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\begin{document}

\title{IMPROVED SURVIVAL FOR CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IN A LOW
MIDDLE-INCOME COUNTRY: REDUCTION IN ABANDONMENT and relapse}



\author[1]{George Bogonko}%
\author[1]{Festus Njuguna}%
\author[1]{Fredrick Odongo}%
\author[2]{GILBERT OLBARA}%
\author[2]{Sandra Langat}%
\author[2]{Martha Kipng'etich}%
\author[2]{Dennis Njenga}%
\author[3]{Saskia Mostert}%
\author[4]{Gertjan Kaspers}%
\author[5]{Terry Vik}%
\affil[1]{Moi University}%
\affil[2]{Moi Teaching and Referral Hospital}%
\affil[3]{Emma Kinderziekenhuis Amsterdam UMC}%
\affil[4]{Prinses Maxima Centrum voor Kinderoncologie}%
\affil[5]{Indiana University Department of Pediatrics}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} In our earlier published outcomes of children with
acute lymphoblastic leukemia (ALL) at Moi Teaching and Referral Hospital
in Kenya (MTRH), we showed low event-free survival (EFS) with high
induction mortality and abandonment. Based on this observation, the team
focused on strategies to reduce both causes of poor outcomes.
\textbf{Intervention:} We dropped doxorubicin from induction therapy as
the supply of L-asparaginase became reliable, improved social and
financial support for insurance coverage and transportation, promptly
initiated empirical antibiotics during episodes of febrile neutropenia,
and enhanced the availability of blood products. \textbf{Objective:} Our
study compared childhood ALL outcomes before (2010-2016) and after
(2017-2020) modification of induction therapy, with improved social and
financial support and supportive care. \textbf{Methods:} We reviewed the
medical records of 123 children with ALL between 2017 to 2020. Their
treatment results were collected and compared to those of 136 children
before the (2010-2016) modification of induction therapy, with improved
social and financial support. \textbf{Results:} Three-year EFS estimates
improved from 18.2\% to 40.7\%. Relapse or progressive disease decreased
from 26\% to 16\%, and abandonment from 24\% to 14\%. Deaths and
survival through induction did not change significantly between the two
periods. Children between 1-9 years and those with white blood cell
(WBC) count \textless{}50x10 \textsuperscript{9}/L had better EFS.
\textbf{Conclusions:} Treatment abandonment and relapse decreased, and
EFS increased significantly. However, strategies to improve early
diagnosis and supportive care are needed to reduce induction mortality.
In addition, enhanced parental education and continuous counseling are
required to minimize treatment abandonment further.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Acute lymphoblastic leukemia (ALL) is globally the most common childhood
malignancy. \textsuperscript{1} Survival of childhood ALL has improved
significantly in high-income countries (HIC) with over 90\% 5-year
overall survival (OS), while low-middle-income countries (LMIC) continue
to register dismal survival rates.\textsuperscript{2-6} In sub-Saharan
Africa, 2-year event-free survival estimates of 22\% and 33\% have been
reported in Rwanda and Tanzania, respectively.\textsuperscript{7-8} The
poor outcomes of childhood ALL in LMICs are characterized by high
induction mortality, treatment abandonment, and leukemia
relapse.\textsuperscript{3,6,7} These poor outcomes are associated with
low socioeconomic status, delayed diagnosis and treatment, and
inadequate medical resources to support the
patients.\textsuperscript{4-6}

Since 2010, in collaboration with twining partners from Princess M\selectlanguage{ngerman}áxima
Center for Pediatric Oncology in the Netherlands and Indiana University
in the United States of America (USA), we have been treating children
with ALL using resource-adapted protocols. The previously published
treatment outcome of children with ALL in our setting between 2010 to
2016 showed low event-free survival associated with high induction
mortality and abandonment rates.\textsuperscript{9} Following this
observation, our team came up with strategies to reduce induction deaths
and abandonment.

In this study, we compared childhood ALL outcomes before (2010-2016) and
after the (2017-2020) modification of induction therapy with improved
social and financial support and supportive care.

