The Impact of Persistent Leukoencephalopathy on Brain White Matter Microstructure in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Chemotherapy Only

Abstract

Background and purpose: Survivors of acute lymphoblastic leukemia are at risk for neurocognitive deficits and leukoencephalopathy. We performed a longitudinal assessment of leukoencephalopathy and its associations with long-term brain microstructural white matter integrity and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a modern chemotherapy-only protocol.

Materials and methods: One hundred seventy-three survivors of acute lymphoblastic leukemia (49% female), treated on a chemotherapy-only protocol, underwent brain MR imaging during active therapy and repeat imaging and neurocognitive testing at follow-up (median, 13.5 years of age; interquartile range, 10.7-17.6 years; median time since diagnosis, 7.5 years; interquartile range, 6.3-9.1 years). Persistence of leukoencephalopathy was examined in relation to demographic and treatment data and to brain DTI in major fiber tracts and neurocognitive testing at follow-up.

Results: Leukoencephalopathy was found in 52 of 173 long-term survivors (30.0%) and persisted in 41 of 52 (78.8%) who developed it during therapy. DTI parameters were associated with leukoencephalopathy in multiple brain regions, including the corona radiata (fractional anisotropy, P = .001; mean diffusivity, P < .001), superior longitudinal fasciculi (fractional anisotropy, P = .02; mean diffusivity, P < .001), and superior fronto-occipital fasciculi (fractional anisotropy, P = .006; mean diffusivity, P < .001). Mean diffusivity was associated with neurocognitive impairment including in the genu of the corpus callosum (P = .04), corona radiata (P = .02), and superior fronto-occipital fasciculi (P = .02).

Conclusions: Leukoencephalopathy during active therapy and neurocognitive impairment at long-term follow-up are associated with microstructural white matter integrity. DTI may be more sensitive than standard MR imaging for detection of clinically consequential white matter abnormalities in childhood acute lymphoblastic leukemia survivors treated with chemotherapy and in children undergoing treatment.

Fig 1.

Examples of leukoencephalopathy grading. Left, mild hyperintensity in the bilateral periatrial white matter in this survivor of childhood ALL is compatible with grade 1 leukoencephalopathy according to the Common Terminology Criteria for Adverse Events (Version 4.0). Right, more extensive and confluent hyperintensity in the periventricular white matter that extends into the bilateral supraventricular frontoparietal white matter is considered grade 2 leukoencephalopathy.

Fig 2.

Leukoencephalopathy and white matter integrity. MD indicates mean diffusivity. Higher MD is indicative of worse white matter integrity. Point estimates represent the differences in white matter integrity between survivors with persistent leukoencephalopathy and survivors without a history of leukoencephalopathy within the global tracts listed on the x-axis. Error bars represent the 95% confidence intervals. The P values compare the MD between survivors with and without acute leukoencephalopathy using general linear modeling, adjusted for current age. All models have been corrected for the false discovery rate within the global tracts. The image shows that survivors with persistent leukoencephalopathy had reduced white matter integrity, demonstrated by higher global MD, in the corpus callosum, corona radiata, posterior thalamic radiations, superior longitudinal fasciculi, and superior fronto-occipital fasciculi. Details on the associations between leukoencephalopathy and lateralized diffusion tensor imaging measures within the specific tracts can be found in On-line Table 2.

Fig 3.

Association between white matter integrity and global neurocognitive impairment. Black circles represent survivors with global neurocognitive impairment. White circles represent survivors without global neurocognitive impairment. Global neurocognitive impairment is defined as having ≥2 neurocognitive tests (listed in On-line Table 3) that fall >1.5 SDs or 1 test that falls >2 SDs below the age-adjusted population normative data. The y-axis represents mean diffusivity. Higher mean diffusivity is indicative of worse white matter integrity. Error bars represent the 95% confidence intervals. P values compare the mean diffusivity between survivors with neurocognitive impairment (closed circle, n = 63) and without neurocognitive impairment (open circle, n = 87) using general linear modeling, adjusted for current age. The image shows that survivors with neurocognitive impairment had reduced white matter integrity demonstrated by higher global mean diffusivity in the corona radiata and superior fronto-occipital fasciculus. Details on the associations between global neurocognitive impairment and lateralized diffusion tensor imaging measures within the specific tracts can be found in On-line Table 4.