Thiopurines for the Treatment of Acute Lymphoblastic Leukemia in Children: What's Old Is New.

Abstract

The treatmentof childrenwithacute lymphoblastic leukemia (ALL) isoneof thegreatestsuccessstories inthehistoryofmedicine. The 5-year overall survival rate for childrenwith ALL has improved fromapproximately 10% in the 1960s togreater than 90%withcontemporarytreatment regimens,1-5 with almost all childrenwho remain in remission for more than 4 years after completion of treatment considered “cured.”5 One of thekeyreasons for this remarkableachievementhasbeenthe enrollmentofchildrenwithALLinsuccessive,prospectiveclinical trials seeking to refine our understanding of disease biology, including clinical, genetic, and response-based prognostic factors,andtooptimize theuseofknowneffective therapies. With the exception of the recent development of highly innovative biologically targeted therapies for children with relapsed and refractory ALL (eg, CD19-directed therapy includingblinatumomabandchimericantigenreceptor [CAR]Tcells), modern ALL therapy remains rooted in a platform of a limited number of effective chemotherapeutic drugs that were developed and approved by the US Food and Drug Administration (FDA)manydecades ago (eg,methotrexate, 1953; 6-mercaptopurine [6MP], 1953; dexamethasone, 1958; vincristine, 1963; daunomycin, 1979; asparaginase, 1994). One of the most important of these drugs is the thiopurine 6MP; it is used intermittently throughout the intensive phases of modern ALL therapy and then forms the backbone of 2 to 3 years ofmaintenance therapy. As a treatment for childrenwithALL, 6MPwas first tested in prospective clinical trials by Burchenal and colleagues6 in 1953. Forty-five children receivedoral 6MP, and remissionperiods of 2 to 9 weeks were demonstrated in 15 children. Since this initialexperience, investigatorshavespent thepast63years trying to understand how to best use 6MP. As a result of significant intra-individual and interindividual variability, investigators have sought to optimize the use of 6MP through prospectivestudiesofdose, timing, lengthof therapy,combination with other effective agents, pharmacokinetics, erythrocyte thioguanine nucleotide (TGN) metabolite levels, host gene polymorphisms (eg, thiopurine methyltransferase [TPMT]), measurement of absolute neutrophil counts [ANC], timing of drug administration according to circadian rhythms, aminotransferase levels, physician compliance, and patient adherence to prescribed therapy).7 As a result of these studies, 6MP maintenance phase dosing is now based on titrating the dose in response to findings from serialmonitoring of the patient’s ANC,platelet count, andhepatic transaminases,with themost recent trials incorporating TPMT genotype and intermittent monitoring of erythrocyte TGN levels in select circumstances (eg, Children’s Oncology Group [COG] trial AALL0932; clinicaltrials.gov identifier: NCT01190930). This practice results in dose reductions, dose increases, and interruptions in therapymost commonly in response to ANCor platelet count outsideof the target ranges.Titrating thedoseof6MP is clearly complex and requires a high level of monitoring, education, communication, and compliance. As a result, it iswell known that achieving adherence to the 6MP therapy regimenby children, adolescents, and their parents is difficult. Key observationsby investigators in theCOGandothershaveclearly shown the negative impact of nonadherence to the 6MP treatment regimen,with an increased risk of relapse of ALL amongnonadherent patients.8 As reported in JAMA Oncology, Bhatia and colleagues9 in the COG now extend their prior studies on 6MP regimen adherence to further understand and assess the impact on patientoutcomesof intra-individual6MPsystemicexposureduring maintenance therapy.9 In this large prospective study of 742 children evaluated over a 6-month period duringmaintenance therapy, investigators evaluated the relationship between adherence, erythrocyte TGN levels, 6MP dose intensity, TPMTgenotype,ANC, and the contributionof the factors to risk of relapse. Adherence was measured using an electronicmonitoringdevice (TrackCapMedicationEventsMonitoring System; MWV Switzerland Ltd) that recorded the date and time of every 6MP bottle opening. Consistent with their prior studies, these investigators found that childrenwhowere not adherent to the prescribed 6MP regimenhad a 2.7-fold increased risk of ALL relapse. The 6MP dose intensity and absoluteTGNlevelsdidnotpredict relapse risk in this study.However, patients with high intra-individual variability in TGN levelswereathigher risk (cumulative incidenceof relapse, 20% vs 7% for those with low TGN variability; P < .001). Oneof themost striking findingsof this study is thatamong children who were adherent to the 6MP regimen, those with high intra-individual variability in TGN levels had a significant risk of relapse (hazard ratio, 4.4; P = .02). This high variability was found to be attributable to varying 6MP dose intensity (odds ratio [OR], 4.5;P = .01) and interruptions indrug delivery (OR, 10.2; P = .003). While pediatric oncologists will undoubtedly continue to struggle with how to make nonadRelated article page 287 Opinion