Measuring mercaptopurine (6MP) adherence using red cell 6MP metabolite levels in children with acute lymphoblastic leukemia (ALL): A COG AALL03N1 study.

Abstract

10514 Background: Non-adherence to 6MP (monitored with medication event monitoring system [MEMs]) is associated with an increased risk of relapse in children with ALL.(JAMA Oncol, 2015) Self-report over-estimates true medication intake, particularly in non-adherent patients.(Blood, 2017) However, monitoring adherence using MEMs is logistically difficult. We investigated whether red cell 6MP metabolite levels (thioguanine nucleotide [TGN] and methylated mercaptopurine [MMP]) taken together, could identify non-adherent patients. Methods: The analysis included children with ALL in maintenance. To minimize variability in TGN and MMP levels due to pharmacogenetics, we excluded TPMT heterozygotes and homozygote mutants. We also excluded Asians to remove variability due to NUDT15. TGN and MMP levels were drawn at 6 consecutive monthly time points for each patient and averaged. TGN and MMP levels (pmol/8 x 108red cells) were standardized, adjusted for 6MP dose intensity, and then analyzed using cluster analysis (Spath, H. [1980]). Results: The 373 patients eligible for analysis yielded 5 clusters. Cluster #1 (n = 119; mean MMP: 15,656; mean TGN: 158); Cluster #2 (n = 211; MMP: 6,042; TGN: 135); and 3 very small outlying clusters (total N = 43). Adjusting for age, sex, race/ethnicity, cytogenetics and NCI risk, we found that patients in Cluster #2 were 2.6 times as likely to be non-adherent (MEMs-based adherence < 95%) compared to Cluster #1 (95% CI 1.5-4.4; P= 0.0007). Mean MEMs-based adherence was significantly higher for patients in Cluster #1 (94.3%) when compared to those in Cluster #2 (87.8%, p = 0.0002). Using Fine-Gray proportional subdistribution hazards models for competing risks and adjusting for clinical and sociodemographic factors, we found that patients in Cluster #2 were at a 2.3-fold higher risk of relapse compared with those in Cluster #1 (95%CI, 1.0-6.4, p = 0.058). Conclusions: These findings illustrate the potential for using a combination of red cell TGN and MMP levels in identifying non-adherent patients. We propose to use these and clinical and demographic factors associated with non-adherence in creating an adherence calculator.