\textbf{METHODS}

\textbf{Setting}

Kenya is a low-middle-income country (LMIC) with an estimated population
of 55 million as of 2021, according to world bank data. The population
below the poverty line is estimated at 36.1\% as of 2015. Children below
the age of 15 accounts for 39\% of the total
population.\textsuperscript{10-12}

Over 80\% of the Kenyan population does not have health insurance
coverage. The National Health Insurance Fund (NHIF) is the primary
insurer covering approximately 16 \%, while private insurers cover about
1\% of the Kenyan population. This leaves most Kenyans paying hospital
bills out of pocket.\textsuperscript{13} The study was carried out at
MTRH, the country's second-largest public hospital that offers pediatric
cancer treatment. It is situated in the western part of the country, in
Eldoret town, Uasin Gishu county. It serves a catchment population of
about 25 million people. On average, 240 children were diagnosed with
cancer annually during the period in review. The pediatric oncology unit
has a capacity of thirty-five beds with a bed occupancy of over 200\%.
Most patients begin their initial treatment in the general wards before
being transferred to the oncology unit. The children with cancer are
cared for by a multidisciplinary team in collaboration with visiting
pediatric hematology-oncology experts from our twinning partner
institutions in the Netherlands and the USA.

\textbf{Intervention}

In the previous (2010-2016) cohort, doxorubicin was used in the
induction therapy (6 weeks). It was dropped in the current cohort
(2017-2020) from the induction phase once the L-asparaginase supply was
consistent. The patients received a three-drug induction (vincristine,
prednisone, and L-asparaginase) lasting six weeks. Additionally,
patients who did not have health insurance (NHIF) were supported to
enroll and transport assistance for needy parents through collaboration
with philanthropic organizations and continuous parental counseling and
support groups. The social work department facilitated this. Supportive
care included better availability and early initiation of antibiotics
during episodes of febrile neutropenia and enhanced availability of
blood products.

\textbf{Study design}

This was a retrospective medical records study of children (0-16 years)
diagnosed with ALL at MTRH from January 2017 to December 2020. We
included all children with a diagnosis of ALL, regardless of their
clinical condition, before the initiation of treatment. Previous medical
record data before (2010-2016) modification of induction therapy, with
improved social and financial support and supportive care, was available
for comparison.

Socio-demographic data, including age, gender, the distance of residence
from MTRH, and duration of symptoms, had been collected at diagnosis for
the current cohort (2017-2020) and was available. In addition, we
obtained data on health insurance status and treatment outcomes from the
medical records. We recorded treatment outcomes as abandonment, death,
relapsed or progressive disease, and event-free. Additional clinical
data for the current cohort (2017-2020) included: white blood cell (WBC)
count at diagnosis, ALL immunophenotype, and central nervous system
(CNS) disease status. We determined survival through induction and the
survival estimates by WBC, sex, age at diagnosis, health insurance
status (NHIF) at diagnosis, event-free and overall survival.

The children with ALL at MTRH were treated with a modification of the
Dutch Oncology Group ALL-6 Study (1984-1988) therapy for non-high-risk
ALL.\textsuperscript{14} All patients received the same standard
protocol without risk stratification and consisted of induction (6
weeks), consolidation (2 weeks), methotrexate phase (7 weeks),
re-induction (3 weeks), and maintenance therapy (83 weeks). For this
cohort study (2017-2020), doxorubicin was dropped from the induction
phase) as the supply of vincristine, prednisone, and especially
L-asparaginase was improved. The additional modification included
intensified L-asparaginase therapy and a fourth high-dose methotrexate.
The duration of ALL treatment lasts for 104 weeks (supplementary
material, TABLE S1).

The diagnosis of ALL was made based on a bone marrow examination by the
pathologists. Due to financial constraints, the use of flow cytometry to
further confirm the diagnosis and determine ALL immunophenotypes could
only be done in some patients.

