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Phase IIB Trial of Aminopterin in Multiagent Therapy for Children with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) at High Risk of Relapse

Authors :
Barton A. Kamen
Angela K. Smith
John Glod
Margaret Masterson
Peter D. Cole
Richard A. Drachtman
Source :
Blood. 108:1860-1860
Publication Year :
2006
Publisher :
American Society of Hematology, 2006.

Abstract

The antifolate aminopterin (AMT) may offer clinical advantages over the related compound methotrexate (MTX), due to its pharmacodynamic and pharmacokinetic properties (Cancer Chemother Pharmacol2006;57:826). 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 (Clin Cancer Res2005; 11: 8089). 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 (JCO1996;14:2803, Cancer Chemother Pharmacol2006;57:826). 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

Details

ISSN :
15280020 and 00064971
Volume :
108
Database :
OpenAIRE
Journal :
Blood
Accession number :
edsair.doi...........78582158af2d5b88e85b4b5e1701b7c0