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\begin{document}

\title{Dasatinib-induced pulmonary arterial hypertension in pediatric acute
lymphoblastic leukemia with Philadelphia chromosome: A report of two
cases}



\author[1]{Sujie Tang}%
\author[2]{hao xiong}%
\author[2]{Zhi Chen}%
\author[2]{Li Yang}%
\author[2]{Ming Sun}%
\author[2]{Wenjie Lu}%
\author[2]{Zhuo Wang}%
\author[2]{Fang Tao}%
\author[2]{Min Wu}%
\author[1]{Linlin Luo}%
\author[3]{Zuofeng Li}%
\affil[1]{Jianghan University School of Medicine}%
\affil[2]{Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital}%
\affil[3]{Wuhan University of Science and Technology School of Medicine}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Long-term oral dasatinib administration can induce
pulmonary arterial hypertension (PAH) in pediatric patients with
Philadelphia chromosome-positive (Ph \textsuperscript{+}) acute
lymphoblastic leukemia (ALL). We describe the findings in two pediatric
cases involving Ph \textsuperscript{+} ALL patients who developed
cardiovascular events such as PAH after dasatinib treatment, and present
a review of the related literature. \textbf{Case presentation:} Two
pediatric patients diagnosed with B-cell ALL ( \emph{BCR-ABL} P190
fusion gene positive) received conventional chemotherapy and imatinib
simultaneously, which was then changed to dasatinib because of a partial
response. The two patients developed PAH after 18 months and 6 years of
dasatinib therapy. All signs and symptoms improved after immediate
discontinuation of dasatinib and symptomatic treatment.
\textbf{Conclusions:} Pediatric Ph \textsuperscript{+} ALL patients
receiving dasatinib should be carefully monitored for serious
cardiopulmonary and vascular events such as PAH. Development of adverse
reactions should be followed by immediate and permanent discontinuation
of oral dasatinib. Dynamic monitoring by echocardiography is recommended
when administering dasatinib for maintenance therapy.%
\end{abstract}%



\sloppy


\textbf{Dasatinib-induced pulmonary arterial hypertension in pediatric
acute lymphoblastic leukemia with Philadelphia chromosome: A report of
two cases}

\textbf{Sujie Tang\textsuperscript{1}, Hao Xiong\textsuperscript{2*},
Zhi Chen\textsuperscript{2}, Li Yang\textsuperscript{2}, Ming
Sun\textsuperscript{2}, Wenjie Lu\textsuperscript{2}, Zhuo
Wang\textsuperscript{2}, Fang Tao\textsuperscript{2}, Min
Wu\textsuperscript{2}, Linlin Luo\textsuperscript{1}, Zuofeng
Li\textsuperscript{3}}

\textsuperscript{1}School of Medicine of Jianghan University, Wuhan
430056, Hubei Province, PRC

\textsuperscript{2}Division of Pediatric Hematology and Oncology,Wuhan
Children's Hospital (Wuhan Maternal and Child Healthcare Hospital),
Wuhan 430016, Hubei Province, PRC

\textsuperscript{3}Medical College of Wuhan University of Science and
Technology, Wuhan, 430081, Hubei Province, China.

*Corresponding author:

Hao Xiong, MD, Division of Pediatric Hematology and Oncology,Wuhan
Children's Hospital (Wuhan Maternal and Child Healthcare Hospital),
Wuhan 430016, Hubei Province, PRC, Email:225847481@qq.com

Text word count: 2047;

Abstract word count: 157;

Brief running title: Dasatinib-induced pulmonary arterial hypertension

Key words: Dasatinib, pulmonary arterial hypertension, acute
lymphoblastic leukemia,

Philadelphia chromosome, childhood

Tables: 3

Figures: 1

Abbreviations\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
PAH & pulmonary arterial hypertension\tabularnewline
Ph\textsuperscript{+} ALL & Philadelphia chromosome-positive acute
lymphoblastic leukemia\tabularnewline
OS & overall survival rate\tabularnewline
EFS & event-free survival rate\tabularnewline
TKI & tyrosine kinase inhibitor\tabularnewline
CML & chronic myeloid leukemia\tabularnewline
FISH & fluorescence in situ hybridization\tabularnewline
PASP & pulmonary artery systolic pressure\tabularnewline
LV & left ventricle\tabularnewline
LA & left atrium\tabularnewline
RA & right atrium\tabularnewline
PA & pulmonary artery\tabularnewline
AA & aortic arch\tabularnewline
FS & fractional shortening\tabularnewline
EF & ejection fraction\tabularnewline
NA & not available\tabularnewline
RT-PCR & reverse transcription polymerase chain reaction\tabularnewline
allo-HSCT & allogeneic hematopoietic stem cell
transplantation\tabularnewline
VEGF & vascular endothelial growth factor\tabularnewline
CR & Complete remission\tabularnewline
\bottomrule
\end{longtable}

\textbf{Dasatinib-induced pulmonary arterial hypertension in pediatric
acute lymphoblastic leukemia with Philadelphia chromosome: A report of
two cases}

\textbf{Sujie Tang\textsuperscript{1}, Hao Xiong\textsuperscript{2*},
Zhi Chen\textsuperscript{2}, Li Yang\textsuperscript{2}, Ming
Sun\textsuperscript{2}, Wenjie Lu\textsuperscript{2}, Zhuo
Wang\textsuperscript{2}, Fang Tao\textsuperscript{2}, Min
Wu\textsuperscript{2}, Linlin Luo\textsuperscript{1}, Zuofeng
Li\textsuperscript{3}}

\textsuperscript{1}School of Medicine of Jianghan University, Wuhan
430056, Hubei Province, PRC

\textsuperscript{2}Division of Pediatric Hematology and Oncology,Wuhan
Children's Hospital (Wuhan Maternal and Child Healthcare Hospital),
Wuhan 430016, Hubei Province, PRC

\textsuperscript{3}Medical College of Wuhan University of Science and
Technology, Wuhan, 430081, Hubei Province, China.

*Corresponding author:

Hao Xiong, MD, Division of Pediatric Hematology and Oncology,Wuhan
Children's Hospital (Wuhan Maternal and Child Healthcare Hospital),
Wuhan 430016, Hubei Province, PRC, Email:225847481@qq.com

\textbf{Abstract}

\textbf{Background:} Long-term oral dasatinib administration can induce
pulmonary arterial hypertension (PAH) in pediatric patients with
Philadelphia chromosome-positive (Ph\textsuperscript{+}) acute
lymphoblastic leukemia (ALL). We describe the findings in two pediatric
cases involving Ph\textsuperscript{+} ALL patients who developed
cardiovascular events such as PAH after dasatinib treatment, and present
a review of the related literature.

\textbf{Case presentation:} Two pediatric patients diagnosed with B-cell
ALL (\emph{BCR-ABL} P190 fusion gene positive) received conventional
chemotherapy and imatinib simultaneously, which was then changed to
dasatinib because of a partial response. The two patients developed PAH
after 18 months and 6 years of dasatinib therapy. All signs and symptoms
improved after immediate discontinuation of dasatinib and symptomatic
treatment.

\textbf{Conclusions:} Pediatric Ph\textsuperscript{+} ALL patients
receiving dasatinib should be carefully monitored for serious
cardiopulmonary and vascular events such as PAH. Development of adverse
reactions should be followed by immediate and permanent discontinuation
of oral dasatinib. Dynamic monitoring by echocardiography is recommended
when administering dasatinib for maintenance therapy.

\textbf{Keywords:} Dasatinib, pulmonary arterial hypertension, acute
lymphoblastic leukemia, Philadelphia chromosome, childhood

\textbf{Background}

Acute lymphoblastic leukemia (ALL) is a malignant blood disorder with a
high prevalence in childhood, particularly in pediatric patients with
B-cell ALL (B-ALL)\textsuperscript{{[}1{]}}. Due to the continuous
improvement in MICM precise staging and multi-drug combination
chemotherapy regimens, the 5-year overall survival rate (OS) of
pediatric patients with ALL has reached over 90\% and the 5-year
event-free survival rate (EFS) has reached
80\%\textsuperscript{{[}2{]}}. However, conventional chemotherapy has
been shown to be ineffective for very high-risk pediatric patients.
Philadelphia chromosome (Ph)-positive ALL was historically associated
with very poor outcomes before the advent of tyrosine kinase inhibitors
(TKIs)\textsuperscript{{[}3{]}}. The long-term survival of pediatric
patients with Ph\textsuperscript{+} ALL has significantly improved with
the use of regimens combining TKI with chemotherapy. The CCCG-ALL-2015
study showed that the 4-year EFS and OS were 71.0\% and 88.4\%,
respectively, for pediatric Ph\textsuperscript{+} ALL patients treated
with TKI\textsuperscript{{[}4{]}}. Nevertheless, while severe and
life-threatening cardiovascular events, such as pulmonary arterial
hypertension (PAH), have been reported in adults with chronic myeloid
leukemia (CML) and Ph\textsuperscript{+} B-ALL patients receiving
long-term TKI therapy\textsuperscript{{[}5{]}}, they have been rarely
reported in pediatric patients. This study reports the clinical findings
for two pediatric Ph\textsuperscript{+} ALL patients who showed PAH as a
result of long-term dasatinib therapy at our department, and also
reviews the relevant literature on the incidence of PAH during the
course of dasatinib treatment.

\textbf{Case presentation}

\textbf{Case 1}

A male pediatric patient aged 6 years and 4 months was admitted for
``coughing for more than half a month'' in April 2014. The bone marrow
aspirate was verified as showing B-ALL by flow cytometry.
The\emph{BCR-ABL} fusion gene was shown to be positive by
fluorescence\emph{in situ} hybridization (FISH). \emph{BCR-ABL} (P190)
was quantified as 76\%; karyotype analysis revealed chromosomal
translocation with t(9; 22) (q34;q11) {[}20{]}. Therefore, the MICM
diagnosis was Ph\textsuperscript{+} B-ALL. In accordance with the
CCLG-ALL-2008 protocol, DVLDex regimen chemotherapy combined with oral
imatinib was administered. After 9 months (June 2015) of treatment, the
patient's \emph{BCR-ABL} (P190) decreased to 0.048\%, as detected in the
bone marrow, and the TKI treatment was changed to dasatinib. In March
2016, the bone marrow \emph{BCR-ABL} fusion gene copy number was below
the detection limit, and the peripheral blood \emph{BCR-ABL} fusion gene
copy number remained below the detection limit in the subsequent
reexamination. The pediatric patient was treated with sequential
chemotherapy until 2017, and then continued to take dasatinib without
regular follow-up after completion of chemotherapy.

On September 11, 2021 (after treatment with dasatinib for more than 6
years), the patient was hospitalized again for paroxysmal cough,
sustained fatigue, and shortness of breath after activity. Chest
radiography demonstrated pulmonary infection and pleural effusion.
Echocardiography showed enlargement of the right cardiac cavities,
widening of the pulmonary artery, moderate to severe tricuspid
regurgitation, pulmonary hypertension (136 mmHg; the normal pulmonary
artery systolic pressure {[}PASP{]} was \textless{}25 mmHg and
\textgreater{}18 mmHg) and massive pericardial effusions. The patient
was told to discontinue oral dasatinib immediately, underwent
pericardial drainage on September 11, 2021, and then received captopril,
plavix, and sildenafil orally to treat PAH. Doppler echocardiography
revealed that the cardiac function had returned to normal and the PASP
was not further aggravated during the treatment period. The patient was
prescribed symptomatic treatment for PAH with continued oral bosentan,
sildenafil tablets, and poliovel after hospital discharge on October 14,
2021, and the TKI treatment was changed to oral nilotinib on December
23, 2021. Cardiac ultrasound showed that the cardiac structure had
returned to normal, and the PASP had decreased to 22 mmHg after
discontinuation of dasatinib for four months (January 2021).
Subsequently, the PASP remained normal at scheduled reexaminations
(Table 1 and Figure 1), and the patient no longer experienced fatigue
and shortness of breath.

\textbf{Table 1 List of dynamic changes in echocardiographic parameters
after discontinuation of dasatinib and treatment in the patient in case
1}\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Date}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{2021/9/11 (D1)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{2021/9/13 (D3)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{2021/9/21 (D11)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{2021/9/27 (D17)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{2021/10/6 (D26)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{2021/11/11 (2 m)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{2021/12/23 (3 m)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{2022/1/13 (4 m)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{2022/3/24 (6 m)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{LV (mm)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
35\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
38\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
39\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
44\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
44\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
46\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
47\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{LA (mm)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Normal\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Normal\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{RA (mm)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
45\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
52\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
48\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
38\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Normal\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Normal\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{RV (mm)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
42\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
42\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
46\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
41\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
40\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
34\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
28\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Normal\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{PA (mm)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
29\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
34\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
28\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
28\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
27\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
23\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
23\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{AA (mm)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
21\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{FS (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
40\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
38\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
37\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
36\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
35\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
35\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
34\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{EF (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
70\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
68\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
67\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
66\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
65\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
64\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
63\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
61\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
64\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{PASP (mmHg)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
136\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
103\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
82\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
79\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
87\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
39\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
36\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
28\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Abbreviations: LV: left ventricle; LA: left atrium; RA; right
atrium; RV: right ventricle; PA: pulmonary artery; AA: aortic arch; FS:
fractional shortening; EF: ejection fraction; PASP: pulmonary artery
systolic pressure; NA: not available.}

\textbf{Case 2}

A female pediatric patient aged 3 years and 7 months was hospitalized
after intermittent fever for 10 days in May 2020. TDT, CD10, CD19, CD22,
CD34, HLA-DR, and Ccd79a expressions were identified in bone marrow
aspirate by flow cytometry. The \emph{BCR-ABL} fusion gene was shown to
be positive by FISH and reverse transcription polymerase chain reaction
(RT-PCR). Karyotype analysis of the pediatric patient revealed
chromosomal translocation with t(9;22) (q34; q11), and the diagnosis was
Ph\textsuperscript{+} B-ALL. A chemotherapy regimen combined with oral
imatinib was administered according to the CCLG-ALL-2018
protocol\textsuperscript{{[}6{]}}. After 1 month of
treatment,\emph{BCR-ABL} was quantified as 2.9\%, and the results for
minimal residual disease in the bone marrow were negative, so the TKI
regimen was changed to oral dasatinib. The \emph{BCR-ABL} fusion gene in
the patient's bone marrow did not show complete remission after 5 months
of sequential chemotherapy. The patient underwent related-donor haploid
allogeneic hematopoietic stem cell transplantation, with the donor being
the patient's biological father. The bone marrow reconstitution was
successful after the allo-HSCT, and the patient continued to take
dasatinib orally for maintenance therapy. Periodic routine examination
indicated negative results for the \emph{BCR-ABL} fusion gene and
minimal residual disease in the bone marrow, and the results of cardiac
ultrasound during the therapy period were normal.

Nevertheless, the patient's echocardiography showed enlargement of the
right cardiac cavities, widening of the pulmonary artery, moderate to
severe tricuspid regurgitation, and pulmonary hypertension in January
2022 (after treatment with dasatinib for 18 months). Dasatinib was
promptly discontinued, and oral captopril was simultaneously started for
treating the PAH. Echocardiography reexaminations demonstrated slightly
expanded right cardiac cavities, a slightly widened pulmonary artery,
moderate tricuspid regurgitation, and a PASP of 28 mmHg (Table 2 and
Figure 1). The patient is currently receiving oral consolidation therapy
with captopril, and echocardiography showed that the PASP was not
elevated.

\textbf{Table 2 List of dynamic changes in echocardiographic parameters}

\textbf{after discontinuation of dasatinib and treatment in the patient
in case 2}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Date\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
2022/1/24 (D1)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
2022/1/28 (D5)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
2022/2/4 (D12)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
2022/2/18 (D26)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
2022/3/12 (D48)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
2022/5/3 (3 m)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
LV (mm)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
20\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
LA (mm)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
35\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
34\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
RV (mm)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
30\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
28\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
28\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
32\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
RV (mm)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
29\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
29\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
27\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
27\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
30\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
PA (mm)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
19\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
19\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
AA (mm)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
FS (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
34\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
38\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
35\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
EF (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
64\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
62\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
69\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
62\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
65\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
65\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
PASP (mmHg)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
62\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
58\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
65\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
28\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
43\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
29\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Abbreviations: LV: left ventricle; LA: left atrium; RA; right
atrium; RV: right ventricle; PA: pulmonary artery; AA: aortic arch; FS:
fractional shortening; EF: ejection fraction; PASP: pulmonary artery
systolic pressure; NA: not available.}

\textbf{Figure 1 Trend of pulmonary artery systolic pressure after
discontinuation of dasatinib and symptomatic treatment in the patient in
case 1 and case 2}

\textbf{Abbreviations: PASP: pulmonary artery systolic pressure;NPASP:
Normal pulmonary artery systolic pressure}

\textbf{Discussion and Conclusions}

Approximately 3\%--5\% of the cases of childhood ALL show a t(9;22)
(q34;q11)/Ph\textsuperscript{+} status\textsuperscript{{[}7{]}}. In
comparison with Ph\textsuperscript{-} ALL, Ph\textsuperscript{+} ALL
cases show a higher degree of malignancy and a poor response to
conventional chemotherapy with lower rates of survival. TKIs can inhibit
tyrosine kinase activation by competitively binding to the active site
of tyrosine kinase, thereby impeding leukemia cell proliferation. The
long-term survival of pediatric patients with Ph\textsuperscript{+} ALL
has improved significantly since the advent of
TKIs\textsuperscript{{[}4{]}}. In one study of 30 pediatric patients
with Ph\textsuperscript{+} ALL who received TKI treatment in combination
with induction chemotherapy at the early stage of treatment, the
postinduction complete remission rate was 96.7\%, complete remission
rate was 100\%, and the 3-year OS was nearly
80\%\textsuperscript{{[}3{]}}. However, relapse and drug resistance were
relatively frequent events in Ph\textsuperscript{+} ALL patients treated
with the first-generation TKI imatinib. The second-generation TKI
dasatinib is more clinically potent in inhibiting multiple tyrosine
kinases, including Src family tyrosine kinase, \emph{BCR-ABL} kinase,
and C-Kit. Additionally, dasatinib also shows higher selectivity and
affinity to the BCR/ABL kinase domain than imatinib, and dasatinib can
cross the blood--brain barrier to prevent and eradicate central nervous
system leukemia. It is used to treat patients with imatinib resistance
or relapse while receiving imatinib\textsuperscript{{[}8{]}}. According
to the Chinese Children's Cancer Group study ALL-2015 (CCCG-ALL-2015),
patients treated with dasatinib had significantly higher rates of 4-year
EFS (71.0\% vs 48.9\%) and OS (88.4\% vs 69.2\%) and lower relapse rates
(19.8\% vs 34.4\%) than the 97 patients treated with
imatinib\textsuperscript{{[}4{]}}. Therefore, dasatinib in combination
with conventional chemotherapy is currently more recommended for
pediatric Ph\textsuperscript{+} ALL patients.

PAH is a severe disease characterized by elevated pulmonary arterial
pressure and pulmonary vascular resistance, resulting in right
ventricular failure and even death. Changes in pulmonary vascular
structure or function have been attributed to multiple etiologies and
various distinctive pathogeneses. PAH is a rare adverse reaction of
dasatinib, and the mechanisms underlying the occurrence of PAH in
patients receiving dasatinib are unclear. In addition to inhibiting
BCR/ABL kinase activity, dasatinib can also inhibit the activity of
normal Src family tyrosine kinase and platelet-derived growth factor.
This may be one of the factors associated with the occurrence of PAH,
since normal Src family tyrosine kinase is widely expressed in
endothelial cells of blood vessels and promotes proliferation of
vascular smooth muscle cells and vasoconstriction. In addition, the
occurrence of PAH may involve changes in vascular permeability related
to the expression of vascular endothelial growth factor (VEGF), since
inhibition of VEGF expression by dasatinib may induce PAH and secondary
multiplasmic effusion\textsuperscript{{[}9{]}}.

After nine cases of dasatinib-induced PAH were reported by the French
PAH Registry in 2008, 29 cases of dasatinib-induced PAH (including the
two pediatric patients of this study) have been reported in subsequent
studies (Table 3). Of the 29 patients aged 5 to 73 years (24 cases
involved CML, while the remaining five involved ALL), 19 were male and
10 were female. The present study is the first to describe the findings
for pediatric patients. Most of these patients had already developed
associated clinical symptoms before receiving a definitive diagnosis.
Although elevated pulmonary arterial pressure was observed in only one
patient (case 2 of this study) during the routine echocardiography
reexaminations, she did not develop meaningful clinical manifestations
of PAH. Twenty-two of the 29 patients showed different degrees of
comorbid pleural effusion, and 13 had comorbid pericardial effusion. All
of the 29 patients immediately discontinued oral dasatinib and received
symptomatic treatment after the diagnosis of PAH. Subsequently, the
clinical symptoms were alleviated, and the PASP was progressively
restored to normal levels in all patients.

For the two pediatric patients in this study, oral dasatinib was
discontinued immediately after a diagnosis of PAH, and oral captopril
was simultaneously administered to treat PAH. The subsequent
reexaminations using echocardiography demonstrated that the PASP
progressively improved to normal levels. After discontinuation of oral
dasatinib in these 29 patients, five received oral imatinib, two
received oral bosutinib, one received ponatinib, 14 received nilotinib,
and seven did not receive other TKIs. Only one patient who changed to
bosutinib subsequently showed aggregated PAH, while the condition of the
remaining patients improved. Consequently, close monitoring is still
necessary to avoid the reoccurrence of PAH when altering to other TKIs
for therapy.

In summary, Ph\textsuperscript{+} pediatric ALL patients receiving
dasatinib for maintenance therapy should be closely monitored for the
potential adverse effects of dasatinib administration. In patients who
show these adverse effects, dasatinib should be discontinued immediately
and active treatment for complications such as PAH and multiple-cavity
effusion should be administered. Determination of the long-term quality
of life of these patients requires multicenter studies with large sample
sizes.

\textbf{Abbreviations}

ALL Acute lymphoblastic leukemia

CML Chronic myeloid leukemia

CR Complete remission

EFS Event-free survival

FISH Fluorescence in situ hybridization

OS Overall survival

PAH Pulmonary arterial hypertension

PASP Pulmonary artery systolic pressure

TKI Tyrosine kinase inhibitor

VEGF Vascular endothelial growth factor

\textbf{Declarations}

\textbf{Ethics approval and consent to participate}

Not applicable.

\textbf{Consent for publication}

Not applicable.

\textbf{Availability of data and materials}

All data generated or analysed during this study are included in this
published article.

\textbf{Competing interests}

The authors declare that they have no competing interests.

\textbf{Funding}

This study was funded by Wuhan Clinical Medical Research Project
(WX20D20, WZ20Y04, WX21Z48)

\textbf{Authors' contributions}

SJT and HX designed the study. SJT, ZC and HX acquired and analyzed the
data. SJT, HX, ZC and LY discussed the results. SJT, HX, ZC, LY and MS
wrote the manuscript. HX and ZC reviewed and supervised the work. All
authors reviewed the manuscript. All authors read and approved the final
manuscript.

\textbf{Acknowledgements}

Not applicable.

\textbf{Authors' information}

\textsuperscript{1}School of Medicine of Jianghan University, Wuhan
430056, Hubei Province, PRC. \textsuperscript{2}Wuhan Children's
Hospital (Wuhan Maternal and Child Healthcare Hospital), Wuhan 430016,
Hubei Province, PRC. \textsuperscript{3}Medical College of Wuhan
University of Science and Technology, Wuhan, 430081, Hubei Province,
China.