Refusal to start or continue with planned treatment for four or more
weeks consecutively was considered treatment
abandonment.\textsuperscript{9,15} Induction or early deaths were those
that occurred before the start of treatment or during induction
(\textless{}42 days from the start of
treatment).\textsuperscript{3,9}Deaths that occurred before the start of
treatment or following relapsed/progressive leukemia were deemed to be
disease-related. The deaths that occurred after treatment was initiated
were deemed to be treatment-related. The clinical signs and symptoms and
the presence of lymphoblasts on bone marrow aspirate or peripheral blood
smear confirmed the relapsed disease). CNS involvement was evaluated
through cerebral-spinal fluid examination, which was reported as
positive or negative.

This study was approved by the Institutional research and ethics
committee of MTRH and Moi University.

\textbf{Data analysis}

Statistical analysis was performed using R version 4.1.2. Descriptive
statistics were used to analyze patient demographics, clinical
characteristics, and outcomes. Data are reported as medians and
interquartile range (IQR) or means and standard deviation (SD)where
applicable. Comparisons of variables between the earlier cohort and the
current cohort were analyzed for significance using the chi-square test
and t-test. Continuous variables were compared by the two-tailed
chi-square test and Fisher's exact test where applicable. The level of
significance was set for a p-value \textless{}0.05. Survival estimates
were determined using the Kaplan-Meier method.

Event-free survival (EFS) was based on the time of diagnosis to the date
of the first treatment outcome (death, relapse/progressive disease,
abandonment, alive at last follow-up). Overall survival (OS)was based on
the time of diagnosis until the patient's death or the last follow-up if
alive. The analysis of prognostic factors was based on the EFS and the
comparison of curves by the log-rank test.

\textbf{RESULTS}

From January 2010 to December 2016 (before the modification of induction
therapy, with improved social and financial support), 136 medical
records of children with ALL (0-16 years) had previously been reviewed
and published, and data were available for comparison.

From January 2017 through December 2020 (after modification of induction
therapy, with improved social and financial support), 160 children (0-16
years) were diagnosed with ALL at MTRH. Their data on age, sex, duration
of illness, and distance to the hospital had been collected at diagnosis
and was available. In addition, we retrieved medical records for 123 of
the 160 children. We collected data on outcomes (relapse/progressive
disease, death, abandonment of therapy, event-free survival), health
insurance, WBC count at diagnosis, ALL immunophenotype, and CNS disease
status.

Table 1 illustrates the socio-demographic and clinical characteristics
of the two cohorts. There was no difference in age and sex distribution
between the two cohorts before (n=136) and after (n=160) modification of
induction therapy with improved social and financial support. The number
of patients with no health insurance (NHIF) decreased from 16\% to 2\%
before (n=136) and after (n=123), respectively. Patients who had
symptoms for 1-3 months were 68 (52\%) and 72(45\%) before (n=132) and
after (n=156), respectively. The number of patients whose residence is
\textgreater{}100 kilometers from MTRH increased from 60\%(n=136) to
80\%(n=157).

Table 2 shows the first treatment outcomes before (n=136) and after
(n=123) the modification of induction therapy with improved social and
financial support. Death, the most common cause of treatment failure in
our setting, did not change significantly between the two periods. Most
of the deaths were treatment-related in both periods. Abandonment
decreased significantly between the two periods (p\textless{}0.03318).
Most children abandoned treatment during maintenance therapy: 18 out of
33 in 2010-2016 (n=136) and 15 out of 17 in the 2017-2020 (n=123)
period. Relapse/progressive disease decreased significantly
(p\textless{}0.04136). Among children who had a relapse of their
disease, it occurred during maintenance in 19(70\%) and 12(67\%) of them
before (19/27) and after (12/18), respectively. Event-free survival
increased significantly(p\textless{}0.00001) between the two periods.

Figure 1 shows comparisons of survival through induction between the two
periods. Patients who died in induction decreased from 24\% (32/136) to
17\% (21/123) between the two periods. However, the difference was not
statistically significant (p\textless{} 0.198). Figure 2 shows the
comparison of treatment abandonment between the two cohorts. Treatment
abandonment decreased significantly from 24\% to 14\%
(p\textless{}0.03318).

