Maintenance
therapy containing
methotrexate and 6-mercapto -
purine is essential to cure
acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of
thioguanine nucleotides into
DNA (
DNA-TG), and higher leukocyte
DNA-TG is associated with increased relapse-free survival. As
6-thioguanine provides 6- fold higher cytosolic levels of
thioguanine nucleotides than does 6- mercapto
purine, we added low-dose
6-thioguanine to
methotrexate/6- mercapto
purine maintenance
therapy to explore if this combination results in significantly higher
DNA-TG. The target population of the "
Thiopurine Enhanced ALL Maintenance
therapy" (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on
methotrexate/
6-mercaptopurine maintenance
therapy receiving no other systemic
chemotherapy. Incremental doses of
6-thioguanine were added to
methotrexate/
6-mercaptopurine maintenance
therapy (starting
6-thioguanine dose: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). The primary endpoint was
DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance
therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as the maximum
6-thioguanine dose. TEAM resulted in significantly higher
DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mg
DNA higher [95% confidence interval: 160-341; P<0.0001]), and with historical patients receiving standard
methotrexate/6-mercapto -
purine maintenance
therapy (on average 272 fmol/mg
DNA higher [95% confidence interval: 147-398; P<0.0001]). TEAM did not increase myelotoxicity or hepatotoxicity. In conclusion, TEAM is an innovative and feasible approach to improve maintenance
therapy and results in higher
DNA-TG levels without inducing additional toxicity. It may therefore be an effective strategy to reduce the risk of ALL relapse through increased
DNA-TG. This will be tested in a randomized ALLTogether-1 substudy.