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\begin{document}

\title{Central nervous system complications and white matter lesions by brain
MRI in pediatric hematological malignancies}



\author[1]{Minako Sugiyama}%
\author[1]{Shinsuke Hirabayashi}%
\author[2]{Yukayo Terashita}%
\author[1]{Yuko Cho}%
\author[1]{Akihiro Iguchi}%
\author[1]{Atsushi Manabe}%
\affil[1]{Hokkaido University Graduate School of Medicine}%
\affil[2]{Hokkaido University Graduate School of Medicine School of Medicine}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\selectlanguage{english}
\begin{abstract}
Several central nervous system complications in pediatric patients with
hematological malignancies have been reported. We analyzed the frequency
and the correlation with central nervous system involvement and
intrathecal therapy. The frequency was 13 \% (11/85), being almost equal
to those in literature. We investigated high intensity areas, which
indicated leukoencephalopathy, in the white matter by T2-weighted and/or
fluid attenuated inversion recovery images (FLAIR) of the brain magnetic
resonance imaging (MRI). Incidence of white matter lesions was higher in
patients who received over 10 times of intrathecal therapy (p = 0.018).
Patients who received repetitive intrathecal therapy should undergo
close MRI to find out if they need cognitive functioning test. However,
it may be possible to omit brain MRI in patients with acute myeloid
leukemia and lymphoma who have received intrathecal therapies less than
five times in a consideration of their burden in terms of sedation and
cost.%
\end{abstract}%



\sloppy


\textbf{Central nervous system complications and white matter lesions by
brain MRI in pediatric hematological malignancies}

Minako Sugiyama, MD, PhD\textsuperscript{1*}, Shinsuke Hirabayashi, MD,
PhD\textsuperscript{1}, Yukayo Terashita, MD, PhD\textsuperscript{1},
Yuko Cho, MD, PhD\textsuperscript{1}, Akihiro Iguchi, MD,
PhD\textsuperscript{1}, Atsushi Manabe, MD, PhD\textsuperscript{1}

\textsuperscript{1} Department of Pediatrics, Hokkaido University
Hospital, Sapporo, Japan

\textsuperscript{*} Correspondence to:

Minako Sugiyama, MD, PhD, Department of Pediatrics, Hokkaido University
Hospital, N15W7, Kita-ku Sapporo, 060-8638, Japan.

TEL:81-011-706-5954

E-mail: \emph{s-minako@huhp.hokudai.ac.jp}

Text word count: 1,949

Abstract word count: 218

Brief running title: CNS complications in pediatric ALL

Key words: white matter lesions, CNS complications, pediatric
hematological malignancy, brain MRI, intrathecal therapy

Tables: 3

Figures: 1

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

Abbreviations\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
ALL & acute lymphoblastic leukemia\tabularnewline
AML & acute myeloid leukemia\tabularnewline
BCP-ALL & B-cell precursor acute lymphoblastic leukemia\tabularnewline
HL & hodgkin lymphoma\tabularnewline
NHL & non-hodgkin lymphoma\tabularnewline
CNS & central nervous system\tabularnewline
HSCT & Hematopoietic stem cell transplantation\tabularnewline
MRI & magnetic resonance imaging\tabularnewline
FLAIR & fluid attenuated inversion recovery\tabularnewline
ICH & intracranial hemorrhage\tabularnewline
HHV6 & human herpes virus type 6\tabularnewline
PRES & posterior reversible encephalopathy syndrome\tabularnewline
WML & white matter lesion\tabularnewline
IT & intrathecal therapy\tabularnewline
\bottomrule
\end{longtable}

\textbf{Abstract}

\textbf{Background}

Several central nervous system complications in pediatric patients with
hematological malignancies have been reported. And these complications
may limit the quality of life of the patients and lead to fatal outcome.

\textbf{Procedure}

We analyzed the frequency and the correlation with central nervous
system involvement and intrathecal therapy. In addition, we investigated
brain magnetic resonance imaging findings of the patients with
hematological malignancies after intensive chemotherapy or hematopoietic
stem cell transplantation. We focused on high intensity areas in the
white matter by T2-weighted and/or fluid attenuated inversion recovery
image, which indicated leukoencephalopathy.

\textbf{Results}

The frequency of central nervous complications was 13 \% (11/85), being
almost equal to those in literature. We investigated high intensity
areas, which indicated leukoencephalopathy, in the white matter by
T2-weighted and/or fluid attenuated inversion recovery images of the
brain magnetic resonance imaging. Incidence of white matter lesions was
higher in patients who received over 10 times of intrathecal therapy
(\emph{p} = 0.018).

\textbf{Conclusions}

Patients who received repetitive intrathecal therapy should undergo
close magnetic resonance imaging to find out if they need cognitive
functioning test. However, it may be possible to omit brain magnetic
resonance imaging in patients with acute myeloid leukemia and lymphoma
who have received intrathecal therapies less than five times in a
consideration of their burden in terms of sedation and cost.

\textbf{Introduction}

It is important for pediatricians to predict the risk of central nervous
system (CNS) complications in patients who suffer from hematological
malignancies. Various CNS complications have been
reported,\textsuperscript{1,2} including intracranial hemorrhage
(ICH),\textsuperscript{3} human herpes virus type 6 (HHV6)-associated
encephalitis,\textsuperscript{4} and posterior reversible encephalopathy
syndrome (PRES),\textsuperscript{5,6} and they are more prominent in
those receiving hematopoietic stem cell transplantation
(HSCT).\textsuperscript{7} However, even after chemotherapy only, these
complications may lead to fatal outcome, or they will influence the
patient's quality of life for a long time. Moreover, Bhojwani, et al.
reported that 20.6\% of asymptomatic patients with acute lymphoblastic
leukemia (ALL) had evidence of leukoencephalopathy on brain magnetic
resonance imaging (MRI).\textsuperscript{8}

In children with hematological malignancies, we investigated the
frequency of CNS complications during chemotherapy, the possible courses
such as CNS involvement at diagnosis, and the intensity of intrathecal
therapy (IT). In addition, we performed brain MRI for the patients with
hematological malignancies after intensive chemotherapy or HSCT. We
focused on high intensity areas in the white matter by T2-weighted
and/or fluid attenuated inversion recovery (FLAIR) image, which
indicated leukoencephalopathy as a consequence of demyelination or
edema.

\textbf{Methods}

All the patients who received chemotherapy and/or stem cell
transplantation for hematological malignancies between January 2011 and
December 2018 at the department of Pediatrics, Hokkaido University
Hospital, Children's Cancer Center. We obtained their clinical
information from their medical records. The frequency of central nervous
system infiltration at diagnosis, the intensity of IT, and CNS
complications of \textgreater{}grade 2 according to the common
terminology criteria for Adverse Events version 5.0. High intensity
areas in the white matter were evaluated by T2 and/or FLAIR image of
brain MRI (Fig.1). MRI was taken before maintenance chemotherapy, after
HSCT or intensive chemotherapy. Transient coma and seizure caused with
metabolic changes were not defined as CNS complications. We had an
agreement of a clinical research review board of our institution and
publicized the study through a website.

\textbf{Statistical analysis}

The statistical analysis was carried out using the Fisher's exact
probability test. Each test was performed with a 5\% level of
significance.

\textbf{Results}

\textbf{Patient characteristics}

In total, 85 (55 males and 30 females) patients with hematological
malignancies received chemotherapy and/or stem cell transplantation
during the period at our institution (Table 1). The median age at
diagnosis was 6 years ranging from 6 months to 15 years. Forty-three of
the 85 patients had ALL (B-precursor ALL, n = 32; T-ALL, n = 3; infant
ALL with MLL gene rearrangement, n = 4; Ph1+ALL, n = 3; mature B-ALL, n
= 1), and 21 patients had acute myeloid leukemia (AML) (AML in
non-Down's syndrome, n = 15; acute megakaryoblastic leukemia in Down's
syndrome, n= 6). Nine patients had non-Hodgkin lymphoma (NHL) and 7
patients had Hodgkin lymphoma (HL). Two patients with blastic
plasmacytoid dendritic cell neoplasm, a patient with myeloid sarcoma, a
patient with chronic myeloid leukemia (CML), and a patient with juvenile
myelomonocytic leukemia (JMML) who received chemotherapy were also
included. Twenty-one of the 85 patients received 28 allogeneic HSCT and
1 autologous HSCT. CNS involvement at diagnosis was noticed in 9
patients: B-precursor ALL, n = 4; T-ALL, n = 1; infant ALL with MLL gene
rearrangement, n = 1; Ph1+ALL, n = 1; and NHL, n = 2).

