Pediatric Hematology Oncology Journal 5 (2020) 11e16

Contents lists available at ScienceDirect

Pediatric Hematology Oncology Journal

journal homepage: https://www.elsevier.com/journals/pediatric-
hematology-oncology-journal/

Malaysia-Singapore (MASPORE) leukaemia study group: From

common history to successful collaboration
Hany Ariffin a, *, Syaza Ab Rahman a, Sheng Hoay Leong a, Edwynn Kean-Hui Chiew b,
Hai Peng Lin c, Thuan Chong Quah b, Allen Eng-Juh Yeoh b, **
a
Department of Paediatrics, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
b
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
c
Subang Jaya Medical Centre, Kuala Lumpur, Malaysia

a r t i c l e i n f o a b s t r a c t

Article history: The 1970s marked the beginning of childhood cancer services in Malaysia and Singapore, two neighbours
Received 1 January 2020 in South-East Asia. Between 1995 and 2002, Malaysia utilized a treatment regimen based on the Dutch
Received in revised form DCOG 7 and German BFM protocols for children with acute lymphoblastic leukaemia (ALL), whilst
28 February 2020
Singapore in collaboration with Hong Kong employed the HK-ALL 1997 protocol, based on BFM ALL 95. In
Accepted 2 March 2020
Available online 24 March 2020
2002, the overall 6-year event-free survival (EFS) for childhood ALL in Malaysia stood at 56%, while the 5-
year EFS for HK-ALL 1997 was 79%. Formal collaboration between Malaysia and Singapore for the
treatment of childhood ALL began in 2003. The first collaborative trial was the seminal MASPORE
ALL2003 study which utilized a single PCR-based minimal residual disease marker to risk stratify pa-
tients according to disease severity, and used a 3-drug induction regimen for non-high-risk patients. This
effort resulted in an improvement in 6-year EFS for both countries, at 80%, with an overall survival of 88%.
The study showed that treatment could be appropriately tailored to disease risk, and that an
anthracycline-free induction strategy did not compromise outcome for the majority (86%) of patients.
The follow-up study, MASPORE ALL2010 focused on delivering therapy that was more intensive for those
in high-risk group while reducing intensity for standard and intermediate risk groups. The study also
took into consideration patients with IKZF1 gene deletion (IKZF1del) and moved these patients into a
higher risk category. Increasing treatment intensity for patients with IKZF1del resulted in a reduction in 5-
year cumulative incidence of relapse (CIR) from 30 to 13%, and improved overall 5-year survival from 69
to 91%. The MASPORE ALL2010 trial also studied TPMT and NUDT15 gene variants in its patient population
to optimize thiopurine dosing. As the study moves into its next phase (MASPORE ALL2020), precision
medicine and risk-adapted therapy remain the cornerstone strategies for childhood ALL, especially in the
era of increased recognition of late effects amongst survivors of childhood cancer. Future therapies will
likely focus on further targeted treatment for childhood ALL as more molecularly distinct subtypes
become known.
© 2020 Publishing Services by Elsevier B.V. on behalf of Pediatric Hematology Oncology Chapter of Indian
Academy of Pediatrics. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

1. Background having a common ethnic makeup of Malay, Chinese, Indian and

indigenous peoples. Despite their geographical proximity, the
Located in South-East Asia, Malaysia and Singapore are close two countries have large economic differences. Malaysia is an
neighbours with a shared history of being British colonies and upper middle-income country with a GDP per capita of USD
11,373, while Singapore is a high-income country with a GDP per
capita of USD 64,581 (2018) [1]. In 2016, Malaysia allocated 3.6%
* Corresponding author. of its GDP on health expenditure (USD 360 per person) whilst
** Corresponding author. Singapore spent an average of USD 2400 for each of its in-
E-mail address: hany@ummc.edu.my (H. Ariffin). habitants [2].
Peer review under responsibility of Pediatric Hematology Oncology Chapter of Childhood cancer services in Malaysia and Singapore began in
Indian Academy of Pediatrics.

