Gene Polymorphisms and Vincristine-Induced Neuropathy in Patients Who Received R-CHOP Chemotherapy
Authors: Sawaki Akihiko , Miyazaki Kana , Takeuchi Toshifumi , Kobayashi Kyoko , Imai Hiroshi , Tawara Isao , Ono Ryoichi , Nosaka Tetsuya , Yamaguchi Motoko , Katayama Naoyuki 
Published: November 2019

Background: Rituximab with cyclophosphamide, doxorubicin, vincristine (VCR), and prednisone (R-CHOP) chemotherapy is the standard regimen for newly diagnosed diffuse large B-cell lymphoma (DLBCL). VCR has been widely used in the treatment of lymphoid malignancies and is included in R-CHOP. However, VCR causes peripheral neuropathy (PN), which is one of major toxicities that reduce quality of life. VCR-induced PN (VIPN) is associated with the VCR dose, vincristine cumulative dose, age, and comorbidities (e.g., impaired glucose tolerance). During the last decade, more than 10 gene polymorphisms have been reported to be associated with VIPN in studies of children with acute lymphoblastic leukemia (ALL) who were treated with VCR-containing regimens. Among these polymorphisms, CEP72 rs924607 TT, MTNR1B rs12786200, and ETAA1 rs17032980 were associated with VIPN in both children and adult patients (pts) with ALL in a North American cohort. In a few studies of children with ALL outside the US, the CEP72 rs924607 TT genotype was not associated with VIPN, suggesting an ethnic deviation in the association. Recent studies including children with ALL have also reported that CYP3A5 rs776746, rs7963521, and rs1045644 are associated with VIPN. Little is known about the association between these gene polymorphisms and VIPN in adult pts with B-cell lymphoma. The present study aimed to elucidate the relation between VIPN in adult pts with lymphoma and the CEP72 rs924607, MTNR1B rs12786200, ETAA1 rs17032980, CYP3A5rs776746, rs7963521, and rs1045644 polymorphisms.
Methods: This study included 36 pts with mature B-cell lymphoma diagnosed according to the 2008 WHO classification between 2003 and 2017 at Mie University Hospital and who received R-CHOP-like chemotherapy as a first-line therapy. VIPN was graded according to the Common Terminology Criteria for Adverse Events ver. 3.0 from 2003 to 2011 and ver. 4.0 from 2012 to 2017. The specimens used in this study were obtained from the oral mucosa or lymphoma tissue of the pts. Mutation analysis was performed by direct sequencing. CEP72 rs924607, MTNR1B rs12786200, ETAA1 rs17032980, CYP3A5rs776746, rs7963521, and rs1045644 were analyzed in this study.
Results: The median age of pts was 64 years (range, 30-78). All pts were Japanese. Five pts had impaired glucose tolerance with no compliant of PN before chemotherapy. Twenty-two pts were diagnosed as having DLBCL, 13 had follicular lymphoma, and one had marginal zone B-cell lymphoma. All pts with the exception of one were treated with R-CHOP. In the remaining patient who had atrial fibrillation, pirarubicin was used instead of doxorubicin in R-CHOP. The total number of cycles of chemotherapy was 6 in 16 pts, 7 in one patient, and 8 in 19 pts. The median cumulative dose of VCR was 12 mg/m2 (range, 2-16). In all 36 pts, 24 pts (67%) experienced any grade of VIPN during chemotherapy and 4 (11%) developed grade 2-4 VIPN. Grade 1 VIPN was observed in 20 pts (56%). Age, impaired glucose tolerance, and the VCR cumulative dose were not associated with the incidence of VIPN. The number of cycles of chemotherapy was significantly associated with the incidence of any grade VIPN (P = 0.04). The CEP72 TT genotype was detected in 7 pts (19%). Four (57%) of 7 pts with the CEP72 TT genotype and 20 (69%) of 29 pts with the CEP72 CT or CC genotype experienced any grade VIPN (P = 0.7). Frequencies of the other gene genotype were as follows: MTNR1B rs12786200 CC in 12 (33%), CT in 18 (50%), and TT in 6 (17%); ETAA1 rs17032980 AA in 22 (61%), AG in 12 (33%), and GG in 2 (6%); CYP3A5rs776746 AA in 4 (11%), AG in 15 (42%), and GG in 17 (47%); rs7963521 CC in 3 (8%), CT in 9 (25%), and TT in 24 (67%); and rs1045644 CC in 21 (58%), CG in 15 (42%), and GG in 0 (0%) of 36 pts. There was no significant association between the incidence of VIPN and these five gene polymorphisms.
Conclusions: Our results suggest that the CEP72, MTNR1B, ETAA1, CYP3A5, rs7963521, and rs1045644 polymorphisms analyzed in this study are not associated with the incidence of VIPN in adult pts with mature B-cell lymphoma who received R-CHOP-like chemotherapy. To reduce VIPN in pts who receive R-CHOP, a strategy that devises a VCR administration may be more effective than targeting genetic polymorphisms analyzed in this study. Gene polymorphisms associated with VIPN need to be identified in adult pts with lymphoma.

Disclosures
Sawaki: Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Chugai: Honoraria. Miyazaki:Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai: Honoraria; Ono Pharmaceutical: Research Funding; Celgene: Honoraria; Eisai: Honoraria; SymBio Pharmaceuticals: Honoraria; Takeda: Honoraria; Nippon Shinyaku: Honoraria; Astellas Pharma: Research Funding; Janssen Pharmaceutical: Honoraria. Imai:Chugai: Honoraria. Tawara:Astellas Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Yamaguchi:Ono Pharmaceutical: Research Funding; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sorrento: Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Teijin Pharma: Honoraria; MSD: Honoraria; Meiji Seika Kaisha: Honoraria; Janssen: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Eisai: Honoraria; Chugai: Honoraria, Research Funding; Astellas Pharma: Research Funding. Katayama:Taisho Toyama Pharma: Honoraria; Sysmex: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Alexion Pharmaceuticals: Honoraria; Chugai: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Ono Pharmaceutical: Research Funding; Novo Nordisk: Honoraria; Shionogi Pharmaceutical: Honoraria; Shire: Honoraria; Novartis: Honoraria; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; kyowa hakko kirin: Honoraria, Research Funding.