Simplifying 6-MP Delivery

There has been much excitement in the pediatric leukemia community in recent years as survival rates for children with acute lymphoblastic leukemia (ALL) now exceed 90 percent. This success has been attributed to a variety of factors including improvements in risk classification and supportive care as well as advances in therapy, which include several promising new molecularly and immunologically targeted agents. Another critical component of cure is medication adherence. Recent studies have defined the scope and magnitude of medication nonadherence in childhood ALL by demonstrating that less than 95 percent adherence to daily mercaptopurine (6-MP) increases relapse risk 2.7-fold.¹  Moreover, up to one-third of ALL relapses have been attributed to 6-MP nonadherence.²  Thus, defining risk factors for nonadherence and carefully reexamining practices surrounding medication administration is another essential aspect of optimizing chances for cure.

6-MP was discovered by Nobel Prize recipients Drs. Gertrude Elion and George Hitchings and moved into clinical trials in children with ALL in the 1950s.³  Along with methotrexate and corticosteroids, it was one of the first effective agents in the treatment of acute leukemia. Since its discovery, it has been a mainstay of ALL therapy. Throughout the decades, approaches to timing, utilization and administration of 6-MP have evolved. Currently, the majority of regimens using 6-MP prescribe it to be taken orally on a daily basis throughout a two- to three-year maintenance phase of therapy. In the 1980s, 6-MP administration guidelines were established and included restrictions regarding co-ingestion with food and dairy products as well as preferential administration in the evening. Food restrictions stemmed from the observation that xanthine oxidase, highly concentrated in dairy products, converts 6-MP to the inactive metabolites 6-thiouric acid and 6-thioxanthine.⁴  The timing of administration arose out of concern for the diurnal variation in 6-MP absorption. The combination of several small studies reporting increased bioavailability of 6-MP when taken without meals, and reports that patients who took 6-MP in the evening experienced superior outcomes, led to the recommendation for evening administration of 6-MP in a fasting state.^5-7 

However, these recommendations have recently come under scrutiny. Notably, there are data showing that heat pasteurization of milk inactivates xanthine oxidase, thereby decreasing its effects on 6-MP metabolism.⁸  Studies conducted previously also did not take into account 6-MP dosing or measurements of active thioguanine nucleotide (TGN) metabolites. Additionally, treatment protocols have evolved with improved risk classification, leading to more accurate therapeutic stratification. Indeed, a more recent study demonstrated that timing of 6-MP administration did not impact the risk of relapse.⁹ 

Within this context, Dr. Wendy Landier and colleagues performed a prospective study of 441 children with ALL with the goal of examining the association between 6-MP ingestion habits, TGN levels, and outcomes.¹⁰  The study found that nearly 44 percent of patients were nonadherent (defined as <95% adherence rate measured by using the Medication Event Monitoring System). Among adherent patients there was no association between red cell TGN levels and ingestion habits (with or without food, with or without dairy, swallowing vs. crushing/chewing, or dose timing). Most importantly, no association was found between any of the 6-MP ingestion habits and relapse risk.

Historical restrictions regarding 6-MP administration were made based on scientific findings and the most up-to-date biological understanding of 6-MP metabolism at the time. These were intended to improve drug bioavailability, effectiveness, and survival, but with these restrictions came the unintended consequence of complicating an already challenging treatment regimen. Patients in the maintenance phase of treatment for ALL have many risk factors for decreased adherence, including treating asymptomatic disease, treatment fatigue, and medication side effects. Increasing the complexity of medication administration only further contributes to nonadherence.¹¹  Dr. Landier and colleagues provide the most comprehensive analysis of 6-MP ingestion habits to date, demonstrating that common historical instructions for taking 6-MP at night and at least one to two hours before or after a meal or dairy product do not influence outcome and may in fact contribute to nonadherence.

In the words of former U.S. Surgeon General Dr. C. Everett Koop, “Drugs don’t work in patients who don’t take them.”¹¹  While previous studies, including some by Dr. Landier and colleagues have defined the critical adherence threshold and identified risk factors for nonadherence, this study is an important extension of previous work that now identifies a pragmatic solution by markedly simplifying instructions for 6-MP delivery: What is most critical is that 6-MP is taken daily, regardless of the time of day or fasting state. It is noteworthy that more than 60 years later we are still learning ways to optimize the delivery of one of the most essential components of ALL therapy.