https://doi.org/10.1016/j.phoj.2020.03.009
2468-1245/© 2020 Publishing Services by Elsevier B.V. on behalf of Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
12 H. Ariffin et al. / Pediatric Hematology Oncology Journal 5 (2020) 11e16
the 1970’s. Initially, because of the lack of mentors, most paediatric
oncologists were sent overseas for training mainly to UK, Australia
and Europe. They brought back treatment protocols such as the
MRC UKALL and the European (BFM) protocols and adapted these
regimens for use locally.
2. Pre-MASPORE ALL era (1995e2002)
Between 1995 and 2002, a common protocol based on the
Dutch DCOG 7 protocol was used in Malaysia. Ease of delivery
and tolerability were the main criteria especially since the key
concern then was sepsis-related deaths. The MCCG-ALL95 pro-
tocol, as it was known, consisted of a 3-drug induction phase,
consolidation with cyclophosphamide and cytarabine, followed
by medium-dose intravenous methotrexate (2 gm/m2 every 2
weeks for 3 doses) and oral maintenance therapy with mercap-
topurine and methotrexate. Children with T-cell disease,
adolescent age, presenting white cell count of >50,000/ml or
‘poor’ prednisolone response (defined as >1000/ml circulating
blasts after 7 days of prednisolone monotherapy) were treated
with a 4-drug induction and, in addition to the protocol above,
received a re-intensification phase similar to the BFM-based
Protocol II. When the study closed in 2002, 6-year event-free
survival (EFS) was 56%, with 65% EFS in the low-risk group and
52% in the high-risk group. Children in the poorest risk category
(those with presenting white cell count of >100,000/ml) had a 6-
year EFS of only 25% [3].
In Singapore, the earliest collaboration for childhood ALL ther-
apy was between National University Hospital (NUS) and centres in
Hong Kong, led by Professor Li Chi Kong. Due to inferior results of
the chemotherapy intensive UKALL X protocol, Hong Kong doctors
joined the I-BFM consortium and designed a new treatment pro-
tocol called HK-ALL 1997 which was BFM ALL 95 based. The HK-
ALL1997 trial ran between 1997 and 2002. Although the BFM ALL
protocol was more toxic with higher treatment morbidity, the 5-
year EFS was 79%, a 13% improvement from the POG-based
regimen that Singapore had previously used [4]. However, the
toxicity of the 4-drug BFM Protocol Ia and Ib induction and delayed
intensification Protocol II was considerable. Moreover, the majority
of patients who relapsed came from the non-high risk patients
suggesting that risk stratification based primarily on NCI criteria of
age and WBC count and conventional genetic subtype was
insufficient.
With the launch of the Bio-Medical Sciences initiative in
Singapore, research funding quantum increased. NUS investigators
led by Associate Professor Thuan Chong Quah and Dr Allen Yeoh
successfully obtained a large grant from the Singapore National
Medical Research Council (NMRC) to run a minimal residual disease
(MRD) stratified study using IgH PCR markers. Unfortunately, the
Hong Kong investigators did not manage to obtain adequate funds
for their own MRD project and opted to join the I-BFM-Inter-Con-
tinental IC 2002 study, thus ending the Hong Kong e Singapore ALL
collaboration.
During the same time, Malaysia’s University Malaya Medical
Center (UMMC) led by Professor Lin Hai Peng and Dr Hany Ariffin
decided that the best way to move forward with regards to
childhood ALL therapy was to partner a more advanced country
and in so doing, gain parallel improvements in laboratory services
as well as other intangible benefits from participating in a formal
clinical trial [5]. This set the motion for Malaysia to join ranks with
Singapore.
Professor Lin coined the name Ma-Spore Study Group, from the
shortened version of the two country’s names. In colloquial Malay,
“MaS” means “gold” and indeed, the partnership was both precious
and successful.
3. Establishing a working group and launching MASPORE ALL
2003 protocol
The Malaysia-Singapore Study Group (“MASPORE”) was borne
from a collaboration of the childhood cancer units of UMMC, Kuala
Lumpur and NUS in late 2002. The plan was to launch a common
effective, risk-stratified treatment protocol, the MASPORE ALL2003.
In Malaysia, the goal was to improve survival rates for children
with ALL. However, there were two main challenges; (1) lack of
good supportive care services in Malaysia, and (2) geographical
distribution of patients across the country which meant that care
was not equally accessible to all. For Singapore, reduction of the
toxic 4-drug induction Ia protocol was the main focus.
The MASPORE ALL2003 protocol used the backbone of the
experimental arms of BFM-ALL IC 2002 protocol except:
1. Risk stratification was by using one PCR MRD marker at end of
induction (EOI/Day 33) and end of consolidation (EOC/week 12).
2. 85% of patients who were non-high risk i.e., non-cytogenetic
high risk and good Day 8 prednisolone response received 3-
drug dexamethasone-based induction that contained no
anthracyclines.
The intensive delayed intensification experimental ALL-IC 2002
blocks were preserved. This was based on the CCG-105 series
showing that standard induction and a robust delayed intensifica-
tion provided superior outcomes [6]. The MASPORE strategy was to
use a dexamethasone-based 3-drug induction that omitted mye-
losuppressive drugs notably anthracyclines. This was surmised to
be sufficient to destroy lymphoblasts to a sufficient depth yet allow
rapid bone marrow recovery. As patients were often neutropenic
for months and were frequently septic at presentation, this less
myelosuppressive induction reduced the risk of severe bacterial
and fungal infections. The philosophy was “to get the patient safe
first and intensify later”. This strategy was increasingly important
due to real world challenges such as limited access to tertiary care,
increasing costs of supportive care and anti-microbial resistance.
The MASPORE ALL2003 study was designed to better refine risk
assignment using MRD and act on this improved risk assignment by
decelerating therapy in MRD negative patients. This involved
incorporating clinical and genetic presenting features, including
MRD, to reduce treatment-related toxicities for low-risk patients
(Table 1). This was a fundamental difference from most cooperative
groups which used MRD to intensify rather than decelerate therapy.
Participating in a formal clinical trial had a spillover effect to
UMMC. The most notable being the establishment of its own pae-
diatric oncology research laboratory to deliver services which
hitherto were unavailable such as karyotyping and oncogene fusion
transcript screening. UMMC sent staff to train in blast karyotyping
at NUS which significantly improved the rate of successful cyto-
genetic analysis. Together with NUS, UMMC also managed to
develop a simplified method to screen for common oncogene fu-
sions using multiplex real-time PCR assay [7]. For MRD studies,
bone marrow samples of Malaysian patients were processed and
cryopreserved then shipped weekly to the reference laboratory in
NUS.
4. Building an inter-network relationship
In most modern international collaborative trials, a robust IT
infrastructure is a prerequisite. However, when MASPORE was first
launched, a computer network that could support a multi-site real-
time database was still unaffordable. Thus detailed data collection
and standardization were done manually through bi-annual
meetings where both teams huddled together to late evenings to
 H. Ariffin et al. / Pediatric Hematology Oncology Journal 5 (2020) 11e16
Table 1
Risk stratification criteria used in the MASPORE ALL 2003 (MS2003) and MASPORE ALL 2010 (MS2010) studies respectively. Differences in risk assignment criteria between two
studies are highlighted in bold.
Risk Group MS2003
SR (all criteria
MRD1  104 at Week 5 & 12
fulfilled)
CNS 1

No testicular involvement

No HR feature
IR (entry assignment)
All others including the cases without MRD data (no material or

insensitive marker)
HR (any criterion
MRD1  103 at Week 12
fulfilled)
BCR-ABL1, KMT2A rearrangements, or hypodiploidy (<45 chr)

Induction failure

Prednisolone poor response at Day 8
Abbreviations: Chr, chromosome; CNS, central nervous system; HR, high risk; IKZF1del, IKZF1 gene deletion; IR, intermediate risk; MRD, minimal residual disease; SR, standard
risk.
clean up data and update results. To ensure good quality of samples,
NUS staff went to UMMC to share, train and observe lab processes.
As all members of the group were teetotalers, camaraderie was
built around good food, as always is the case in Asia! Courier ser-
vices and electronic communication tools were exploited to ensure
samples were transported properly and results delivered in a timely
manner.
5. Managing patients with regional hospitals through weekly
telephones
Whilst Singapore is a small city-state with an excellent transport
system in place, the UMMC team had to contend with the
geographical landscape and existing infrastructure in Malaysia.
Malaysian patients were not pre-selected but referred from pe-
ripheral hospitals throughout the country and returned to their
home states during large periods of the protocol. General paediatric
colleagues and nurses who were not specifically trained in
oncology administered segments of the chemotherapy protocol. To
bridge this gap, the UMMC team practiced a mandatory weekly
telephone discussion with colleagues serving the areas where the
patients had returned to so that each patient’s progress could be
documented and recommendations could be made based on the
protocol.
Another key element of the clinical trial’s success was active
empowerment of parents. Although over 80% of the patients’ par-
ents only had education up to secondary school level [8], all parents
received active counselling regarding the overall treatment plan
and given a chemo diary to maintain. Parents were also educated
on temperature monitoring of children and an emergency man-
agement plan should the child become unwell. A “hotline” tele-
phone number was established where parents could call. Education
of healthcare personnel regarding emergency treatment of febrile
neutropenia with fast-track admission and administration of anti-
biotics was also emphasized.
6. Obtaining financial support
It takes considerable financial support to conduct an interna-
tional clinical trial. This was a major early challenge for the MAS-
PORE group. Fortunately, the group successfully obtained funding
not only from government agencies but also from charitable or-
ganizations. In Singapore, the Children’s Cancer Foundation, VIVA
Foundation for Children with Cancer, Lee Foundation and Goh
Foundation funded many aspects of MASPORE. In Malaysia, the
13
MS2010

MRD1  104 at Week 5 & 8

CNS 1

No testicular involvement

No HR feature

No IKZF1del

Age<10
All others including the cases without MRD data (no material or
insensitive marker)

MRD negative (≤1£10¡4) with IKZF1del, CNS 2/3, or extra-medullary
involvement

MRD1  102 at Week 5 or MRD1  103 at Week 8

BCR-ABL1, KMT2A rearrangements, or hypodiploidy (<45 chr)

Induction failure

MRD positive (>1  104) with IKZF1del
group’s activities were supported by philanthropic individuals and
corporations such as TESCO. Without such funds, MASPORE ALL
study group would not have been able to deliver the protocol itself,
collect data and perform the many sophisticated laboratory tests
which guided therapy.
When the trial concluded in March 2011, 559 subjects aged less
18 years had been recruited including infants and children with
Down Syndrome. Of these, 86% of subjects had received a
dexamethasone-based, 3-drug induction. Induction deaths were
seen in 12 (2.2%) patients [9]. Most encouraging is the fact that the
results of the trial were comparable to that of large international
groups, such as those of the MRD-guided St Jude Total XV (5-year
EFS, 85.6%) [10] and the Dutch Children’s Oncology Group ALL 9
(81%) [11] during the same era.
Thus, the main lessons learnt from the MASPORE-ALL2003 trial
was that a 3-drug induction protocol without anthracyclines could
be safely used in 86% of patients without comprising treatment
outcome, limiting the most intensive induction regimens to a small
group of poor-risk patients. Additionally, tracking a single MRD
marker was adequate to accurately risk-stratify treatment.
7. MASPORE ALL 2010 trial
The MASPORE-ALL2003 study allowed successful tailoring of
chemotherapy according to early treatment response, as primarily
determined by MRD quantitation. Despite these achievements,
there was still a need to further fine-tune therapy. For example, 4%
of patients on the Standard Risk arm died of sepsis, mainly during
the delayed intensification Protocol III and maintenance phases.
Could patients in the low-risk groups receive lesser chemo-
therapy, including the omission of anthracyclines, without affecting
overall survival? Conversely, could therapy that is more intensive
be delivered to high-risk groups in order to improve survival?
Thus, in the MASPORE ALL 2010 trial (NCT02894645), several
adaptations to the 2003 regimen were made. These were:

Deceleration of chemotherapy intensity in the standard risk
patients (~40%) by using two blocks of anthracycline-free re-
intensification blocks and replacing daunorubicin with an
intensified vincristine and L-asparaginase regimen (named
“Protocol V”).

Deceleration of chemotherapy intensity in the intermediate risk
patients (~40%) by replacing the last block of protocol III with
one block of protocol V.
14 H. Ariffin et al. / Pediatric Hematology Oncology Journal 5 (2020) 11e16

Intensification of therapy in high risk patients (~20%) using
fludarabine and daunorubicin

