Mercaptopurine/Methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction

Abstract

The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients' ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens to improve therapy for the individual patient.

FIGURE 1

Distribution of mean prescribed 6-mercaptopurine (m6MP) doses during maintenance therapy (protocol starting oral dose: 75 mg/m²/d) for 538 patients included in the NOPHO ALL-92 maintenance therapy study. Means are based on a total of >28,000 registered drug doses and calculated by weighting each registered dose according to the time interval to the next measurement. The median m6MP dose for all patients is 59.4 mg/m²/d.

FIGURE 2

Distribution of mean white blood cell count (mWBC) and prescribed mean 6-mercaptopurine (m6MP) doses during maintenance therapy for 538 patients included in the NOPHO ALL-92 maintenance therapy study. Means are based on a total of >28,000 registered drug doses and blood counts and calculated by weighting each registration according to the time interval to the next registration. The median m6MP (59.4 mg/m²/d) and median mWBC (3.3×10⁹/L) are significantly correlated (r_S=0.20; P<0.001).

FIGURE 3

Simplified draft of 6-mercaptopurine (6MP) metabolism and methotrexate (MTX)-6MP interactions. DNA-TG indicates thioguanine nucleotides incorporated into DNA; GDP, guanosine diphosphate; GMP, guanosine monophosphate; GMPS, guanosine monophosphate synthetase; GTP, guanosine triphosphate: HGPRT, hypoxanthine guanine phosphoribosyl transferase; IMP, inosine monophosphate; IMPDH, inosine monophosphate dehydrogenase; ITP, inosine triphosphate; ITPA, inosine triphosphate pyrophosphatases; M+DPK, monophosphate and diphosphate kinases; MP, mercaptopurine; PDNS, purine de novo synthesis; TDP, thymidine diphosphate; TMP, thymidine monophosphate; TPMT, thiopurine methyltransferase; TTP, thymidine triphosphate; U, uridine monophosphate; XO, xanthine oxidase.

FIGURE 4

A, Mean white blood cell (mWBC) and absolute neutrophil counts (mANC) for 538 patients included in the NOPHO ALL-92 maintenance therapy study. Means are based on a total of >28,000 blood counts and calculated by weighting each measurement according to the time interval to the next measurement. Each dot represents 1 patient. mWBC and mANC are highly correlated (r_S=0.77; P<0.001). The target range for WBC was 1.5 to 3.5×10⁹/L in the NOPHO ALL92 protocol from which the data were retrieved. B, Kaplan-Meier relapse risk plots for patients with a mean absolute neutrophil count (mANC) at the end of maintenance therapy above or below 2.0×10⁹/L=median mANC for all patients (upper curve, N=248, relapse risk 23.5%±2.7%; lower curve, N=280, relapse risk 10.9%±1.9%; P<0.001). Mean absolute neutrophil counts during maintenance therapy are calculated by weighting each measurement according to the time interval to the next measurement.