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\textbf{Table 3 Summary of the cases of dasatinib-associated pulmonary
arterial hypertension}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllll@{}}
\toprule
\begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Serial number}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Sex}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Age (years)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Age (years)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Dasatinib dose (mg/d)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Clinical presentation}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{PASP (mmHg)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Pleural effusion}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Pericardial effusion}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{PAH appearance time (months)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Treatment plan}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Evaluation} \textbf{time (months)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Evaluation results}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1\textsuperscript{{[}10{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
41\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, cough, edema\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
26\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + glucocorticoids + diuretics, replacement of oral
nilotinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
2.5\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
2\textsuperscript{{[}11{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
48\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140-50\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140-50\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, jugular vein dilation, edema, hepatosplenomegaly\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
61\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + diuretic + glucocorticoids, dasatinib reduction
therapy, discontinuation after exacerbation\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3\textsuperscript{{[}12{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinued + Sildenafil\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
4\textsuperscript{{[}13{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
53\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100-70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100-70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, edema, hepatosplenomegaly\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
65-70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
31\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + sildenafil + diuretic, replacement of oral nilotinib
treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
5\textsuperscript{{[}14{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
47\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140-100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140-100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, jugular vein dilation, edema, hepatosplenomegaly\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
61\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
39\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + sildenafil and replace oral nilotinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6\textsuperscript{{[}15{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
61\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140-70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140-70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
27\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + sildenafil and replace oral nilotinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
7\textsuperscript{{[}16{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
57\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, edema\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
elevated\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
37\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Sildenafil + diuretic, discontinuation and replacement with nilotinib
treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
8\textsuperscript{{[}17{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
114\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
35\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + prostaglandin + diuretic, replacement of oral
nilotinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
9\textsuperscript{{[}18{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
105\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
63\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + sildenafil and replace oral nilotinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
10\textsuperscript{{[}19{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
50\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, cough, chest pain\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
60\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
48\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + sildenafil and replace oral nilotinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
11\textsuperscript{{[}20{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
43\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
90\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
69\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + sildenafil + calcium channel blocker + diuretic,
switch to oral treatment with Ponatinib\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
12\textsuperscript{{[}20{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
52\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
75\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
38\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + sildenafil and replace oral nilotinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
13\textsuperscript{{[}21{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
55\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Chest tightness, fatigue, edema\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
115\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
36\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + diuresis with intermittent oral dasatinib
treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
36\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
14\textsuperscript{{[}9{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
61\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, cough\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
26\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + tadalafil + ambrisentan + diuretic, replacement of
oral treatment with nilotinib\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
15\textsuperscript{{[}22{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
52\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
48\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + Ambrisentan, replacement of oral bosutinib
treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Na\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
16\textsuperscript{{[}8{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
46\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
98\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
144\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + Tadalafil + Ambrisentan\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
17\textsuperscript{{[}23{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
67\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, edema\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
42\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + sildenafil and replace oral imatinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
18\textsuperscript{{[}24{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
24\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, edema\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
48\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + sildenafil + bosentan + diuretic, replacement of
bosutinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
19\textsuperscript{{[}25{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
46\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, chest tightness\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
78\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
59\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + tadalafil + bosentan, replacement of oral imatinib
treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
20\textsuperscript{{[}26{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
63\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140-50\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140-50\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, jugular vein dilation, hepatosplenomegaly\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
60\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + tadalafil + macitentan + sellepag and replacement of
oral imatinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
21\textsuperscript{{[}27{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
73\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation, replacement of oral imatinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
22\textsuperscript{{[}28{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
59\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, chest pain\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
54\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + tadalafil + macitentan + diuretic + bronchodilator,
replacement of nilotinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23\textsuperscript{{[}29{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
38\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, chest pain, cough, syncope\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
57\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
18\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + Anrisentan + Diuretic\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
24\textsuperscript{{[}5{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
56\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Chest tightness, shortness of breath\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
117\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
47\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + liothyronine + diuretic, resumed dasatinib treatment,
replaced nilotinib + bosentan + sildenafil after exacerbation\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
25\textsuperscript{{[}30{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
24\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, jugular vein dilation\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
67\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
10d\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinue the drug\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1W\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
26\textsuperscript{{[}31{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
50\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
140\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, jugular vein dilation, edema, hepatosplenomegaly\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
70\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
24\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + bosentan + glucocorticoids + diuretics, replacement of
nilotinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
27\textsuperscript{{[}32{]}}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
47\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Dyspnea, chest tightness\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
80\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + sildenafil + glucocorticoids + diuretics +
tigecycline\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
28\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
60\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
60\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Cough, fatigue,shortness of breath\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
137\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
75\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + diuretic + digitalis + bosentan + poliovir +
sildenafil + captopril, replacement of nilotinib treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
29\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
40-50\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
40-50\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
With no clinical manifestation\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
65\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Discontinuation + captopril + ryanodine, replacement of imatinib
treatment\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Improved\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{PASP: pulmonary artery systolic pressure; PAH: pulmonary artery
hypertension; NA: not available}

\textbf{Patients 1 to 24 had CML, while patients 25 to 29 had ALL
(patients 28 and 29 were the two pediatric patients in this case report}

\textbf{).}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table 1 and 2.docx`  available at \url{https://authorea.com/users/511348/articles/607482-dasatinib-induced-pulmonary-arterial-hypertension-in-pediatric-acute-lymphoblastic-leukemia-with-philadelphia-chromosome-a-report-of-two-cases}

\selectlanguage{english}
\FloatBarrier
\end{document}

