Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children's oncology group

Abstract

Purpose: Systemic exposure to mercaptopurine (MP) is critical for durable remissions in children with acute lymphoblastic leukemia (ALL). Nonadherence to oral MP could increase relapse risk and also contribute to inferior outcome in Hispanics. This study identified determinants of adherence and described impact of adherence on relapse, both overall and by ethnicity.

Patients and methods: A total of 327 children with ALL (169 Hispanic; 158 non-Hispanic white) participated. Medication event-monitoring system caps recorded date and time of MP bottle openings. Adherence rate, calculated monthly, was defined as ratio of days of MP bottle opening to days when MP was prescribed.

Results: After 53,394 person-days of monitoring, adherence declined from 94.7% (month 1) to 90.2% (month 6; P < .001). Mean adherence over 6 months was significantly lower among Hispanics (88.4% v 94.8%; P < .001), patients age ≥ 12 years (85.8% v 93.1%; P < .001), and patients from single-mother households (80.6% v 93.1%; P = .001). A progressive increase in relapse was observed with decreasing adherence (reference: adherence ≥ 95%; 94.9% to 90%: hazard ratio [HR], 4.1; 95% CI,1.2 to 13.5; P = .02; 89.9% to 85%: HR, 4.0; 95% CI, 1.0 to 15.5; P = .04; < 85%: HR. 5.7; 95% CI, 1.9 to 16.8; P = .002). Cumulative incidence of relapse (± standard deviation) was higher among Hispanics (16.5% ± 4.0% v 6.3% ± 2.2%; P = .02). Association between Hispanic ethnicity and relapse (HR, 2.6; 95% CI, 1.1 to 6.1; P = .02) became nonsignificant (HR, 1.8; 95% CI, 0.6 to 5.2; P = .26) after adjusting for adherence and socioeconomic status. At adherence rates ≥ 90%, Hispanics continued to demonstrate higher relapse, whereas at rates < 90%, relapse risk was comparable to that of non-Hispanic whites.

Conclusion: Lower adherence to oral MP increases relapse risk. Ethnic difference in relapse risk differs by level of adherence-an observation currently under investigation.

Fig 1.

Adherence rates (A) for the entire cohort over the 6 months of observation, (B) over time according to ethnicity (solid and dashed lines represent estimated values for Hispanics and non-Hispanic whites, respectively), (C) over time according to age at study participation (solid and dashed lines represent estimated values for older [age ≥ 12 years] and younger [age < 12 years] patients, respectively), and (D) over time according to family structure (single mother v multiple caregivers; solid and dashed lines represent estimated values for single-mother and multiple-caregiver households, respectively). In each panel, 95% CIs of model estimates are presented on the plots.

Fig 2.

Cumulative incidence of relapse in a cohort of 327 children with ALL according to (A) adherence to oral mercaptopurine (solid and dashed lines represent nonadherers [< 95%] and adherers [≥ 95%], respectively) and (B) ethnicity (solid and dashed lines represent Hispanics and non-Hispanic whites, respectively).

Fig A1.

Study design. MP, mercaptopurine; TGN, thioguanine nucleotide; TPMT, thiopurine methyltransferase.

Fig A2.

MEMS medication bottle with (arrow) TrackCap (Aprex, Union City, CA).

Fig A3.

Examples of adherence output using MEMS device from two patients: (A) adherent and (B) nonadherent.