Abstract LB-049: Low plasma levels of 13-cis-retinoic acid (isotretinoin) and its active metabolite 4-oxo-13-cis-retinoic acid are associated with lower overall survival of high-risk neuroblastoma patients
Authors: Cho Hwangeui , Naranjo Arlene , Ryn Collin Van , Yang Shengping , Sonawane Poonam , Villablanca Judith G. , You Alice L. , Park Julie R. , Kreissman Susan , Reynolds C Patrick , Kang Min H. 
Published: July 2017

Background and purpose: Isotretinoin (13-cis-retinoic acid; 13-cisRA), a differentiation inducer, improves outcome for high-risk neuroblastoma when given after myeloablative therapy. Published pharmacokinetic (PK) studies suggested that many patients achieve 13-cisRA levels lower than 5 μM (effective against neuroblastoma in vitro) and that 4-oxo-13-cisRA is an active metabolite of 13-cisRA. We assessed the pharmacokinetics (PK) of 13-cisRA and 4-oxo-13-cisRA and their relation to treatment outcome in Children’s Oncology Group (COG) phase III studies that treated high-risk neuroblastoma patients with 13-cisRA and immunotherapy.

Methods: Blood samples from COG high-risk neuroblastoma phase III clinical trials (A3973, ANBL0532, ANBL0032, and ANBL0931) were obtained for PK analyses. Plasma levels of 13-cisRA and 4-oxo-13-cisRA were measured using high-performance liquid chromatography for all patients treated with 13-cisRA. The relationship of PK to outcome was analyzed for the patient subgroup treated with 13-cisRA and ch14.18 anti-GD2 antibody + cytokines. PK variables analyzed included plasma levels of 13-cisRA, 4-oxo-13-cisRA, and the sum of both.

Results: Of 617 patients, 370 (60%) achieved median plasma concentrations of 13-cisRA + 4-oxo-13-cisRA (combined) &gt;5 μM. Plasma levels were higher in patients taking intact capsules relative to open-capsule takers (13-cisRA: 1.74 vs. 1.03, 4-oxo-13-cisRA: 7.2 vs. 3.3 μM, P &lt; 0.001). Both 13-cisRA and 4-oxo-13-cisRA concentrations positively correlated with older age (P &lt; 0.001). The relationship of PK to overall survival (OS) was analyzed for 524 patients treated with 13-cisRA and immunotherapy on ANBL0032 or ANBL0931. In patients ≥18 months old at diagnosis (n=445/524) the 5-year OS was significantly higher for patients with upper quartile 13-cisRA levels (2.5 μM, 73%) relative to lower quartile (0.6 μM, 60%, P = 0.039) although event-free survival was not significantly different (P = 0.44). Higher active metabolite concentrations (4-oxo-13-cisRA &gt;5 µM, 76%) was also associated with significantly higher OS relative to lower levels (&lt;1 µM, 66%, P = 0.032).

Conclusions: Age and route of administration influenced plasma levels of 13-cisRA and 4-oxo-13-cisRA. Combined levels of 13-cisRA and the active metabolite (4-oxo-13-cisRA) were &gt;5 µM in 85% of patients. In patients ≥18 months old, low plasma levels of 13-cisRA and 4-oxo-13-cisRA were associated with a lower overall survival.

Citation Format: Hwangeui Cho, Arlene Naranjo, Collin Van Ryn, Shengping Yang, Poonam Sonawane, Judith G. Villablanca, Alice L. You, Julie R. Park, Susan Kreissman, C Patrick Reynolds, Min H. Kang. Low plasma levels of 13-cis-retinoic acid (isotretinoin) and its active metabolite 4-oxo-13-cis-retinoic acid are associated with lower overall survival of high-risk neuroblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-049. doi:10.1158/1538-7445.AM2017-LB-049