The antifolate aminopterin (AMT) may offer clinical advantages over the related compound methotrexate (MTX), due to its pharmacodynamic and pharmacokinetic properties (
). These properties may lead to greater ease of administration and less pharmacodynamic variability than is seen with oral MTX. In our phase II trial, we demonstrated that AMT at its MTD (4 mg/m2/week in two doses, 12 h apart) had significant activity among children with relapsed/refractory ALL (
Cancer Chemother Pharmacol
). The phase IIB trial was conducted to test whether AMT can be safely incorporated at its MTD in multiagent therapy in place of oral MTX for children with newly diagnosed ALL at high risk (HR) of relapse by NCI criteria. The backbone of intensive antimetabolite-based therapy has been previously published (
Clin Cancer Res
). Thirty-three HR patients have been treated with AMT. With median follow up of 2.5 years, 2-yr EFS is 85% ± 7%. Seventeen have completed all planned therapy, and all have completed the Consolidation phase of weekly AMT at its MTD (along with mercaptopurine twice daily and intrathecal therapy every other week), allowing a description of the toxicity possibly attributable to AMT in the setting of multiagent ALL therapy. Oral AMT had complete bioavailability (compared to IV AMT kinetics on the Phase I and II trials). Bone marrow penetration by AMT, as indicated by steady state RBC AMT concentrations, is identical to that of MTX when MTX is given at 25-fold higher doses (100 mg/m2/week). During maintenance therapy, RBC AMT is proportional to the average weekly AMT dose, but was not predictive of hematologic toxicity. Hematologic toxicity among HR patients is similar to that observed among concurrent standard risk patients who receive identical therapy except for MTX in place of AMT and no delayed intensification. HR patients who are homozygous wild-type for both polymorphisms in the gene for methyl-tetrahydrofolate reductase (MTHFR C677T and A1298C) had higher mean neutrophil counts during weekly AMT therapy than those with one or more polymorphic allele (2687 ± 333, N=7 vs. 1613 ± 83, N=22; P<0.001). Patients homozygous for a polymorphism in methionine synthase reductase (MTRR G66A) had lower average neutrophil counts (P<0.01). Grade 3–4 mucositis has occurred in only 15% of HR patients during AMT therapy. HR patients were less likely to have grade 3–4 hepatotoxicity (SGPT elevation) than concurrent SR patients (28% vs 60%; P<0.05). Two of the first five HR patients experienced reversible grade 3–4 neurotoxicity during Consolidation. However, no grade 3–4 neurotoxicity attributable to AMT has occurred among the subsequent 28 patients, treated after a protocol amendment added leucovorin rescue after oral AMT (analogous to rescue given to patients receiving oral MTX;
Cancer Chemother Pharmacol
). In summary, AMT can be safely given to children with ALL in place of systemic MTX, with neither excessive toxicity nor risk of relapse. RBC AMT content is indicative of recent AMT exposure, and may be a useful tool for monitoring compliance. Functional polymorphisms in genes relevant to folate metabolism are predictive of AMT-induced toxicity, as is seen for MTX. The proper role for AMT in therapy for patients with ALL deserves further study. This well-tolerated therapy, centered on outpatient oral antimetabolite therapy may be especially suitable for adolescents and young adults with ALL.
Disclosure: No relevant conflicts of interest to declare.
2006, The American Society of Hematology