The new Pharmacogenomics Global Research Network (PGRN) is an independent society that builds on the National Institutes of Health (NIH)–funded Pharmacogenomics Research Network that was established in 2000. Leveraging the original PGRN’s previous success, the new network continues to be a leader in the field of personalized medicine focusing on research, discovery, and translation of genomic variation influencing drug efficacy and adverse events, while simultaneously increasing inclusion in the field and expanding globally.

Background

Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML).

Methods

To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m² ) before and in combination with fludarabine and cytarabine.

Results

All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status.

Conclusions

Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.

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.