Comparison of Vincristine Pharmacokinetics (PK) in Adolescent/Young Adult (AYA) Versus Younger Patients Defined By Tanner Stage during Treatment for Acute Lymphoblastic Leukemia (ALL)

Introduction: For many forms of cancers, survival improvement in the AYA population has lagged behind that of younger patients. One contributing factor could be differences in drug metabolism and tolerance of cancer treatment. Although previous studies have documented greater vincristine-related neurotoxicity (VRNT) in AYA vs. younger patients, comparative vincristine PK studies have yielded mixed results with no clear difference in PK related to age. One limitation of these studies is that age, rather than a more physiological assessment of developmental maturity, was used for the comparison. The primary aim of this study was to determine whether developmental differences in vincristine PK related to Tanner Stage could be detected in a sample of children and AYAs undergoing treatment for ALL. Our hypothesis was that vincristine PK would be related to Tanner Stage.

Methods: From September 2014-March 2015, a purposeful sample of 30 patients with a diagnosis of ALL treated at Children's Hospital of Los Angeles were recruited to this IRB-approved study either prior to starting Induction phase or during Maintenance phase. Tanner Stage was classified as ≤2 or ≥4, excluding Tanner Stage 3. Vincristine blood levels were obtained around the first dose during Induction or any single monthly dose during Maintenance at pre-specified time points: 0 min, 10 min, 30 min, 1 hour, 12 hour (Induction only), and 24 hours. For all patients, the vincristine dose was 1.5 mg/m²(max 2 mg). Vincristine levels were determined by high performance liquid chromatography. Mean vincristine clearance was compared using the independent T-test. Univariate and multivariate linear regression analysis via backward selection was performed using Tanner Stage, age, sex, BMI, fluconazole exposure, and treatment phase as predictors. P-values were two-sided with significance set at < 0.05.

Results: The age range was 1-24 yrs (< 10 yrs, n=12; 10+ yrs, n=18). 15 (50.0%) patients were female; and 26 (86.7%) were Hispanic. BMI was underweight/normal for 20 (66.7%). Fluconazole was being administered to 19 (63.3%). Tanner Stage was ≤ 2 for 14 patients (46.7%) and ≥ 4 for 16 (53.3%).  Mean vincristine clearance (standard error) for the Tanner ≤ 2 and ≥ 4 groups was 61.14 (18.42) and 68.75 (10.05) L/h*m², respectively (p=0.71). As summarized in Tables 1 and 2, in both univariate and multivariate analyses no predictors, including Tanner Stage, were associated with vincristine clearance.

Conclusions: In this pilot study, we were unable to detect an association between vincristine clearance and Tanner Stage. These data suggest that even when using a measure more reflective of physiological maturity than age, substantial developmental differences in vincristine clearance appear to be lacking. This calls into question the potential explanation of altered clearance for the increased VRNT observed in AYAs, and suggests that future investigations should be directed toward potential developmental differences in vincristine pharmacodynamics. Our data may have implications for understanding other differences in chemotherapy toxicity observed in AYAs.

         Table 1: Univariate Analysis of Vincristine Clearance

Predictor	Clearance Unit: L/h*m2
	Diff (SE)	F-test P-value
Tanner stage ≥4 vs. ≤2	7.615 (20.279)	0.71012
Age 10+ vs. <10	13.523 (20.545)	0.51577
Phase of therapy Maintenance vs. Induction	-6.971 (20.288)	0.73371
Gender Female vs.  Male	4.307 (20.269)	0.83326
BMI group OW/Obese vs. UW/Normal	9.931 (21.434)	0.64669
Fluconazole use Yes vs. No	-2.799  (21.041)	0.89512

                                   

                                  Table 2: Multivariate analysis  of Vincristine Clearance

	Model #1			Model # 2
Endpoint	Predictor	Diff (SE)	LRT P-value	Predictor	Diff (SE)	LRT P-value
Clearance Unit: L/h*m2	Age 10+ vs <10	21.4211   (23.3859)	0.3380	Tanner stage ≥4 vs. ≤2	13.8334  (23.1741)	0.5306
	Phase Maintenance vs Induction	-16.7252   (22.9644)	0.4449	Phase Maintenance vs Induction	-13.3936   (23.1741)	0.5436