JCO 21:3940, 2003). In the current report, we correlated FcγR polymorphisms with clinical outcomes after post-transplant rituximab. A total of 35 patients with diffuse large cell (25 patients), mantle cell (3 patients), transformed (3 patients) or other (4 patients) subtypes of B cell lymphoma received high-dose therapy, autologous HCT and rituximab, administrated as 4-weekly infusions (375 mg/m2) starting around day 42 and 6 months after HCT. Genomic DNA was available for FcγR polymorphism analysis in 33 cases. For the FcγRIIIa polymorphism, 4 (12%) patients were homozygous valine/valine (158 V/V), 14 (42%) patients were heterozygous valine/phenylalanine (158 V/F) and 15 (46%) patients were homozygous phenylalanine/phenylalanine (158 F/F). For the FcγRIIa polymorphism, 8 (24%) patients were homozygous histidine/histidine (131 H/H), 16 (49%) patients were heterozygous histidine/arginine (131 H/R) and 9 (27%) patients were homozygous arginine/arginine (131 R/R). We did not find a correlation of either the FcγRIIIa V/F polymorphism or the FcγRIIa H/R polymorphism with time to relapse after HCT. But the small number of relapses limited our power. Although rituximab infusions were well tolerated in this group of patients, 32% of the treatment courses in this study were associated with rituximab-induced grade 3 or grade 4 neutropenia (ANC < 1000/μl), which was recorded in 51% of patients. These neutropenic episodes were not associated with infection and responded well to G-CSF treatment. The reason for this high incidence of rituximab-induced neutropenia is unclear. Among the 33 patients analyzed for FcγR polymorphisms, FcγRIIIa 158 V/V homozygotes experienced relatively greater neutropenia (V/V : 3/4, 75%; V/F: 8/14, 57%; F/F: 5/15, 33%). For the 57 treatment courses, the FcγRIIIa 158 V/V genotype was associated with a greater chance of rituximab-induced neutropenia, compared to F carriers (158 V/F and 158 F/F). The incidence of rituximab-induced neutropenia was 71% for V/V, 39% for V/F, 19% for F/F and 28% for F carriers (V/V vs F carriers, p = 0.035). In contrast, the FcγRIIa H/R polymorphism had no impact on rituximab-induced neutropenia. Although the mechanism of rituximab-induced neutropenia is unknown, this report implicates an FcγR-mediated process, such as ADCC. It is possible that B cell depletion by rituximab affects either directly or indirectly cytokine (e.g. G-CSF) production as a mechanism for neutropenia. It will be of great interest to study the correlation between FcγR polymorphisms and the prevalence and duration of B cell depletion after rituximab therapy in larger clinical studies both after HCT and in conjunction with other myelosupressive therapies.