The sex, duration of symptoms, distance to the hospital, and health
insurance status did not significantly influence treatment outcomes and
event-free survival estimates in both cohorts. Patients with relapsed or
progressive disease were offered palliative therapy, and all died. In
the 2017- 2020 cohort alone (no data for the 2010-2016 cohort), out of
24 children with CNS disease, 14(58\%) died, 4(17\%) were referred for
craniospinal radiation (there were no radiotherapy services at MTRH),
3(13\%) were among those who abandoned treatment, and 4(17\%) were still
alive with enhanced intrathecal chemotherapy.

However, age and WBC count at diagnosis significantly influenced
event-free survival in the 2017- 2020 cohort. Figure 3(A) shows
event-free survival by WBC count at diagnosis. Patients with WBC count
\textless{}50 x 10\textsuperscript{9}/L had better event-free survival
compared to those with \textgreater{}50 x 10\textsuperscript{9}/L
(p\textless{}0.017). Figure 3(B) shows that children between the age of
1 year to 9 years had better event-free survival, while those below one
year of age had the worst outcome (p\textless{}0.0001).

Figure 4(A) compares event-free survival estimates between the two
cohorts. The EFS at three years significantly improved from 18\%
(95\%CI, 0.123-0.268) to 41\% (95\%CI, 0.319-0.518)
(p\textless{}0.0001). Figure 4(B) shows the overall survival estimates
for the 2017- 2020 cohort alone (no data for the old cohort). This
cohort's 3-year overall survival (OS) estimate was 49.2\% (95\% CI,
39.1\% to 62\%).

\textbf{DISCUSSION}

This study shows a significant improvement in 3-year EFS estimates of
children diagnosed with ALL at MTRH (from 18\% to 41\%). This could be
attributed to a reduction in the abandonment of therapy and relapse.
However, death was the most common cause of treatment failure, with a
significant proportion of deaths occurring during induction in the two
cohorts.

Treatment abandonment as a cause of treatment failure reduced
significantly (from 27\% to 14\%) in this study. It is modestly lower
than Honduras, 22\% and Indonesia, 35\%.\textsuperscript{4-5} However,
this was higher than observed in Pakistan, 7.5\%, and Rwanda,
10\%.\textsuperscript{3,7} Abandonment has been directly associated with
low socioeconomic status and long travel time in some
LMICs.\textsuperscript{3,6} Lack of medical insurance has been
associated with higher rates of treatment abandonment and lower overall
survival of cancer patients in previous studies in
Kenya.\textsuperscript{16} With most patients abandoning treatment
during maintenance, it is probable that because patients look relatively
well during maintenance, parents may think they are cured. The long
duration of ALL treatment is also likely to cause families to become
lethargic over time. The reduction in abandonment in this study can be
attributed to continuous counseling of parents, assessing for the
economic challenges, and mitigating them whenever possible. That
includes assisting parents in enrolling in health insurance (NHIF) and
parent support groups by the social-work services department.

The relapsed leukemia decreased significantly as a first treatment
outcome. Out of those that achieved remission, the proportion of
children that had a relapse (19\%) was similar to what has been found in
other studies where relapses are reported to range between 12\% and
20\%.\textsuperscript{17} Due to decreased abandonment, there were
probably more patients at risk of relapse in this study. Like other
centers in LMIC, our patients are treated with a standard treatment
protocol without risk stratification. That means sub-optimal intensity
post-induction therapy for high-risk ALL children and corresponding poor
EFS. In Rwanda, in a study by Rubagumya et al. children with ALL who
were treated with low-intensity treatment had EFS of 22\%, with relapse
as the leading cause of treatment failure (53\%). However,
treatment-related toxicity was acceptably
low.\textsuperscript{7}Therefore, there is a need to adopt a risk
stratification criterion at MTRH, with more intensification of therapy
for the high-risk group to reduce relapses.

