Reinforcing natural killers.

weight to a finding published a decade ago by the group at St Jude Children’s Research Hospital. That finding stated that patients with low TPMT activity receiving 6-MP in combination with radiotherapy have increased risk of SMNs.6 The paper leaves many questions unanswered. Whether this association is caused by 6-MP therapy alone or whether high-dose MTX given along with 6-MP in maintenance contributes to the incidence of SMNs is unclear. Increased risk of SMNs in the NOPHO cohort is further associated with high hyperdiploidy, and the type of SMNs that occur differs from other reports, with a high incidence of tAML/MDS with aberrations of chromosomes 5 or 7. Although the authors speculate on reasons for these observations, the mechanisms behind these findings have yet to be elucidated. Finally, what other groups should do with the observations presented here is unclear. The NOPHO group initiated genotypic and phenotypic screening for lowactivity TPMT polymorphisms in 2001, lowering 6-MP maintenance dosing from 75 to 50 mg/m2 when low TPMT activity patients are detected by their screen. It is too soon to know whether this intervention has decreased SMNs. The approaches of other groups vary in dosing levels and length of administration of 6-MP, and an association of SMNs with different dosing schemes has yet to be described. These questions aside, this work provides convincing evidence that high dose levels or poorly methylated 6-MP in the context of extended maintenance with methotrexate is associated with SMNs. It poses a challenge to either identify patients at increased risk, or identify methods of administration of 6-MP that minimize or eliminate risk of SMNs without sacrificing ALL treatment efficacy. Conflict-of-interest disclosure: The author declares no competing financial interests. ■