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\begin{document}

\title{Early response to treatment and adverse events in pediatric acute
promyelocytic leukemia: a single center observational study in
Bangladesh}



\author[1]{Eshita Khan}%
\author[2]{Afiqul Islam}%
\affil[1]{Government of Bangladesh Ministry of Health and Family Welfare}%
\affil[2]{Bangabandhu Sheikh Mujib Medical University}%


\vspace{-1em}



  
  \date{May 08, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Abstract: Objective: Pediatric acute promyelocytic leukemia (APL) is one
of the most curable subtypes of acute myeloid leukemia of childhood. But
it may have many early complications, especially in developing
countries. This study aims to describe the early course of disease and
adverse events in the management of pediatric APL cases in Bangladesh.
Method: This prospective observational study was conducted in the
Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh
Mujib Medical University, Dhaka from September 2017 to March 2019. The
study included twenty PML:RAR-\selectlanguage{greek}α \selectlanguage{english}(ProMyelocytic Leukemia-Retinoic Acid
Receptor-\selectlanguage{greek}α\selectlanguage{english}) positive APL cases. After taking informed written consent
from the parents, patients were treated with risk directed ATRA
(All-trans-retinoic acid) based chemotherapy. Results: The mean age was
6.8 years with male-female ratio of 1:1.2. Hemorrhagic manifestations
were observed in 95\% of patients, with mucosal bleeding in 55\% and CNS
hemorrhage in one patient. Fever was the present in 95\% of children.
Most of the children (65\%) were in the high risk group. DIC was present
in 90\% cases and mean D-Dimer was 4.1 \selectlanguage{greek}µ\selectlanguage{english}g /ml. Overall 90\% (18/20)
patients achieved clinical and peripheral remission with resolution of
coagulopathy. But only 75\% patients (15/20) reached maintenance therapy
in bone marrow remission. Causes of deaths were neutropenic sepsis,
intracranial hemorrhage, complicated differentiation syndrome and
stroke. Neutropenic sepsis was the most common adverse event.
Conclusion: In Bangladeshi pediatric APL patients, neutropenic sepsis is
the most common and also the most severe adverse event. Key words: acute
promyelocytic leukemia, children, response to treatment%
\end{abstract}%



\sloppy


\textbf{}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Abbreviation & Full term\tabularnewline
\midrule
\endhead
APL & Acute promyelocytic leukemia\tabularnewline
ATRA & All-\emph{trans}-retinoic acid\tabularnewline
DIC & Disseminated intravascular coagulation\tabularnewline
PML:RAR-\selectlanguage{greek}α & Promyelocytic Leukemia : Retinoic acid
receptor-\selectlanguage{greek}α\selectlanguage{english}\tabularnewline
\bottomrule
\end{longtable}

\textbf{}

\par\null

\textbf{Introduction:}

Pediatric Acute Promyelocytic leukemia (APL) is the most curable subtype
of acute myeloid leukemia (AML) of childhood, due to its unique
responsiveness to the All-\emph{Trans}-Retinoic-Acid (ATRA), a vitamin A
derivative\textsuperscript{1}. Currently, APL is classified by World
Health Organization (WHO) as AML with recurrent genetic abnormality, a
reciprocal balanced translocation involving Retinoic acid Receptor-\selectlanguage{greek}α
\selectlanguage{english}(RAR-\selectlanguage{greek}α\selectlanguage{english}) gene at chromosome 17q21 and usually associated with features of
disseminated intravascular coagulation (DIC)\textsuperscript{2}.
Malignant promyelocytes release tissue factor, cancer procoagulant and
microparticles causing abnormal, excessive activation of coagulation
cascade. Also, there is excessive fibrinolysis due to release of
plasminogen activators, Annexin II and proteases; and endothelial damage
due to release of interleukin 1\selectlanguage{greek}β, \selectlanguage{english}tumor necrosis factor \selectlanguage{greek}α \selectlanguage{english}and vascular
endothelial growth factor, leading to characteristic
DIC\textsuperscript{3,4,5,6}. When ATRA is administered, it causes
conformational change in malignant RAR-\selectlanguage{greek}α \selectlanguage{english}gene and removes the blockage
in promyelocyte differentiation\textsuperscript{7,8}. Although ATRA
decreases the inappropriate activation of coagulation cascade, low level
of fibrinolysis and expression of cytokines may continue for some
period\textsuperscript{9}. APL should be considered as a medical
emergency, because hemorrhagic complications within the first hours and
days are frequent and can be lethal. The treatment must be started
immediately with ATRA, even before confirmation of the diagnosis has
been made\textsuperscript{1}. With current treatment protocols
consisting of ATRA and anthracyclines, clinical remission rate in
pediatric APL is 85-95\%, 5 year overall survivals rate is 75-90\% and 5
year event-free-survivals rate is 72-83\%\textsuperscript{10-17}. Most
of the studies suggest that higher leukocyte count is the single most
significant predictor of poor outcome\textsuperscript{18,19}. In most of
the current management protocols, the patients are categorized into
standard and high risk groups based on total leukocyte count, which is
known as Sanz criteria\textsuperscript{20}. Despite excellent long term
outcome, early deaths (ED), defined as deaths within 30 days of
diagnosis, were found to occur at high rates in adult APL patients,
usually from severe hemorrhages, which were 26\% in USA and 30\% in
Bangladesh\textsuperscript{21,22}. Early death rate is also high in
pediatric APL patients of India (39\%) and is found to be the major
impediment to excellent long term outcome\textsuperscript{23}.
Post-chemotherapy neutropenic sepsis may occur in APL. Its incidence is
30\% in a Canadian study and 33\% In an Indian
study\textsuperscript{24,25}. Differentiation syndrome or Retinoic acid
syndrome, a unique treatment related complication of APL, occurs in 8-
29\%of cases\textsuperscript{10-13,23}. It is a clinico-pathological
syndrome characterized by any 3 of the 7 features: unexplained fever,
unusual weight gain, dyspnea, pulmonary infiltrates and
pleuro-pericardial effusion, episodic hypotension and renal
insufficiency. It may be also associated with peripheral edema or
hyperbilirubinemia\textsuperscript{26,27}. Severe headache (isolated or
associated with pseudotumor cerebri), an adverse effect of ATRA, may
occur in 8- 39\% cases\textsuperscript{10-12}. Patients with APL may
also develop thrombotic complications. A pediatric study in Turkey
reported thrombotic stroke in one patient out of a total of 17
patients\textsuperscript{16}. In adult studies, thrombotic complications
occur in 5.1\% cases\textsuperscript{28}. Thrombosis in APL may be
attributable to hypercoagulability caused by malignant promyelocytes and
circulating cytokines\textsuperscript{29,30}. As far as known, there is
no published study on pediatric APL in Bangladesh. This prospective
observational study aims to describe the clinical manifestations,
hematological profile, response to treatment and adverse events in
pediatric APL in a tertiary care hospital in Bangladesh.

\textbf{Materials and Method}

\textbf{Study population:} All pediatric (\textless{}15 years) cases of
APL, admitted in Pediatric Hematology and Oncology ward, Bangabandhu
Sheikh Mujib Medial University (BSMMU), Dhaka, Bangladesh, from
September 2017 to March 2019 were included in the study. The patients
were tested for Promyelocytic Leukemia:Retinoic acid receptor-\selectlanguage{greek}α
\selectlanguage{english}(PML:RAR-\selectlanguage{greek}α\selectlanguage{english}) transcript assay through Reverse Transcriptase-Polymerase
Chain Reaction (RT-PCR) technique of bone marrow aspiration sample.
PML:RAR-\selectlanguage{greek}α \selectlanguage{english}negative cases were excluded from the study. Another exclusion
criterion was presence of cardiac contraindication of anthracycline
therapy.

\textbf{Study procedure:} Ethical clearance of the study protocol
(\href{http://No.BSMMU/2017/8715-23.08.2017}{No.BSMMU/2017/8715-23.08.2017})
was obtained from Institutional Review Board (IRB) of Bangabandhu Sheikh
Mujib Medial University. Informed written consent from the parents was
obtained at the time of study enrollment. All features from detailed
clinical history, physical findings and laboratory investigations were
documented in the clinical data collection sheet.

\textbf{Treatment protocol and supportive care:}The treatment was
started according to modified protocol of International Consortium for
Childhood (ICC) APL, sponsored by AIEOP (Associazione Italiana di
Ematologiaed Oncologia Pediatrica) which has been shown in figure 1. The
result of ICC-APL clinical trial has been published recently with 5 year
overall survival of 94.6\%\textsuperscript{17}. After confirmation of
diagnosis, the patients were categorized into risk groups based on total
leukocyte count, the patients with total leukocyte count
10x10\textsuperscript{9}/L or more were categorized in the high risk
group and those having the lower count were assigned to standard risk
group. ATRA was included in all phases: induction, consolidation and
maintenance. Induction consisted of oral ATRA (25
mg/m\textsuperscript{2}/day) for 30 consecutive days and 3 doses of
Idarubicin. In high risk patients, dexamethasone
(5mg/m\textsuperscript{2}/day) was given during the first 5 days as
differentiation syndrome prophylaxis. Then, standard risk and high risk
patients received 2 or 3 consolidation blocks, respectively, after
peripheral blood count recovery (neutrophil count
[?]1.0x10\textsuperscript{9}/L and platelet count
[?]100x10\textsuperscript{9}/L). A 14 day course of ATRA was associated
with cytarabine and mitoxantrone in the first block, with idarubicin in
the second block and with cytarabine and idarubicin in the third block.
Intrathecal cytarabine (age adjusted dose) was administered at the start
of each consolidation therapy. Standard risk patients, still PML:RAR-\selectlanguage{greek}α
\selectlanguage{english}positive at the end of the 2\textsuperscript{nd} consolidation block,
would receive a 3\textsuperscript{rd} consolidation block. All patients
who were PML:RAR\selectlanguage{greek}α \selectlanguage{english}negative at the end of consolidation therapy would
receive low-dose maintenance chemotherapy for 2 years. Patients who were
PCR-positive after third consolidation therapy would be considered as
refractory disease and would receive salvage therapy, including
ArsenicTrioxide + Gemtuzumab-Ozogamycin+/-ATRA. Platelets and fresh
frozen plasma were transfused to maintain the platelet count
\textgreater{}50x10\textsuperscript{9}/L and the fibrinogen level
\textgreater{}1.5g/dl, respectively during the first 10 days of
induction or longer in the presence of coagulopathy. As APL is a medical
emergency, ATRA was started as soon as possible after diagnosis was
confirmed or strongly suspected. The end point of the study was the
beginning of maintenance phase of chemotherapy.

\textbf{Operational definitions: Coagulopathy/DIC:} It is based on the
diagnostic criteria for DIC in hematologic disorders from the Japanese
Society on Thrombosis and Hemostasis (JSTH), which includes platelet
count, prothrombin time: INR, fibrinogen level, fibrin related markers-
Fibrin Degradation Product (FDP) or D-Dimer; and absence of liver
dysfunction. A score [?] 4/13 was considered as DIC\textsuperscript{31}.

\textbf{Response to treatment}: Response to treatment includes
achievement of clinical remission and peripheral remission, resolution
of coagulopathy and bone marrow remission (morphological and molecular)
at the end of consolidation phase of chemotherapy.

\textbf{Early Death:} Early death includes deaths that occurred within
30 days of diagnosis.

\textbf{Clinical remission}: Clinical remission is defined as a patient
becoming afebrile with absence of pallor, hemorrhagic manifestations or
organomegaly after initiation of chemotherapy.

\textbf{Peripheral remission}: Peripheral remission is defined as
absence of blast/promyelocyte in peripheral blood smear after initiation
of chemotherapy.

\textbf{Bone marrow remission:} Bone marrow remission is defined as
absence of blast/malignant promyelocyte with negative RT-PCR for
PML:RAR-\selectlanguage{greek}α \selectlanguage{english}in bone marrow sample at the end of consolidation phase of
chemotherapy.

\textbf{Resolution of coagulopathy:} Normalization of PT and APTT,
platelet count \textgreater{} 50,000/cumm and plasma fibrinogen
\textgreater{}150 mg/dl. Isolated raised D-Dimer or FDP was not
considered to be a sign of non-resolution of coagulopathy as low grade
fibrinolysis may persist for prolong period in a compensated
manner\textsuperscript{9}.

\textbf{Differentiation syndrome:} Any 3 of the following features after
initiation of ATRA: Unexplained fever, dyspnea, pulmonary infiltrates,
pleuro/pericardial effusion, weight gain, peripheral edema, episodic
hypotension, renal function impairment, hyperbilirubinemia.

\textbf{Pseudotumor cerebri:} Patients having severe headache, vomiting,
visual disturbance and response to withholding ATRA were designated as
suspected pseudotumor cerebri. If they also have papilledema and/or
suggestive neuro-imaging, they were assigned as definitive pseudotumor
cerebri.

\textbf{Refractory disease:} Refractory disease is defined as patients
having PML:RAR-\selectlanguage{greek}α \selectlanguage{english}positive post-consolidation bone marrow sample.

\textbf{Data analysis:} All data were documented in preformed data
collection form. Statistical analysis was performed by using SPSS
(Statistical Package for the Social Sciences) for windows version 23.
Quantitative data were presented as mean, standard deviation and range.
Qualitative data were expressed as total numbers and percentages.

\textbf{Results:}

\textbf{Clinical and hematological characteristics:} The total number of
patients of APL (PML:RAR-\selectlanguage{greek}α \selectlanguage{english}positive) in this study was 20. Among the
study population, 7 patients were in the standard risk group and 13
patients were in the high risk group. Mean age was 6.8 years and 30\% of
patients were below 5 years of age. Male: female ratio was 1:1.2. The
commonest clinical features were fever (95\%) and hemorrhage (95\%).
Mucosal bleeding was observed in 55\% patients and one patient had fatal
CNS hemorrhage. Hepatomegaly was present in 70\% cases and 40\% had
splenomegaly. Among hematological parameters, mean hemoglobin was 6.28
gm/dl, mean total leukocyte count was 56.8 x 10\textsuperscript{9}/L,
and mean platelet count was 16.6 x10\textsuperscript{9}/L. Total
leukocyte count was \textgreater{} 100 x10\textsuperscript{9}/L in 25\%
of patients. DIC was present in 90\% of patients, mean plasma fibrinogen
was 232.6 mg/dl and mean plasma D-Dimer was 4.1 \selectlanguage{greek}µ\selectlanguage{english}g /ml. (Table 1).

\textbf{Response to therapy:} Clinical and peripheral remission was
achieved in 90\% patients (18/20) during induction chemotherapy. Failure
to achieve remission was due to early hemorrhagic death (intracranial
hemorrhage) on 1\textsuperscript{st} day of admission before initiation
of ATRA in one patient. Another patient who failed to achieve remission
developed hyperleukocytosis (despite getting ATRA, steroid and later
hydroxyuia), differentiation syndrome, severe sepsis and profuse
gastro-intestinal hemorrhage leading to death. One patient died from
massive ischemic stroke on 26\textsuperscript{th} day of induction after
achieving clinical and peripheral remission. Two patients died from
septic shock due to neutropenic sepsis after completion of consolidation
chemotherapy. Finally, 15 patients (75\%) successfully reached
maintenance therapy and are currently in clinical, peripheral and bone
marrow remission. The commonest cause of death was post-chemotherapy
neutropenic sepsis (Table 2).

\textbf{Adverse events:} Incidence of post-chemotherapy sepsis was 58\%
which most frequent after induction and consolidation III (84\% and 70\%
respectively). Among the neutropenic sepsis events, the commonest causes
were febrile neutropenia with no specific focus and respiratory tract
infection (Table 3).

Differentiation syndrome was found to occur in 4 patients (20\%). All
four patients developing differentiation syndrome were in the high risk
group, having cough, tachypnea, pulmonary infiltrates and associated
infection. Unexplained fever was observed in 3 patients (75\%), pleural
effusion, ascitis, abnormal weight gain, hyperbilirubinemia were
observed in 2 patients each (50\%). No patient had renal impairment. One
patient did not respond to steroid and died from progressive
hyperleukocytosis, severe sepsis, gastrointestinal hemorrhage and
multiorgan failure. Pseudotumor cerebri was observed in 3 patients
during induction therapy. All patients had intense headache with
vomiting which were improved after transient dose reduction of ATRA and
steroid. One patient also had papiloedema, bradycardia and generalized
seizure, which responded to intravenous midazolam, mannitol and
dexamethasone. Other adverse events were hyperpigmentation of skin,
cheilitis, visual disturbance due to retinal hemorrhage, elevated liver
enzymes (\textgreater{}4 folds of upper limit) and ischemic stroke
(Table 4).

\textbf{Discussion}

This prospective observational study, total number of PML:RAR-\selectlanguage{greek}α \selectlanguage{english}positive
APL patients was 20. The mean age was 6.8 years (ranging from 3-13
years). There was slight female predominance with male-female ratio of
1:1.2 which is consistent with previous European
studies\textsuperscript{10,11}.

In this study, mean duration of illness was 31 days (7-90 days).
Hemorrhagic manifestations were observed in 95\% of patients, with
mucosal bleeding in 55\% cases. These features are also consistent with
previous European studies which found hemorrhagic manifestations in 80\%
of children with mucosal bleeding in 59\% cases\textsuperscript{10}.
Fever was present in 95\% of patients which is higher than previous
studies in Italy (42\%), Korea (62\%) or in Turkey
(59\%)\textsuperscript{12,13,16 .} Hepatomegaly was present in 70\% of
cases, also higher previous studies in Europe (19\%) and in Korea
(32\%)\textsuperscript{10,13} .

In this study, most of the patients (63\%) were in the high risk group,
which is also higher than studies in Europe (48\%), Spain (39\%), Italy
(38\%), Korea (35\%), China (26\%) and India
(46\%)\textsuperscript{10-13,15,23}. Mean plasma fibrinogen in this
study was 232 mg/dl and mean D-Dimer was 4.1 \selectlanguage{greek}µ\selectlanguage{english}g /ml. Mean plasma
fibrinogen level is found to be higher than the previously published
data, as it was 140 mg/dl in both of the two European studies and 149.5
mg/dl in a Turkish study\textsuperscript{10,14,16}. This may be due to
the fact that, in this study, most of the patients (75\%) received prior
blood or blood product transfusion.

Early death occurred in three patients (15\%). This incidence is higher
than a previous multinational pediatric APL study, which documented
5.6\% of early death, but lower than early death rate in another
previous pediatric study in India\textsuperscript{18,23}. Early
hemorrhagic death occurred in one patient (5\% ) in this study, which
was 3.1- 3.8\% in Europe, 2.8\% in Italy, 7.5\% in Spain, 13\% in Korea,
11.7\% in Turkey and 30\% in India\textsuperscript{10-14, 16,23}.

The frequency of post-chemotherapy neutropenic sepsis was 58\%. The rate
of infection is much higher than the study performed in Canada (30\%)
and India (33\%)\textsuperscript{24,25}. This difference may be due to
poor adherence to infection control measures. Neutropenic sepsis was the
cause of death in two patients.

The incidence of differentiation syndrome was 20\%. In previous studies
its incidences were 13-16\% in Europe, 20\% in Spain, 6\% in Italy, 17\%
in Korea and 29\% in India\textsuperscript{10-14,16,23}. Differentiation
syndrome was the cause of death in one patient. This patient had
progressive leukocytosis after initiation of ATRA, which is thought to
be a predictor of differentiation syndrome and early death in adult
cases\textsuperscript{32}.

Incidence of pseudotumor cerebri (suspected and definitive) was 15\%. In
previous studies its incidences were 14\% in Europe, 6\% in Spain and
8\% in Italy \textsuperscript{10-12, 14}.

One patient died from ischemic stroke during later period of induction
therapy. This thrombotic event in pediatric APL was also documented in a
previous study in Turkey\textsuperscript{16}.

All five deaths occurred in the high risk group. This finding is
consistent with the most of the studies which suggest that higher
leukocyte count is the single most significant predictor of poor
outcome\textsuperscript{18,19}. In this developing country, delayed
presentation is very common which leads to more aggressive disease
presentations. Here, crowded hospital settings and rapid turnover of
patients make infection control measures difficult. These challenges
still creates barrier to achieve greater outcome in this highly curable
malignancy.

\textbf{Limitation of the study:} This is a relatively small study
involving only 20 cases. The patients were followed up only till the
beginning of maintenance therapy.

\textbf{Conclusion}

In Bangladesh, clinical and peripheral remission rate of pediatric APL
after induction chemotherapy is 90\%, but post-consolidation bone marrow
remission rate is only 75\%. Causes of deaths are neutropenic sepsis,
severe hemorrhage, differentiation syndrome and stroke. Neutropenic
sepsis is the most common adverse event.

\textbf{Recommendations}

Large, multi-center studies with long term follow up plan should be
performed in developing countries.

\textbf{Acknowledgments~}This study was supported by all teachers and
resident physicians of pediatric hematology and oncology department of
BSMMU, Dhaka, Bangladesh.

\textbf{Conflicts of interest} Authors declare no conflicts of
interests.

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\end{enumerate}

\textbf{Legends:}

Figure 1: Chemotherapy protocol for pediatric APL patients

TABLE 1: Clinico-hematological profile of pediatric APL cases

TABLE 2 Response to treatment of pediatric APL cases

TABLE 3 Adverse events: neutropenic sepsis in pediatric APL cases

TABLE 4 Adverse events (other than sepsis) in pediatric APL cases\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/FIG-TIF-1200/FIG-TIF-1200}

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\textbf{Hosted file}

\verb`TAB 1.docx`  available at \url{https://authorea.com/users/350854/articles/475579-early-response-to-treatment-and-adverse-events-in-pediatric-acute-promyelocytic-leukemia-a-single-center-observational-study-in-bangladesh}

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\verb`TAB 2.docx`  available at \url{https://authorea.com/users/350854/articles/475579-early-response-to-treatment-and-adverse-events-in-pediatric-acute-promyelocytic-leukemia-a-single-center-observational-study-in-bangladesh}

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\verb`TAB 3.docx`  available at \url{https://authorea.com/users/350854/articles/475579-early-response-to-treatment-and-adverse-events-in-pediatric-acute-promyelocytic-leukemia-a-single-center-observational-study-in-bangladesh}

\textbf{Hosted file}

\verb`TAB 4.docx`  available at \url{https://authorea.com/users/350854/articles/475579-early-response-to-treatment-and-adverse-events-in-pediatric-acute-promyelocytic-leukemia-a-single-center-observational-study-in-bangladesh}

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