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2483 Role of Genetic Polymorphisms on Response to R-Chopregimen in Diffuse Large B-Cell Lymphoma Patients: An Interim Analysis of a Multicenter Prospective Pharmacogenetic Study

Molecular Pharmacology, Drug Resistance – Lymphoid and Other Diseases
Program: Oral and Poster Abstracts
Session: 605. Molecular Pharmacology, Drug Resistance – Lymphoid and Other Diseases: Poster II
Sunday, December 6, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Luigi Rigacci1*, Gabriele Perrone2*, Stefania Nobili2*, Sofia Kovalchuk1*, Benedetta Puccini1*, Federica Lancia1*, Renato Tassi2*, Marco Brugia2*, Ida Landini2*, Lara Mannelli1*, Gemma Benelli1*, Cristina Napoli2*, Emanuele Cencini3*, Alberto Fabbri4*, Lorenzo Iovino5*, Mario Petrini5, Silvia Birtolo6*, Alessandro Melosi7*, Varesco Martini8*, Simone Santini9*, Carla Breschi10*, Paolo Bernardeschi11*, Carmelo Bengala12*, Alberto Bosi, MD1 and Enrico Mini2*

1Hematology Department, University and Hospital Careggi, Firenze, Italy
2Dipartimento di Scienze della Salute, University of Florence, Firenze, Italy
3Hematology Unit, Ospedale Santa Maria alle Scotte and University of Siena, Siena, Italy
4Az. Ospedaliera Universitaria Senese, Siena, Italy
5Hematology Department, University of Pisa, Pisa, Italy
6Oncology Department, Hospital, Pescia, Italy
7Oncology, Hospital, Lucca, Italy
8Oncology, Hospital, Firenze, Italy
9Oncology, Hospital, Prato, Italy
10Oncology, Hospital, Pistoia, Italy
11Oncology, Hospital, Empoli, Italy
12Oncology, Hospital, Grosseto, Italy

Introduction: Standard chemotherapy represented by the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen is successful in about 60% of patients (pts) with diffuse large B-cell lymphoma (DLBCL). Pts who do not benefit from this treatment, due to the development of tumor drug resistance, have a very poor prognosis.

Currently, knowledge on reasons of treatment related failures in DLBCL are scanty and predictive biomarker of response are largely unknown. We hypothesized that polymorphisms of gene involved in the pharmacokinetics and pharmacodynamics of drugs included in R-CHOP regimen may play a role in predicting the outcome in DLBCL pts.Thus, we designed a multicentre prospective pharmacogenetic trial aimed at identifying gene polymorphisms potentially predictive of drug efficacy/resistance in DLBCL pts treated with R-CHOP.An interim analysis on the first 80 enrolled ptswas planned and has been performed.

Methods: The study included chemonaive DLBCL pts at various stages of disease candidate to an R-CHOP standard treatment. The Ethical Committee of each participating centre approved the pharmacogenetic protocol, and all pts signed a written informed consent.

According to the aims of this interim analysis, the impact of single nucleotide polymorphisms (SNPs) on R-CHOP efficacy was evaluated by objective response (OR) rate at the end of treatment.

The efficacy of R-CHOP was evaluated according to the Cheson criteria by performing standard hematochemical and instrumental (TC and FDFG-PET) tests and defining complete remission (CR), partial remission (PR), non response or progressive disease (PD).

Genomic DNA wasextracted from peripheral blood of 80 pts. Twentysingle nucleotide polymorphisms (SNPs) from18candidate genes (ABCB1, ABCC1, ABCC2, ABCG2, CYBA, CYP2C9, FCGR2A, GSTP1, IL2, MLH1, NCF4, NQO1, NQO2, RAC2, TNF, TOP2A, TP53, TUBB)involved in pharmacokinetics and pharmacodynamics of R-CHOP (www.pharmgkb.org)have been analysed by a genotyping array based on Affimetrix methodology.

Univariate analysis was performed to evaluate associations between polymorphisms and clinical/pathological characteristics or OR (Fisher exact test). Multivariate logistic regression analysis was performed to estimate adjusted odds ratios along with the corresponding 95% confidence intervals for the polymorphisms and OR.

Results: Median age was 63 years. There were 37 men and 43 women. 47.5 % of pts were in stage I-II,52.5 % of pts in stage III-IV. 27.5% of ptshad bulky disease, 43.8 % of pts had involvement of extranodal site. 47.5% of pts had pathological LDH value. According to the revised IPI, 15 % pts were in the low risk group, 58.7 % in the intermediate risk group, and 26.3 % in the high risk group.Overall, 468 courses of R-CHOP had been administered (mean: 5.85 courses, range: 4-6).

81% of pts had CR to R-CHOP whereas the remaining showed PR (14%) or PD(5%).

No statistically significant correlation was found between OR and clinical characteristics of pts.However, stage III-IV pts showed a worst OR than stage I-II pts (77% vs 87% of CR, respectively); pts with bulky disease had worst OR than non-bulky disease pts(73% vs 84.5% of CR, respectively); ptswith R-IPI 3-5 a worst OR than pts with R-IPI 0-2 (71.5% vs 85% of CR, respectively).

Univariate and multivariateanalysis identified TOPOIIrs13695as a predictor of OR (p=0.042). Pts with CT or TT genotypesshowed worst OR than CC wild-type homozygous pts (odds ratio 3.070, CI95% 1.113-13.457). Also, a statistical trendtoward significance was observed for MLH1rs1800734 polymorphism (p=0.062): ptswith homozygous genotype for the mutant allele showed a better OR than wild-type and heterozygous pt genotypes.

Conclusions: No significant relationship between clinical/pathological characteristics and OR was observed.

Our preliminary data show that SNPs affecting a gene involved in doxorubicin pharmacodynamics, i.e. the drug target TOPOII,as well asone of the major components of DNA mismatch repair, i.e. MLH1gene,may predict response in DLBCL pts treated with R-CHOP.

These preliminary results from the interim analysis are promising and warrant completion of pt accrual to reach the planned number of cases at the end of our study.

Acknowledgements

This work was supported by a grant from the Associazione Giacomo Onlus, Castiglioncello (LI), Italy to E.M. and Cassa di Risparmio di Firenze, Firenze, Italy to S.N.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH