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Research ArticlePediatrics
Open Access

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

N.D. Sabin, Y.T. Cheung, W.E. Reddick, D. Bhojwani, W. Liu, J.O. Glass, T.M. Brinkman, S.N. Hwang, D. Srivastava, C.-H. Pui, L.L. Robison, M.M. Hudson and K.R. Krull
American Journal of Neuroradiology October 2018, 39 (10) 1919-1925; DOI: https://doi.org/10.3174/ajnr.A5791
N.D. Sabin
aFrom the Departments of Diagnostic Imaging (N.D.S., W.E.R., J.O.G., S.N.H.)
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Y.T. Cheung
bEpidemiology and Cancer Control (Y.T.C., T.M.B., L.L.R., M.M.H., K.R.K.)
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W.E. Reddick
aFrom the Departments of Diagnostic Imaging (N.D.S., W.E.R., J.O.G., S.N.H.)
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D. Bhojwani
fChildren's Center for Cancer and Blood Diseases (D.B.), Children's Hospital Los Angeles, Los Angeles, California.
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W. Liu
cBiostatistics (W.L., D.S.)
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J.O. Glass
aFrom the Departments of Diagnostic Imaging (N.D.S., W.E.R., J.O.G., S.N.H.)
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T.M. Brinkman
bEpidemiology and Cancer Control (Y.T.C., T.M.B., L.L.R., M.M.H., K.R.K.)
dPsychology (T.M.B., K.R.K.)
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S.N. Hwang
aFrom the Departments of Diagnostic Imaging (N.D.S., W.E.R., J.O.G., S.N.H.)
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D. Srivastava
cBiostatistics (W.L., D.S.)
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C.-H. Pui
eOncology (C.-H.P., M.M.H.), St. Jude Children's Research Hospital, Memphis, Tennessee
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L.L. Robison
bEpidemiology and Cancer Control (Y.T.C., T.M.B., L.L.R., M.M.H., K.R.K.)
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M.M. Hudson
bEpidemiology and Cancer Control (Y.T.C., T.M.B., L.L.R., M.M.H., K.R.K.)
eOncology (C.-H.P., M.M.H.), St. Jude Children's Research Hospital, Memphis, Tennessee
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K.R. Krull
bEpidemiology and Cancer Control (Y.T.C., T.M.B., L.L.R., M.M.H., K.R.K.)
dPsychology (T.M.B., K.R.K.)
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    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.

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    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.

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    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.

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    Table 1:

    Demographics and treatment characteristics (N = 173)

    No. (%)Mean (SD)Median (IQR)
    Demographics
        Sex
            Male89 (51)
            Female84 (49)
        Race/ethnicity
            White124 (72)
            Asian3 (2)
            Black21 (12)
            Hispanic18 (10)
            Others7 (4)
        Current age (yr)14.4 (4.6)13.5 (10.7–17.6)
        Patient's highest education (yr)7.7 (3.9)7.0 (4.0–11.0)
        Maternal education (yr)13.6 (2.5)13.0 (12.0–16.0)
        Paternal education (yr)13.6 (3.1)12.0 (12.0–16.0)
    Treatment characteristics
        Age at diagnosis (yr)6.7 (4.3)5.3 (3.5–8.6)
        Time since diagnosis (yr)7.7 (1.8)7.5 (6.3–9.1)
    Treatment risk stratum
            Low102 (59)
            Standard71 (41)
    Chemotherapy dosesa
        Oral dexamethasone (mg/m2)1096.4 (303.2)1099.9 (985.3–1246.1)
        IV high-dose cytarabine (g/m2)8.5 (3.5)8.0 (8.0–8.0)
        IV leucovorin (mg/m2)343.5 (207.1)300.0 (220.0–390.0)
        IV high-dose methotrexateb (g/m2)15.4 (6.7)14.2 (11.4–19.0)
        IT MHA (No. of counts)14.4 (4.0)13.0 (12.0–16.0)
    • Note:—IQR indicates interquartile range; IT MHA, intrathecal injection of methotrexate plus hydrocortisone plus cytarabine.

    • ↵a Except for IT MHA, all drug doses are presented as cumulative doses (g/m2 or mg/m2).

    • ↵b High-dose IV methotrexate was defined as a daily dose of >1 g/m2 of IV methotrexate.

