Non-Adherence to Oral 6-Mercaptopurine (6MP) Explains Ethnic Differences In Disease-Free Survival In Children with Acute Lymphoblastic Leukemia (ALL) – a Children's Oncology Group (COG) Study (AALL03N1)
Authors: Bhatia Smita , Landier Wendy , Shangguan Muyun , Hageman Lindsey , Leisenring Wendy , Kornegay Nancy , Relling Mary V. , Wong F. Lennie 
Published: October 2019

Abstract
Abstract 7

Background:
Hispanic children with ALL have a significantly inferior outcome compared with non-Hispanic whites (Blood, 2002). Low systemic exposure to 6MP adversely affects prognosis (N Engl J Med 1990), and red cell (RBC) levels of its metabolite (thioguanine nucleotide [TGN]) correlate with survival (Blood, 1999). Significant inter-patient variability in RBC TGN levels exists due either to inherited difference in thiopurine methyltransferase (TPMT) activity, or failure to adhere to prescribed 6MP. Non-adherence to 6MP has been reported, and could be related to differences in cultural beliefs, possibly accounting for ethnic differences in ALL survival.

Methods:
We tested this hypothesis in Hispanic and non-Hispanic white children with ALL diagnosed at age ≤21 yrs, and receiving maintenance therapy at 78 participating COG institutions. 6MP adherence was measured over 6 months using Medication Event Management System (MEMS) and RBC TGN. Electronic MEMS cap collected real-time data on dates/ times when the 6MP bottle was opened. Whether the bottle opening was followed by ingestion of 6MP was assessed by monthly (6 assessments/ patient) measurement of TGN. TPMT activity was also measured. Self-reported sociodemographics and reasons for non-adherence were also collected. MEMS-based adherence (outcome of interest) was defined as the ratio of days that 6MP bottle was opened to days 6MP doses were prescribed, reported as a percentage: “% adherence”. All prescribed doses were reviewed for each patient, and the period of time when 6MP was withheld by the prescriber due to toxicity/ illness taken into account. Longitudinal analysis was performed using Generalized Estimating Equations.

Results:
333 patients (173 Hispanics; 160 non-Hispanic whites) contributed 54,193 person-days of observation for 6MP adherence. Median age at study participation was 6 yrs (2-20); 67% were males; 38% presented with high-risk disease per NCI criteria. While age, sex and disease characteristics did not differ by ethnicity, Hispanics were significantly more likely to report indices of lower SES (Table). Mean % adherence over the 6 month study period was significantly lower among Hispanics (86±20%) compared with non-Hispanic whites (93±9%, p<0.0001). Multivariate longitudinal analysis identified the following at risk for lower adherence: Hispanic ethnicity (p<0.0001, Fig A); age ≥12 yrs at study entry (p=0.004, Fig B); single mothers as caregivers (p=0.003, Fig C); and time on study (p<0.0001). Reasons for missing 6MP doses included forgetfulness (55%), disruption of usual routine (22%), logistical barriers (15%), and side effects (5%). With a median follow-up of 4.5 yrs, disease-free survival (DFS) was significantly inferior for Hispanics (81±5% at 6 yrs) compared with non-Hispanic whites (94±2%, p=0.01, Fig D). After adjusting for sex, NCI risk, TPMT activity, and 6MP dose-intensity, each 1% decrease in adherence was associated with a 3% increase in risk of relapse (p=0.01). Most importantly, in the multivariate model without adherence, Hispanic ethnicity was associated with a significantly increased risk of relapse (HR=3.2, p=0.01); however upon inclusion of adherence in the model (p=0.01), the association between ethnicity and recurrence diminished in magnitude and significance (HR=2.1, p=0.18). A cutpoint in adherence at 85% was accompanied by a statistical separation in DFS (DFS: 92±2.2% vs. 77.0±5.1%, p<0.0001, Fig E), as well as a large separation in TGN levels (198 vs. 174, p=0.07), making 85% a clinically relevant level of adherence.

Conclusion:
Non-adherence to 6MP is prevalent in children with ALL. Hispanic children are more likely to be non-adherent, even after adjusting for sociodemographic variables. Non-adherence is associated with significantly inferior DFS. Non-adherence explains the ethnic differences in DFS. This study has informed a targeted intervention to reduce non-adherence to oral chemotherapy, with the goal to reduce disparities in ALL outcome.

Disclosures:
Relling: St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding.