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Original Investigation
February 24, 2015

Association of an Inherited Genetic Variant With Vincristine-Related Peripheral Neuropathy in Children With Acute Lymphoblastic Leukemia

Author Affiliations
  • 1Hematological Malignancies Program, Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 2Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta/Emory University, Atlanta, Georgia
  • 3Department of Biostatistics, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 4Department of Structural Biology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 5Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 6Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
  • 7Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville
  • 8Division of Pediatric Hematology/Oncology, University of Texas Southwestern School of Medicine, Dallas
  • 9New York University Cancer Institute, New York, New York
  • 10Department of Pediatrics, University of California, San Francisco, School of Medicine, San Francisco
  • 11Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Center for Cancer and Blood Disorders, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora
  • 12Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee
JAMA. 2015;313(8):815-823. doi:10.1001/jama.2015.0894
Abstract

Importance  With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is a need to mitigate treatment toxicities that can compromise quality of life, including peripheral neuropathy from vincristine treatment.

Objective  To identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL.

Design, Setting, and Participants  Genome-wide association study of patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genome-wide single-nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years; range, 0.1-18.8 years) enrolled in 1994-1998 in the St Jude Children’s Research Hospital protocol Total XIIIB with toxic effects follow-up through January 2001, and 99 patients (median age, 11.4 years; range, 3.0-23.8 years) enrolled in 2007-2010 in the Children’s Oncology Group (COG) protocol AALL0433 with toxic effects follow-up through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity.

Exposure  Treatment with vincristine at a dose of 1.5 or 2.0 mg/m2.

Main Outcomes and Measures  Vincristine-induced peripheral neuropathy was assessed at clinic visits using National Cancer Institute criteria and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life threatening (grade 4).

Results  Grade 2 to 4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) in the COG cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta-analysis P = 6.3×10−9). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%; 95% CI, 11.6%-19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 (56%; 95% CI, 41.2%-70.0%) developed at least 1 episode of grade 2 to 4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotypes (58/271 patients [21.4%; 95% CI, 16.9%-26.7%]; P = 2.4×10−6). The severity of neuropathy was greater in patients homozygous for the TT genotype compared with patients with the CC or CT genotype (2.4-fold by Poisson regression [P<.0001] and 2.7-fold based on mean grade of neuropathy: 1.23 [95% CI, 0.74-1.72] vs 0.45 [95% CI, 0.3-0.6]; P = .004 by t test). Reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine.

Conclusions and Relevance  In this preliminary study of children with ALL, an inherited polymorphism in the promoter region of CEP72 was associated with increased risk and severity of vincristine-related peripheral neuropathy. If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent.

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