Optimizing the Maintenance Phase of Childhood Acute Lymphoblastic Leukemia AIEOP Protocol Through Mercaptopurine Therapeutic Drug Monitoring and Proactive Strategies for Adherence

Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in children (<18 years). The success of pediatric ALL therapy is remarkable (5 years survival ~90%). However, important challenges still need to be faced, including cure rates in specific patients' subsets (e.g.: adolescents and relapsed patients, 5 years survival ~60-70% and ~40-50%, respectively), and short- and long-term chemotherapy-related toxicities. The therapeutic scheme of the Associazione Italiana Emato-oncologia pediatrica (AIEOP) ALL protocols consists in a more intensive and toxic earlier phase (to induce and consolidate remission, ~ 6 months), followed by a prolonged period of immunosuppression (achieved by self- or parent-administered daily mercaptopurine (MP) and weekly methotrexate (MTX) per os). It is now well established that the length of the maintenance phase (up to 24 months after diagnosis) is as necessary as the early remission induction for sustained event-free survival (EFS). Ideally, the combination of antimetabolites MP and MTX is safe enough to provide the required antileukemic effects with minimal adverse events. However, both drugs can lead to potentially serious complications, including potentially life-threatening myelosuppression and infections. To exert its therapeutic effect, MP requires an intracellular enzymatic conversion into active thionucleotides (TGN) and is thus susceptible to intra- and inter-individual variations in efficacy and toxicity. In particular, patients carrying variants in TPMT and NUTD15 genes are at risk of adverse effects when treated with standard MP doses: these patients are identifiable by pre-emptive genotyping, and pharmacogenetic-based dose adjustment guidelines are already available. Recent studies of the Children's Oncology Group (COG) and of the Nordic Society of Pediatric Hematology and Oncology (NOPHO) demonstrated that an adequate and constant MP exposure during maintenance is associated with higher therapeutic success. Prescribed MP doses are often changed by physicians to target a white blood cell count (WBC) range of 2.0-3.0 × 109/L during maintenance. In the AIEOP ALL 2009 protocol, patients with lower mean TGN exposure during maintenance (below median cut-off of 272.44 pmol/10x108 RBC) showed a trend towards a higher risk of relapse compared to others (11.5% vs 5.5%, respectively). Similarly, patients with higher intra-individual variability in TGN over time (above the 75th percentile of the coefficient of variation (CV)) showed a trend towards a worse outcome (10.3% vs 4.8%). These preliminary data were obtained in 265 ALL patients (age: median (interquartile range): 4.82 (3.03-8.53) years; 58.5% male; follow up from maintenance beginning: 1338 (1377-4162) days; 27 relapsed, TGN measured in 391 blood samples of 209 patients). Daily compliance to prescribed MP over time is a challenging issue for patients and may result in less effective therapy: indeed, the recent use of an electronic device - the medication bottle cap opening (MEMS)- revealed that patients' self-reported MP intake overestimates true intake, in particular in some sociodemographic groups. Adherence is generally poorer in adolescents compared to younger children, likely because drug administration may no more be under strict parents' supervision: this lower compliance can in part contribute to the survival disparity observed between the two age groups. Thus, the high intra-individual variability in exposure due to the frequent dose adjustments and the potential lack of patients' adherence to oral MP therapy over time might contribute to the risk of relapse.