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

The treatment of children with acute lymphoblastic leukemia (ALL) is one of the greatest success stories in the history of medicine. The 5-year overall survival rate for children with ALL has improved from approximately 10% in the 1960s to greater than 90% with contemporary treatment regimens,^1-5 with almost all children who remain in remission for more than 4 years after completion of treatment considered “cured.”⁵ One of the key reasons for this remarkable achievement has been the enrollment of children with ALL in successive, prospective clinical trials seeking to refine our understanding of disease biology, including clinical, genetic, and response-based prognostic factors, and to optimize the use of known effective 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 including blinatumomab and chimeric antigen receptor [CAR] T cells), 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) many decades 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 of maintenance therapy.

As a treatment for children with ALL, 6MP was first tested in prospective clinical trials by Burchenal and colleagues⁶ in 1953. Forty-five children received oral 6MP, and remission periods of 2 to 9 weeks were demonstrated in 15 children. Since this initial experience, investigators have spent the past 63 years 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 prospective studies of dose, timing, length of 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 serial monitoring of the patient’s ANC, platelet count, and hepatic transaminases, with the most 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 therapy most commonly in response to ANC or platelet count outside of the target ranges. Titrating the dose of 6MP is clearly complex and requires a high level of monitoring, education, communication, and compliance. As a result, it is well known that achieving adherence to the 6MP therapy regimen by children, adolescents, and their parents is difficult. Key observations by investigators in the COG and others have clearly shown the negative impact of nonadherence to the 6MP treatment regimen, with an increased risk of relapse of ALL among nonadherent 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 patient outcomes of intra-individual 6MP systemic exposure during maintenance therapy.⁹ In this large prospective study of 742 children evaluated over a 6-month period during maintenance therapy, investigators evaluated the relationship between adherence, erythrocyte TGN levels, 6MP dose intensity, TPMT genotype, ANC, and the contribution of the factors to risk of relapse. Adherence was measured using an electronic monitoring device (TrackCap Medication Events Monitoring System; MWV Switzerland Ltd) that recorded the date and time of every 6MP bottle opening. Consistent with their prior studies, these investigators found that children who were not adherent to the prescribed 6MP regimen had a 2.7-fold increased risk of ALL relapse. The 6MP dose intensity and absolute TGN levels did not predict relapse risk in this study. However, patients with high intra-individual variability in TGN levels were at higher risk (cumulative incidence of relapse, 20% vs 7% for those with low TGN variability; P < .001).

One of the most striking findings of this study is that among 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 in drug delivery (OR, 10.2; P = .003). While pediatric oncologists will undoubtedly continue to struggle with how to make nonadherent children and adolescents adherent to their prescribed treatment, this study raises the provocative question of whether frequent dose adjustments during maintenance therapy, with resultant variable TGN levels, may be counterproductive in adherent patients. The results of this study will help to guide the development of future prospective clinical trials aimed at minimizing fluctuations in TGN levels, even among patients with high levels of adherence to therapy.

This unique study is being published at an opportune time. At his recent State of the Union Address and in a subsequent press release,¹⁰ President Obama announced his Precision Medicine Initiative. The objectives of this initiative, to be included in the President’s 2016 budget, are to develop more and better treatments for cancer, create a voluntary national research cohort, protect privacy, modernize regulation, and develop public-private partnerships. To achieve these goals, $215 million will be provided to the National Institutes of Health, National Cancer Institute, FDA, and Office of the National Coordinator for Health Information Technology. As defined in President Obama’s initiative, precision medicine is “an innovative approach to disease prevention and treatment that takes into account individual differences in people’s genes, environments, and lifestyles.”¹⁰ In the context of the development of better treatments for cancer, precision medicine is often synonymous with the development of new, innovative, expensive, and biologically targeted treatments that are increasingly directed toward specific patient populations and individuals. This strategic approach to new drug and cellular therapy development has already led to a number of spectacular successes and is likely to be the key approach to further improving the outcome for patients with cancer.

This is especially true for children with ALL, in whom improvements in outcome have started to slow after 6 decades of almost continuous progress.¹ New, innovative therapies that can be added to the current platform of highly effective, increasingly optimized chemotherapy will certainly be needed to further improve the cure rate for children with ALL. However, we must not lose sight of the fact that precision medicine also applies to optimizing known effective therapy. This study by the COG clearly demonstrates that even after 63 years of use and study on numerous prospective clinical trials, there is still an opportunity to improve how we use this old but highly effective and important drug. Put into the context of everyone’s current focus on precision medicine, it is clear that what is old is still very new.

Corresponding Author: Franklin O. Smith, MD, Medpace, 5375 Medpace Way, Cincinnati, OH 45227 (f.smith@medpace.com).

Published Online: March 26, 2015. doi:10.1001/jamaoncol.2015.0435.

Conflict of Interest Disclosures: None reported.