Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia.

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.

• Authors: Barthelemy Diouf, Kristine R Crews, Glen Lew, Deqing Pei, Cheng Cheng, Ju Bao, Jie J Zheng, Wenjian Yang, Yiping Fan, Heather E Wheeler, Claudia Wing, Shannon M Delaney, Masaaki Komatsu, Steven W Paugh, Joseph Robert McCorkle, Xiaomin Lu, Naomi J Winick, William L Carroll, Mignon L Loh, Stephen P Hunger, Meenakshi Devidas, Ching-Hon Pui, M Eileen Dolan, Mary V Relling, William E Evans
• Journal: JAMA (JAMA) Vol. 313 Issue 8 Pg. 815-23 (Feb 24 2015) ISSN: 1538-3598 [Electronic] United States
• PMID: 25710658 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• CEP72 protein, human
• Microtubule-Associated Proteins
• Vincristine

Topics

• Adolescent
• Antineoplastic Agents, Phytogenic (administration & dosage, adverse effects)
• Child
• Child, Preschool
• Female
• Genome-Wide Association Study
• Genotype
• Humans
• Male
• Microtubule-Associated Proteins (genetics)
• Peripheral Nervous System Diseases (chemically induced, genetics)
• Polymorphism, Single Nucleotide
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (complications, drug therapy)
• Vincristine (administration & dosage, adverse effects)
• Young Adult