Addition of a tyrosine-kinase inhibitor such as imatinib in all
patients with Philadelphia-positive ALL (Table 2).
Two other research questions were also investigated in the
MASPORE ALL2010 study. The first was a pharmacokinetic and ef-
ficacy study of vincristine, an agent that has been used for treating
ALL for the last 5 decades. Intravenous vincristine was administered
at the start of induction therapy as either a 15-min bolus or a 3-h
slow infusion and correlated with clearance of MRD at end of in-
duction. The second question related to treatment intensification in
children whose lymphoblasts had deletions in the IKZF1 gene
(IKZF1del). A deletion in the IKZF1 gene results in a reduction in the
lymphoid transcription protein IKAROS and had been reported to
confer a poor prognosis in childhood ALL [12,13].
In the MASPORE ALL2003 study, where IKZF1del was not used in
risk assignment, it was discovered that IKZF1del conferred a
significantly higher 5-year cumulative incidence of relapse (CIR)
(30.4% vs 8.1%; p ¼ 8.7  107), particularly in the intermediate-risk
group who lacked high-risk features (25.0% vs 7.5%; p ¼ 0.01) [14].
For patients with BCR-ABL1enegative disease, IKZF1del conferred a
higher 5-year CIR (20.5% vs 8.0%; p ¼ 0.01). Patients treated on the
MASPORE ALL2010 study who had IKZF1del (50 of 275) had their
treatment upgraded to the next risk arm. The 5-year CIR of these
patients with IKZF1del significantly decreased to 13.5% (p ¼ 0.05).
The 5-year overall survival for patients with IKZF1del improved from
69.6% in MASPORE ALL2003 to 91.6% in MASPORE ALL2010
(p ¼ 0.007) [13]. (Fig. 1). Thus, intensifying therapy for childhood B-
ALL with IKZF1del significantly reduced the risk of relapse and
improved overall survival. Incorporating IKZF1del screening signif-
icantly improved treatment outcomes in modern-day ALL therapy.
8. Optimizing thiopurine dosing
The thiopurines, particularly 6-mercaptopurine (6 MP), are
essential components of ALL therapy. The TPMT gene is subject to
genetic polymorphisms, leading to an almost 50-fold variation in
enzyme activity between individuals [15]. Several mutant alleles
have so far been identified, with three mutant alleles (TPMT*2,
TPMT*3A, TPMT*3C) accounting for the majority of intermediate or
low enzyme activity [16]. Pharmacogenetic studies have demon-
strated marked ethnic differences in the frequency and type of
these mutant alleles [17]. Funded by Children’s Cancer Foundation
(Singapore), NUS investigators sequenced >1000 multi-ethnic
healthy blood donors from the population as well as patients and
found that TPMT variants were the cause for 3% of thiopurine
sensitivity. Yet, 20% of Asians are sensitive to 6 MP, thus it was likely
other genes could account for this difference.
Germline variants in NUDT15 gene, which encodes for an
enzyme that catalyzes the hydrolysis of nucleoside diphosphates
which in turn contributes to slow metabolism of thiopurines, has
been increasingly recognized. The MASPORE group, in collabora-
tion with researchers from St Jude Children’s Research Hospital, has
reported increased thiopurine sensitivity in children with NUDT15
variants [18] as well as identified novel variants of NUDT15 in those
of East Asian ancestry [19].
Variants in either TPMT or NUDT15 cause delayed breakdown of
thiopurines and consequently lead to thiopurine-induced leuko-
penia. The problem is compounded in children with ALL who
inherit variants in both TPMT and NUDT15, resulting in exquisite
sensitivity to mercaptopurine. Inadvertent prescribing of ‘normal’
doses of mercaptopurine in these affected children can lead to a
profound, prolonged period of neutropenia and sepsis.
The knowledge of a patient’s TPMT and NUDT15 status is espe-
cially important in countries such as Malaysia where a large pro-
portion of children with ALL undergo maintenance phase
chemotherapy in centres outside of the main paediatric oncology
centres. Failure of timely and precise adjustments to the mercap-
topurine doses may cause these children to be at risk of fatal
neutropenic sepsis.
In the MASPORE ALL2010 trial currently, children are screened
for a panel of both TPMT and NUDT15 variants which are common to
the Malay and Chinese ethnic groups. These findings are incorpo-
rated into treatment decisions of starting, as well as maintenance,
doses of mercaptopurine. Treatment diaries are collected with the
aim of establishing a genotype-based thiopurine dosing schedule in
the near future.

Table 2
Risk assignment and protocol outline in MASPORE ALL 2003, MASPORE ALL 2010 and MASPORE ALL 2020.