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    Table 2:

    Association between methotrexate and white matter integritya

    TractsIntrathecal MHAbHigh-Dose Methotrexateb
    Mean DiffusivityFractional AnisotropyMean DiffusivityFractional Anisotropy
    Est.SEPEst.SEPEst.SEPEst.SEP
    Corpus callosum0.00170.0008.04c−0.00090.0007.21−0.00030.0005.600.00060.0004.17
        Genu0.00160.0009.07−0.00150.0012.21−0.00010.0005.82−0.00020.0007.76
        Body0.00080.0010.450.00000.0009.99−0.00080.0006.210.00110.0005.05
        Splenium0.00220.0011.04c−0.00110.0007.130.00000.0006.950.00070.0004.09
    Corona radiata0.00140.0007.04c−0.00040.0005.36−0.00030.0004.440.00020.0003.57
        Anterior (left)0.00170.0009.06−0.00100.0005.06−0.00020.0005.73−0.00010.0003.75
        Anterior (right)0.00110.0009.19−0.00050.0006.41−0.00050.0005.310.00010.0003.78
        Superior (left)0.00130.0005.02c0.00030.0007.70−0.00010.0003.690.00040.0004.33
        Superior (right)0.00150.0005.005c−0.00030.0007.66−0.00020.0003.580.00020.0004.53
        Posterior (left)0.00090.0007.230.00030.0007.65−0.00070.0004.080.00070.0004.12
        Posterior (right)0.00160.0007.02c−0.00020.0007.79−0.00030.0004.420.00020.0004.58
    Posterior thalamic radiation0.00150.0007.03c−0.00030.0007.630.00000.0004.940.00070.0004.11
        Left0.00110.0010.290.00000.0008.98−0.00030.0006.650.00090.0005.05
        Right0.00180.0006.003c−0.00060.0007.420.00010.0004.690.00050.0004.24
    Superior longitudinal fasciculus0.00070.0005.160.00060.0005.25−0.00010.0003.750.00050.0003.14
        Left0.00060.0005.220.00080.0006.16−0.00010.0003.610.00040.0003.30
        Right0.00070.0005.130.00050.0006.410.00000.0003.870.00060.0003.10
    Superior fronto-occipital fasciculus0.00200.0009.02c−0.00040.0009.65−0.00030.0005.600.00090.0005.09
        Left0.00210.0010.04c−0.00040.0009.63−0.00050.0006.410.00090.0005.10
        Right0.00190.0007.01c−0.00030.0010.730.00000.0005.970.00080.0006.14
    • Note:—Est. indicates parameter estimate; SE, standard error; MHA, methotrexate plus hydrocortisone plus cytarabine.

    • ↵a General linear modeling was applied for the test of strength of association between treatment variables with mean diffusivity and fractional anisotropy for each tract, adjusted for age at evaluation. Higher mean diffusivity and lower fractional anisotropy are indicative of worse white matter integrity.

    • ↵b Intrathecal MHA was defined as the number of intrathecal injections of methotrexate plus hydrocortisone plus cytarabine; high-dose IV methotrexate was defined as a daily dose of >1 g/m2, presented as cumulative doses (g/m2).

    • ↵c Significant.

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American Journal of Neuroradiology: 39 (10)
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N.D. Sabin, Y.T. Cheung, W.E. Reddick, D. Bhojwani, W. Liu, J.O. Glass, T.M. Brinkman, S.N. Hwang, D. Srivastava, C.-H. Pui, L.L. Robison, M.M. Hudson, K.R. Krull
The Impact of Persistent Leukoencephalopathy on Brain White Matter Microstructure in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Chemotherapy Only
American Journal of Neuroradiology Oct 2018, 39 (10) 1919-1925; DOI: 10.3174/ajnr.A5791

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The Impact of Persistent Leukoencephalopathy on Brain White Matter Microstructure in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Chemotherapy Only
N.D. Sabin, Y.T. Cheung, W.E. Reddick, D. Bhojwani, W. Liu, J.O. Glass, T.M. Brinkman, S.N. Hwang, D. Srivastava, C.-H. Pui, L.L. Robison, M.M. Hudson, K.R. Krull
American Journal of Neuroradiology Oct 2018, 39 (10) 1919-1925; DOI: 10.3174/ajnr.A5791
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