Historically, WBC and age at diagnosis, sex, initial treatment response
determined by end induction bone marrow morphological remission, and
immunophenotype have been used to stratify patients' risk status and
predict the outcome. In this study, we showed that ALL patients with an
initial WBC \textless{}50 x 10\textsuperscript{9}/L and patients in the
age group 1 to 9 years had better event-free and overall survival with
the current treatment protocol. Patients with CNS involvement were at
high risk of death despite intensified intra-thecal chemotherapy alone,
as there were no radiotherapy services available during the period, and
few patients were referred out for craniospinal radiation. Studies from
HIC have shown that determination of end-induction measurable residual
disease (MRD) by flow-cytometry or PCR has proven to be a reliable
predictor for relapse and overall outcome. Post-induction treatment
intensification for end-induction MRD-positive patients improved overall
survival.\textsuperscript{18,19} However, treatment intensification for
high-risk patients demands more intensive supportive care that is not
readily achievable in most centers in LMICs. Also, we do not have the
resources to monitor MRD in our setting.

The proportion of patients who died during induction decreased (from
24\% to 17\%) between the two periods, although the difference was not
statistically significant. Most of the deaths were treatment-related.
These induction deaths approximate what was observed in other LMICs. In
a study by Jabeen, K et al. (2016) in Pakistan, Induction deaths
accounted for 19.2\%, most of which were
infection-related.\textsuperscript{6} In Egypt, in a study by
Abdelmabood S et al. (2020), induction deaths were 23\%, the majority
related to infections.\textsuperscript{3} One factor for the decrease in
deaths in our cohort is likely due to dropping doxorubicin from the
induction regimen when L-asparaginase was more available. Using a less
intensive three-drug induction regimen (prednisone, asparaginase,
vincristine) has been associated with decreased early mortality (toxic
deaths) and improved short-term survival compared to a more intensive
anthracycline-containing induction regimen.\textsuperscript{20,21} The
other factor includes prompt recognition of neutropenic fever and
initiation of empiric antibiotics. The use of antimicrobial prophylaxis
has been shown to reduce significantly induction deaths related to
infections.\textsuperscript{22} In our setting, we have used
cotrimoxazole, fluconazole, and ciprofloxacin prophylaxis during severe
neutropenia (\textless{}0.5 x 10\textsuperscript{9}/L). Invasive
infections are a common complication and cause of death during
induction, requiring more effective infection prevention
strategies.\textsuperscript{23} Improved supply of blood products,
especially platelets, has also contributed to the supportive care of the
patients during induction. At MTRH, there is an urgent need to create
more space to allow for better isolation, develop antibiotic therapy
guidelines based on local antimicrobial sensitivity patterns, and
improve supplies of blood products to reduce induction deaths further.

Delay in diagnosis and initiation of treatment is also among the reasons
for poor outcomes in LMICs.\textsuperscript{24} Although the duration of
illness did not significantly influence the outcome in the two periods,
more than half of the patients had had symptoms for more than 1-month
before presentation at MTRH. In India, prolonged symptom-to-diagnosis
interval in childhood acute ALL adversely impacted survival, with those
less than eight weeks having a better median survival of 59 +/- 5
months.\textsuperscript{25} Dai Q et al. (2022) found that diagnosis
delay was an independent predictor for treatment outcomes in childhood
ALL.\textsuperscript{26} Longer time interval to the diagnosis of ALL
has been associated with more extensive disease, increased toxicity from
chemotherapy, and death. Almost all the patients diagnosed at MTRH are
referred from lower-level County health facilities, with no adequate
expertise and diagnostic capacity, resulting in a delay in referral,
diagnosis, and initiation of treatment.

Like in the earlier cohort, further analysis of event-free survival
estimates of those with NHIF at diagnosis and those without did not
reveal any statistically significant difference. This could be
attributed to the fact that 40 out of the 43 who did not have health
insurance were assisted to be enrolled through the social work services
department during the first weeks of therapy. Moreover, there is a
possibility of waiver for the poorest.

Being a retrospective study, the limitations experienced included
missing medical records and lack of documentation of information in some
of the retrieved records.

