title: 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).
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara.
authors.forename: Alessio
authors.initials: A
authors.lastname: Bruscaggin
authors.affiliation: Division of Hematology, AOU "Policlinico V. Emanuele", Catania.
authors.forename: Piera
authors.initials: P
authors.lastname: La Cava
authors.affiliation: Department of Oncology, Transplants and Advanced Technologies, Section of Haematology, University of Pisa.
authors.forename: Sara
authors.initials: S
authors.lastname: Galimberti
authors.affiliation: Department of Oncology, Transplants and Advanced Technologies, Section of Haematology, University of Pisa.
authors.forename: Elena
authors.initials: E
authors.lastname: Ciabatti
authors.affiliation: Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena.
authors.forename: Stefano
authors.initials: S
authors.lastname: Luminari
authors.affiliation: Division of Hematology, Azienda Ospedaliero Universitaria Careggi, Florence.
authors.forename: Luigi
authors.initials: L
authors.lastname: Rigacci
authors.affiliation: Division of Hematology, Spedali Civili Hospital and University, Brescia.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tucci
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pulsoni
authors.affiliation: Department of Oncology, Civic Hospital, Noale, Venice.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bertoldero
authors.affiliation: Division of Hematology, Ospedale Civile, Piacenza.
authors.forename: Daniele
authors.initials: D
authors.lastname: Vallisa
authors.affiliation: Division of Hematology, Department of Hematology and Oncology, Niguarda Hospital, Milan.
authors.forename: Chiara
authors.initials: C
authors.lastname: Rusconi
authors.affiliation: Division of Medical Oncology A, National Cancer Institute, Aviano.
authors.forename: Michele
authors.initials: M
authors.lastname: Spina
authors.affiliation: Divisions of Hematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia.
authors.forename: Luca
authors.initials: L
authors.lastname: Arcaini
authors.affiliation: Department of Hematology, Local Health Unit of Pescara.
authors.forename: Francesco
authors.initials: F
authors.lastname: Angrilli
authors.affiliation: Division of Hematology, Ospedale di Reggio Calabria.
authors.forename: Caterina
authors.initials: C
authors.lastname: Stelitano
authors.affiliation: Hematology Unit, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Merli
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena.
authors.forename: Massimo
authors.initials: M
authors.lastname: Federico
authors.affiliation: Division of Hematology, AOU "Policlinico V. Emanuele", Catania palumbo.ga@gmail.com.
authors.forename: Giuseppe A
authors.initials: GA
authors.lastname: Palumbo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008224:Lymphoma, Follicular / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D017452:Receptors, IgG / Q000235:genetics; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D017452:Receptors, IgG; D004317:Doxorubicin; D000070957:MutL Protein Homolog 1