High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphatic leukemia

To the editor:

May I suggest that the ALL-REZ BFM 90 study published recently in Blood¹  may be interpreted differently from that presented?

The study results are not unexpected (no improvement in cure rate with either dose) because both doses of methotrexate (MTX) used were suboptimal. A cerebral spinal fluid (CSF) level of 1 molar is usually accepted as the required effective level in newly diagnosed ALL obtainable with 5 g/m² intravenous MTX and additional intrathecal MTX.²  But as the authors themselves state, for relapsed lymphocytic leukemia as studied here a 3-fold higher resistance to MTX has been described. Therefore there is no reason to expect that 1 or 5 g/m² intravenous MTX with 12 mg intrathecal MTX would have an effect on long-term results.

The authors did not perform analysis of the toxicity data, but other studies that used similar doses have been examined. The doses of folinic acid used (30 mg/m² after 1 g/m² intravenous MTX plus intrathecal MTX and 45 mg/m² intravenous MTX after 5 g/m² intravenous MTX plus intrathecal MTX) have caused significant neurotoxicity. More than 8% of patients had neurotoxicity when 25 mg/m² of folinic acid was given after 1 g/m² MTX.³  A dose of 45 mg/m² was adequate to prevent neurotoxicity after 1 g/m² intravenous MTX together with intrathecal MTX.⁴ l-folinic acid (37.5 mg/m², equivalent to approximately 75 mg/m² folinic acid) resulted in neurotoxicity in 5.8% of children after 5 g/m² MTX.⁵ 

A promise of improved prognosis by reducing the folinic acid dose was suggested by Borsi et al,⁶  who showed a trend (but no statistical significance) toward better prognosis when less than 315 mg/m² folinic acid was given after 6 to 8 g/m² MTX: hardly justification for reducing the folinic acid dose to 15% of this critical value. Folic acid doses have been reduced again and again by the Berlin-Frankfurt-Munster (BFM) group in successive studies until the doses used here have been reached, by simply ignoring neurotoxicity. Neurotoxicity has been avoided with adequate folinic acid even with doses as high as 33.6 g/m² MTX.⁷  Recently others have based claims that increasing the dose of folinic acid lowers cure rate on a rather flimsy base. The MTX and folinic acid doses were examined in 4 risk groups. The folinic acid levels were higher in relapsing patients in 2 groups and lower in the other 2: hardly convincing evidence!⁸  Not all groups feel high- or intermediate-dose MTX is needed to treat ALL, and recently gene expression profiling seems to explain the lack of a consistent response to MTX.⁹  However when MTX is used, the conclusion from this study should be that MTX doses be increased in future studies rather than reduced to 1 g/m². “Minimal” dose folinic acid failed to improve prognosis and so this approach should be abandoned and appropriate doses that do not cause neurotoxicity should be adopted, such as 180 mg/m² folinic acid after 8 g/m² MTX.¹⁰  I would suggest that a randomized study be performed comparing the toxicity and efficacy of “minimal” and “appropriate” doses of folinic acid after high-dose MTX to end this very deep controversy.