\textbf{Intrathecal therapy}

Lumbar puncture was not performed in patients with acute
megakaryoblastic leukemia in Down's syndrome, a patient with CML, and a
patient with JMML. Intrathecal therapy was administered over 5 times in
67 of the 85 patients, and it was over 10 times in 44 patients before
brain MRI. Sixteen patients received total body irradiation at over 8Gy
or whole-brain irradiation at 12 Gy.

\textbf{CNS complications}

CNS complications occurred in 11 patients during hospitalization
(12.9\%) (Table 2). Two of the 11 patients experienced HHV6-associated
encephalitis after HSCT. Three had ICH, two of whom experienced this
complication before the initiation of chemotherapy. Two patients with
ALL had severe depression induced by dexamethasone, and other two had
PRES during induction-chemotherapy. One patient with ALL had intrathecal
methotrexate (MTX)-associated encephalopathy during
maintenance-chemotherapy, and the other one patient with HL had cerebral
venous thrombosis during the chemotherapy, which included prednisolone
but no L-asparaginase. Except for the two patients who experienced ICH
before the initiation of chemotherapy, only two of the remaining nine
patients were evaluated as CNS2 at the time of diagnosis (22.2\%). In
patients who did not have CNS involvement initially, 7 of the 74
patients suffered from CNS complications later (9.5\%). The frequency of
the CNS complications was lower in patients without CNS involvement
(9.2\%). Three patients suffered from CNS complications after HSCT. The
frequency of the CNS complications was not higher in patients who
received HSCT (14.3\%). Serious neurological symptoms persisted in a
patient with HHV6 encephalitis and another with ICH after HSCT. All the
other nine patients with CNS complications recovered, with no severe
sequelae. A patient with ICH and two patients with PRES died of chronic
graft-versus-host disease (GVHD) after HSCT.

Twelve of the eighty-five patients died (14.1\%). Seven of the 12
patients died of their original diseases, and five patients including
three patients with CNS complications died of treatment-related
complications. The occurrence of CNS complications was not related with
the prognosis (\emph{p} = 0.18).

\textbf{White matter lesions in brain MRI}

Seventy patients received brain MRI after HSCT and intensive
chemotherapy (82.4\%) (Table 3), while MRI was not carried out in the
remaining 15 patients (B-precursor ALL, n = 9; CML, n = 1; AML in
non-Down's syndrome, n = 2; HL, n = 3). White matter lesions in the
white matter by T2 and/or FLAIR image were revealed in 14 patients of
the 70 patients (20.0\%) who underwent brain MRI. Eleven of the 14
patients (78.6\%) received over 10 times of IT. Eleven of the 35
patients who underwent brain MRI with over 10 times of IT had white
matter lesions (WMLs) (31.4\%). One of the 23 patients who underwent
brain MRI with over 5 times of the IT had WMLs (4.3\%). Two of the 12
patients who underwent brain MRI without IT had WMLs (16.7\%). In
patients who received over 10 times of IT, the incidence of WMLs was
higher than the patients with IT less than 5 times and the patients
without IT (\emph{p} = 0.018). Anyone did not need additional
examination or treatments in association with the WMLs.

For 57 patients who visited our department regularly after discharge,
the median period of follow-up after the end of chemotherapy was 56
months (range of 14-110 months). Except for 11 patients with CNS
complication during hospitalization, 2 patients showed symptoms of
depression after completion of the chemotherapy. One of them had WML
around the lateral cerebral ventricle by T2 and FLAIR image.

