Prevalence of leukoencephalopathy in children treated for acute lymphoblastic leukemia with high-dose methotrexate

Abstract

Background and purpose: An effective treatment for acute lymphoblastic leukemia (ALL), intravenous (IV) methotrexate (MTX) has a notable toxic effect on the CNS, with leukoencephalopathy (LE) being the most common form. The purpose of this study was to use objective quantitative MR imaging to prospectively assess potential risk factors on the temporal evolution of LE in patients treated for ALL.

Methods: We evaluated the longitudinal prevalence of LE in 45 children treated for ALL in a single institutional protocol including seven courses of IV MTX and no cranial irradiation. Differences in signal intensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images between hyperintense regions and normal-appearing genu were used to quantitatively detect LE. Cox proportional regression was used to estimate the effect of covariates (e.g., sex, MTX dose, age at diagnosis) on the prevalence of LE. After influential factors were identified, a generalized linear model was determined to predict the probability of LE in new patients. The model was necessary to facilitate statistical testing between examinations.

Results: Increasing exposure, which corresponding to more courses and higher doses of IV MTX, influenced the prevalence of LE. The prevalence of LE was significant reduced approximately 1.5 years after the completion of IV MTX.

Conclusion: Higher doses and more courses of IV MTX placed patients at a higher risk for LE; many of the changes resolved after the completion of therapy. The effect of these changes on neurocognitive functioning and quality of life in survivors remains to be determined.

Fig 1.

T1-, T2-, and proton density–weighted and FLAIR images (left to right) from a typical examination. LE can be seen in the white matter posterior to the ventricles.

Fig 2.

Cumulative risk for LE as a function of time since diagnosis. Solid line represents patients in the standard- and high-risk treatment arm; dashed line, those in the low-risk treatment arm.

Fig 3.

Observed prevalence of LE in patients in the standard- or high-risk arm (gray bars) and patients in the low-risk arm (black bars) of the treatment protocol.

Fig 4.

Predicted probability of LE according to the general linear model for patients in the standard- or high-risk arm (gray bars) and patients in the low-risk arm (black bars) of the treatment protocol.

Fig 5.

FLAIR images from a typical examination. Left to right, Sections after one course, four courses, and seven courses of high-dose IV MTX therapy; at the end of therapy; and at 2 years after the completion of therapy. A, Transient LE. Although the first image is normal, the second and third show LE, which resolves by the fourth and remains normal on the final image. B, Persistent LE. First image is normal, but all others, including the 2-year follow-up image, show LE.