New Light on an Old Drug

As excitement surrounding new agents and immunotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL) develops, there may be a tendency to overlook the importance of medications that have been a backbone of ALL therapy since effective treatments were first developed. Mercaptopurine (MP) has been a mainstay of ALL therapy since the early 1950s,¹  and prolonged daily administration during the maintenance phase of treatment is routine practice. Why a prolonged maintenance phase is so critical for the cure of ALL is not understood.

In recent years, there have been several different lines of evidence highlighting the essential role of this component of ALL treatment. Namely, the prognostic importance of maintaining MP dose intensity through adequate chronic daily exposure during maintenance has been demonstrated in several studies. Low levels of active MP metabolites and dosing interruptions have been associated with relapse risk and shown to negatively impact outcomes.^2,3  Dr. Smita Bhatia and colleagues also recently reported a 3.9-fold increased risk of relapse with less than 90 percent adherence to MP in a multiracial cohort of children.⁴  Finally, another line of evidence regarding the importance of MP in maintenance therapy is that activating mutations in NT5C2, which confer resistance to thiopurines, are among the most common mutations noted at the time of disease recurrence.^5,6 

Tolerance to the adverse effects of MP is another important factor for optimizing treatment delivery. Protocols commonly specify dosing modifications for myelosuppression, and achieving adequate MP dosing without frequent treatment interruptions, which can negatively impact outcomes, can be a challenge for some patients. Previous studies have demonstrated that genetic variation in thiopurine methyltransferase (TPMT) is a major contributing factor to MP intolerance.^7,8 TPMT is an enzyme responsible for the methylation and inactivation of MP, and testing for inherited nonfunctional alleles has allowed MP dosing adjustments to achieve therapeutic benefit and/or to avoid excessive toxicity. While inherited deficiencies of TPMT lead to higher levels of active thiopurine metabolites and hematologic toxicity, MP intolerance is observed in many children with wild-type TPMT as well.

Following up on these observations, Dr. Jun Yang and colleagues investigated the genetic basis of inter-patient and inter-racial/interethnic variability in MP tolerance in children at the genome-wide level.⁹  A genome-wide association study (GWAS) was performed in two prospective clinical trials for childhood ALL. The discovery GWAS cohort consisted of 657 children treated on Children’s Oncology Group ALL protocols where there were specifications for dosing adjustments for myelosuppression. The replication cohort consisted of 371 children with ALL treated on St. Jude Children’s Research Hospital protocols. The authors reported that East Asian ancestry was significantly associated with lower MP dose intensity (p < 0.001; Figure). In the discovery GWAS, in addition to variants in TPMT, a germline variant in nucleoside diphosphate–linked moiety X-type motif 15 (NUDT15) was also strongly linked to MP intolerance in East Asian children. Patients with homozygous TT genotype were extremely sensitive to MP and tolerated only 8.3 percent of the scheduled MP dose. Defective NUDT15 is hypothesized to lead to accumulation of an excessive amount of the cytotoxic thio-dGTP metabolite with normal doses of MP. The association of these risk alleles in TPMT and NUDT15 with MP dose intensity was confirmed in the validation cohort. Notably, the risk allele in NUDT15 varied by race and ethnicity and was most common in East Asians (9.8%), followed by Hispanics (3.9%). In contrast, it was very rare in Europeans, occurring in only 0.2 percent of cases. Taken together, the higher frequency of the NUDT15 germline variant in East Asians suggested this could be a contributory factor to higher rates of MP intolerance in this group.