In conclusion, there was an improvement in event-free survival and a
reduction in treatment abandonment and relapse. However, induction
deaths did not reduce significantly. Although the survival outcomes are
much lower compared to HIC, this study highlights the importance of
collaboration with institutions in HIC and LMIC.\textsuperscript{27} and
continuous quality improvement strategies that are adapted to available
resources. Future strategies to reduce induction mortality should
include working in collaboration with county lower-level facilities to
improve early recognition, referral, diagnosis, and initiation of ALL
treatment. Improved availability of blood products, especially
platelets, adequate ward space for isolation, and other infection
prevention strategies, including handwashing and prophylactic
antimicrobial use, need to be implemented. There is a need for advocacy
for universal health care through NHIF coverage and improved parental
education and counseling to reduce treatment abandonment further. Proper
risk stratification, use of risk-adapted protocols, and treatment of
relapsed disease in resource-limited settings such as MTRH need to be
studied. Collaboration with institutions in HIC through the existing
twinning programs needs to be enhanced for knowledge and skills
transfer. Implementing all or most of this will help us to achieve a
60\% cure of patients with ALL by 2030, as stated by the WHO Global
initiative on Childhood Cancer.\textsuperscript{1}

\textbf{ACKNOWLEDGEMENTS}

We thank the collaborating institutions, The Moi Teaching and Referral
Hospital, Princess Máxima Center for Pediatric Oncology, Utrecht, The
Netherlands, and Indiana University School of Medicine, Indianapolis,
Indiana, USA.

\textbf{CONFLICT OF INTEREST}

All authors declare no conflict of interest.

\textbf{ETHICS APPROVAL}

This study was approved by the Institutional Research and Ethics
Committee of Moi University/Moi Teaching and Referral Hospital.

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  Oncology Group study AALL0232. \emph{Blood} 2015;126(8):964-71.
\item
  Messinger Y, \& Uckun FM. A critical risk-benefit assessment argues
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  diagnosed childhood acute lymphoblastic leukemia. \emph{Leukemia and
  Lymphoma} 1999;34(5--6):415--432.
\item
  Hunger S, Reyes D, Negrin O, et al. Decreased early mortality and
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  leukemia in the Dominican Republic. \emph{Pediatric Blood Cancer} 2011
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\item
  Yeh TC, Liu HC, Hou JY, et al. Severe infections in children with
  acute leukemia undergoing intensive chemotherapy can successfully be
  prevented by ciprofloxacin, voriconazole, or micafungin
  prophylaxis.\emph{Cancer} , 2014;120(8):1255--1262.
\item
  Burns JE, Perez DR, Li Y, et al. Assessment of the impact of inpatient
  infectious events in pediatric patients with newly diagnosed acute
  leukemia at Dr. Robert Reid Cabral Children's Hospital, Dominican
  Republic. \emph{PLOS ONE} 2020;15(12): e0243795.
\item
  Njuguna F, Martijn H, Langat S, et al. Factors influencing time to
  diagnosis and treatment among pediatric oncology patients in
  Kenya.\emph{Pediatr Hematol Oncol} 2016;33(3):186-99.
\item
  Kulkarni KP, \& Marwaha RK. Symptom diagnosis interval in childhood
  acute lymphoblastic leukemia: Prognostic impact and association with
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\item
  Dai Q, Liu R, Wang Y, et al. Longer Time Intervals from Symptom Onset
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\item
  Rivera GK, \& Ribeiro RC. Improving treatment of children with acute
  lymphoblastic leukemia in developing countries through technology
  sharing, collaboration, and partnerships. \emph{Expert Review of
  Hematology} 2014;7(5):649-657.\textbf{FIGURE LEGENDS}Figure 1.
  Comparison of survival of children through the induction phase of
  therapy between the two cohorts before (n=136) and after (n=123)
  Figure 2. Comparison of treatment abandonment between the two cohorts
  before (n=136) and after (n=123) Figure 3: (A) Comparisons of
  event-free survival of children with low WBC (\textless{}50 x 109/L)
  to those with high WBC (\textgreater{}50 x 109/L), (B) comparison of
  event-free survival by age group. Figure 4: (A) comparisons of
  event-free survival estimates before (n=136) and after (n=123) (B)
  overall-survival estimates for the 2017-2020 cohort (n=123)
\end{enumerate}