\textbf{Discussion}

CNS involvement in pediatric hematological malignancies are associated
with a poor prognosis.\textsuperscript{9} It is not clear whether CNS
involvement predisposes the patients to develop severe CNS complications
later.\textsuperscript{1,2} In the current study, the frequency of CNS
complications was nearly equal to what has been previously published,
though only 2 of our patients had received cranial
irradiation.\textsuperscript{2} Recently, cranial irradiation tends to
be avoided even in a patient with CNS
involvement.\textsuperscript{9,10}However, it may not result in a
decrease in CNS complications. Two patients who suffered PRES died of
chronic GVHD. It has been reported that even PRES is not a transient
disorder, and the patients who had experienced PRES need continuous
observation because they often need antiepileptic
agents.\textsuperscript{6} In addition, CNS complications in pediatric
HSCT recipients with neurologic sequelae and extensive chronic GVHD had
significant risk for mortality.\textsuperscript{7}Therefore, it is
important to identify the risk factors associated with these CNS
complications in order to prevent them.

In patients receiving chemotherapy, WMLs which suggest
leukoencephalopathy have been reported even if they did not suffer from
CNS complications.\textsuperscript{8,11,12,13} During chemotherapy for
ALL, 20.6\% of asymptomatic patients had evidence of leukoencephalopathy
on brain MRI.\textsuperscript{8} Higher cumulative number of IT was
associated with increased risk of leukoencephalopathy. And the ratio of
42-hour plasma MTX concentration to leucovorin dose at the first course
of high-dose (HD)-MTX retained significance in a multivariable analysis.
When we analyzed the frequency of WMLs, it was not higher in the
patients with CNS involvement. Notably, WMLs increased in patients who
received over 10 times of IT. Although WMLs have been considered as a
result of blood vessel impairment \textsuperscript{14}, it was reported
that the polymorphism of 13 genes involved in inflammation-related
pathways were significantly associated with WMLs in
adults.\textsuperscript{15} It suggested that WML is a consequence of
not so much CNS involvement but the inflammation, which may be caused by
repetitive IT. However, we observed that our two patients without CNS
involvement or IT had WMLs. Only intravenous or oral chemotherapies may
also cause inflammation which induces WMLs. HSCT had not increased the
frequency of WMLs. It suggested that the intensity of chemotherapies did
not correlate with the predisposition toward WMLs. In addition, the
association of polymorphism and MTX-related leukoencephalopathy has been
reported,\textsuperscript{8,16} This also sustains the high frequency of
WMLs observed in patients with ALL who received repetitive HD-MTX in the
present study. The minor allele CC genotype of rs2298383,\emph{ADORA2A}
, was significantly associated with MTX-related leukoencephalopathy.
\textsuperscript{8} And it should be investigated in our patients in the
future.

In patients with CNS involvement, the frequency of WMLs was higher in
those who received IT 12 times compared to those who received cranial
irradiation at a dose of 12Gy, and IT 8
times.\textsuperscript{10}Although the correlation between WMLs by brain
MRI and neurocognitive impairment was not clear in the study, WMLs were
associated with increased neurocognitive impairment in other
reports.\textsuperscript{12,16} Sabin et al. \textsuperscript{16}
reported that there was not significant association between
neurocognitive performance measures and the presence of persistent
leukoencephalopathy. However, higher mean diffusivity of WMLs was
associated with overall neurocognitive impairment. Combined with the
current study, patients who receive repetitive IT should undergo close
MRI and a cognitive functioning test in particular. However, it may be
possible to omit brain MRI in patients with AML and lymphoma who have
received less than five times of IT in consideration of their burden in
terms of sedation and cost.

\textbf{Conflicts of interest}

The authors declare no conflicts of interest.

\textbf{Acknowlegements}

We thank all participating pediatricians who performed examinations and
neuroradiologists who made diagnosis about brain MRI. Their comments and
suggestions were inestimable value for the cases and clinical practices.

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\textbf{Figure Legend}

Figure 1. High intensity areas in the white matter by fluid attenuated
inversion recovery image of a 10-year-old patient with ALL, who received
intrathecal therapies over 10 times.\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/CNS-FIGURE-1/CNS-FIGURE-1}

\end{center}
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