The genotype of MLH1 identifies a subgroup of follicular lymphoma patients who do not benefit from doxorubicin: FIL-FOLL study

Abstract

Though most follicular lymphoma biomarkers rely on tumor features, the host genetic background may also be relevant for outcome. Here we aimed at verifying the contribution of candidate polymorphisms of FCγ receptor, DNA repair and detoxification genes to prognostic stratification of follicular lymphoma treated with immunochemotherapy. The study was based on 428 patients enrolled in the FOLL05 prospective trial that compared three standard-of-care regimens (rituximab-cyclophosphamide-vincristine-prednisone versus rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone versus rituximab-fludarabine-mitoxantrone) for the first line therapy of advanced follicular lymphoma. Polymorphisms were genotyped on peripheral blood DNA samples. The primary endpoint was time to treatment failure. Polymorphisms of FCGR2A and FCGR3A, which have been suggested to influence the activity of rituximab as a single agent, did not affect time to treatment failure in the pooled analysis of the three FOLL05 treatment arms that combined rituximab with chemotherapy (P=0.742, P=0.252, respectively). These results were consistent even when the analysis was conducted by intention to treat, indicating that different chemotherapy regimens and loads did not interact differentially with the FCGR2A and FCGR3A genotypes. The genotype of MLH1, which regulates the genotoxic effect of doxorubicin, significantly affected time to treatment failure in patients in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone arm (P=0.001; q<0.1), but not in arms in which patients did not receive doxorubicin (i.e., the rituximab-cyclophosphamide-vincristine-prednisone and rituximab-fludarabine-mitoxantrone arms). The impact of MLH1 on time to treatment failure was independent after adjusting for the Follicular Lymphoma International Prognostic Index and other potential confounding variables by multivariate analysis. These data indicate that MLH1 genotype is a predictor of failure to benefit from rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone treatment in advanced follicular lymphoma and confirm that FCGR2A and FCGR3A polymorphisms have no impact when follicular lymphoma is treated with rituximab plus chemotherapy (clinicaltrials.gov identifier: NCT00774826).

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

CONSORT diagram representing the number of patients included in the analysis. BM: bone marrow; PB: peripheral blood.

Figure 2.

Kaplan-Meier estimates of time to treatment failure in the pooled treatment arms according to FCGR2A and FCGR3A genotypes. (A) Comparison of time to treatment failure (TTF) between patients homozygous for the common FCGR2A rs1801274 allele (blue line), patients heterozygous for the FCGR2A rs1801274 genotype (yellow line), and patients homozygous for the variant FCGR2A rs1801274 allele (red line). (B) Comparison of TTF between patients homozygous for the common FCGR3A rs396991 allele (blue line), patients heterozygous for the FCGR3A rs396991 genotype (yellow line), and patients homozygous for the variant FCGR3A rs396991 allele (red line). P: P values by log-rank test.

Figure 3.

Kaplan-Meier estimates of time to treatment failure and overall survival in patients randomized to the R-CHOP arm according to the MLH1 rs1799977 genotype. (A) Comparison of time to treatment failure (TTF) between patients homozygous for the common MLH1 rs1799977 allele (blue line), patients heterozygous for the MLH1 rs1799977 genotype (yellow line), and patients homozygous for the variant MLH1 rs1799977 allele (red line). (B) Comparison of overall survival (OS) between patients homozygous for the common MLH1 rs1799977 allele (blue line), patients heterozygous for the MLH1 rs1799977 genotype (yellow line), and patients homozygous for the variant MLH1 rs1799977 allele (red line). P: P values by log-rank test; q, q values by false discovery rate.

Figure 4.

Kaplan-Meier estimates of time to treatment failure stratified according to the MLH1 rs1799977 genotype and treatment randomization. (A) Comparison of time to treatment failure (TTF) between R-CHOP (blue line), R-CVP (red line) and R-FM (yellow line) among patients harboring the MLH1 rs1799977 AA/AG genotype. (B) Comparison of time to treatment failure (TTF) between R-CHOP (blue line), R-CVP (red line) and R-FM (yellow line) among patients harboring the MLH1 rs1799977 GG genotype. P, P values by log-rank test.