TABLE 1 Socio-demographic and clinical characteristics of patients for
the two periods\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Categories & 2010-2016 (n=136) & 2017-2020 (n=160)\tabularnewline
\midrule
\endhead
Age at diagnosis (years) & Mean (SD) & 7.9(4) & 6.9 (4.2)\tabularnewline
& Median (IQR) & 7.8(4.5-11.2) & 6 (3, 10)\tabularnewline
Sex & Male & 73(54\%) & 91 (57\%)\tabularnewline
& Female & 63(46\%) & 69 (43\%)\tabularnewline
Distance to MTRH & & (n=136) & (n=157)\tabularnewline
& \textless{}100 Km & 54(40\%) & 32 (20\%)\tabularnewline
& \textgreater{}100 Km & 82(60\%) & 125 (80\%)\tabularnewline
Duration of symptoms before admission at MTRH & & (N=132) &
(N=156)\tabularnewline
& \textless{}1 month & 31(23\%) & 57 (36\%)\tabularnewline
& 1-3 months & 68(52\%) & 72 (45\%)\tabularnewline
& \textgreater{} 3months & 33(25\%) & 27 (17\%)\tabularnewline
Health insurance (NHIF) status & & (n=136) & (n=123)\tabularnewline
& NHIF at the start of treatment & 71(52\%) & 80 (65\%)\tabularnewline
& NHIF during treatment & 43(32\% & 40 (33\%)\tabularnewline
& No NHIF & 22(16\%) & 3 (2\%)\tabularnewline
WBC count at diagnosis (x10\textsuperscript{9} /L) (n=123) &
\textless{}50 & & 81 (66\%)\tabularnewline
& [?]50 & & 42 (34\%)\tabularnewline
ALL immunophenotypes (n=123) & B-cell precursor & & 33
(27\%)\tabularnewline
& T-cell & & 8 (6\%)\tabularnewline
& Not determined & & 82 (67\%)\tabularnewline
CNS status (n=123) & Negative & & 94 (76\%)\tabularnewline
& Positive & & 24 (20\%)\tabularnewline
& Not determined & & 5 (4\%)\tabularnewline
\bottomrule
\end{longtable}

TABLE 2 Treatment outcome comparing the two cohorts before (n=136) and
after (n=123)\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& & 2010-2016 cohort (n=136) & 2017-2020 cohort (n=123 &
p-value\tabularnewline
\midrule
\endhead
First treatment outcome & Death & 40(30\%) & 31(25\%) &
NS\tabularnewline
& Relapse/progressive & 35(26\%) & 19(16\%) & 0.04136\tabularnewline
& Abandonment & 33(24\%) & 17(14\%) & 0.03318\tabularnewline
& Event free & 27(20\%) & 56(46\%) & 0.00001\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1 Comparison of survival of children through the induction phase
of therapy between the two cohorts before (n=136) and after (n=123).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2 Comparison of treatment abandonment between the two cohorts
before (n=136) and after (n=123).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 3: (A) Comparisons of event-free survival of children with low
WBC (\textless{}50 x 10\textsuperscript{9}/L) to those with high WBC
(\textgreater{}50 x 10\textsuperscript{9}/L), (B) comparison of
event-free survival by age group.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure 4: (A) comparisons of event-free survival estimates before
(n=136) and after (n=123) (B) overall-survival estimates for the
2017-2020 cohort (n=123)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-1-survival-through-induction/Fig-1-survival-through-induction}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-2-treatment-abandonment/Fig-2-treatment-abandonment}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-survival-by-WBC-and-AGE-group/Figure-3-survival-by-WBC-and-AGE-group}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4-EFS-and-OS-estimates/Figure-4-EFS-and-OS-estimates}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`TABLE 1 Sociodemographic and clinical characteristics.docx`  available at \url{https://authorea.com/users/589671/articles/626394-improved-survival-for-childhood-acute-lymphoblastic-leukemia-in-a-low-middle-income-country-reduction-in-abandonment-and-relapse}

\textbf{Hosted file}

\verb`TABLE 2 Treatment outcomes.docx`  available at \url{https://authorea.com/users/589671/articles/626394-improved-survival-for-childhood-acute-lymphoblastic-leukemia-in-a-low-middle-income-country-reduction-in-abandonment-and-relapse}

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