Protocol MASPORE ALL 2003 MASPORE ALL 2010 MASPORE ALL 2020

Risk assignment Day 8 prednisolone response PCR MRD IgH/TCR PCR MRD IgH/TCR
PCR MRD IgH/TCR Cytogenetics/ETV6-RUNX1, TCF3-PBX1, MLL-AF4, RNA-Seq
Cytogenetics/ETV6-RUNX1, TCF3-PBX1, MLL-AF4, BCR-ABL1 IKZF1del
BCR-ABL1 Age 1-9y. B-lineage ALL including infant.
IKZF1del Does not include T-ALL
Infants and T-ALL treated on MaSpore ALL 2003
protocol
CNS-directed IT MTX starting Day 1 IT MTX starting Day 8 induction IT MTX starting Day 8 induction
therapy Cranial RT if CNS 3 Intensified IT twice weekly during induction for Intensified IT twice weekly during induction for
CNS 2/3 CNS 2/3
Cranial RT if CNS 3. No cranial RT.
Induction 3-drug induction for SR/IR 3-drug induction for SR/IR 3-drug induction for all groups
4-drug induction for HR 4-drug induction for HR Add Dasatinib for BCR-ABL1 and ABL class
Add Imatinib for BCR-ABL1
HDMTX SR 2 g/m2 x 4 SR 2.5 g/m2 x 2 x 2 blocks SR 2.5 g/m2 x 2 and LDMTX 150 mg/m2 x3
IR/HR 5 g/m2 x 4 IR/HR 5 g/m2 x 2 x 2 blocks IR/HR 5 g/m2 x 2 x 2 blocks
Delayed SR III x 2 SR V x 2 (no anthracyclines) SR V x 2 (no anthracyclines)
intensification IR III x 3 IR III x2 þ V x1 IR III x2 þ V x1. Rituximab for CD20þ
HR II x2 HR FLAD x 2, III x 3 HR FLAD x 2, III x 3
HR e HSCT HR - HSCT CAR-T CD19 or HSCT for HR

Abbreviations: ALL, acute lymphoblastic leukaemia; CAR-T, chimeric antigen receptor T-cell therapy; CNS, central nervous system; HDMTX, high-dose methotrexate; HR, high
risk; HSCT, haematopoietic stem cell transplantation; IgH, immunoglobulin H; IKZF1del, IKZF1 gene deletion; IR, intermediate risk; IT, intrathecal; LDMTX, low-dose meth-
otrexate; MRD, minimal residual disease; MTX, methotrexate; PCR, polymerase chain reaction; RNA-Seq, RNA sequencing; RT, radiotherapy; SR, standard risk; TCR, T-cell
receptor.
 H. Ariffin et al. / Pediatric Hematology Oncology Journal 5 (2020) 11e16 15

Fig. 1. Comparison of (A) cumulative incidence of relapse (CIR; n ¼ 106) and (D) overall survival (OS) in patients with B-cell acute lymphocytic leukaemia (B-ALL) with IKZF1
deletion (IKZF1del; n ¼ 106) between the Malaysia-Singapore ALL 2003 (MS2003) and Malaysia-Singapore ALL 2010 (MS2010) studies.
Abbreviations: CIR, cumulative incidence of relapse; IKZF1del, IKZF1 gene deletion; OS, overall survival.
Yeoh AEJ, Lu Y, Chin WHN
et al. Intensifying Treatment of Childhood B-Lymphoblastic Leuka
emia With IKZF1 Deletion Reduces Relapse and Improves Overall Survival: Results of Malaysia-Singapore ALL 2010 Study. J Clin Oncol 2018; 36(26):2726e2735.

9. Future directions methotrexate at 2500 mg/m2/block. High Risk category patients

Multi-institutional collaborations and participation in modern
clinical trials have driven survival rates for childhood ALL to above
80% in many, including middle-income, countries. Unfortunately,
large cohort studies have revealed that survivors of childhood
cancer have an increased risk of chronic, age-related comorbidities
[20]. In a Malaysian cohort of 87 asymptomatic survivors of child-
hood ALL, with a median age of 25 years, these young adults had a
biological profile of chronic inflammation, leukocyte telomere
shortening and metabolic derangements [21]. These findings
concur with those of other large groups such as the Childhood
Cancer Survivor Study and the St Jude Lifetime Cohort Study; both
of which have raised concerns about the late effects of therapy in
individuals who received chemotherapy or irradiation, or both,
during their childhood [22,23].
It is envisioned that in the not-too-distant future most child-
hood cancers will be separated into molecularly distinct subtypes,
with different therapeutic approaches required for each subtype. In
parallel, drug discovery efforts will concentrate on developing
compounds to target these molecular aberrations. To some extent,
the huge successes seen in childhood ALL has arisen from im-
provements in detailed biological profiling of lymphoblasts and
analyzing disease response via minimal residual disease tracking.
Lastly, as the group moves towards MASPORE ALL2020 and
beyond, a paradigm shift is anticipated in designing therapeutic
regimens for children with ALL. Advances in treatment thus far has
led to exceptional survival rates for childhood ALL, with more than
90% overall survival for good-risk patients. Thus, a new benchmark
of success in the treatment of paediatric ALL would be to address
what has long been a secondary issue e the long-term health of
cancer survivors. Chemotherapy will be more distinctly stratified.
Specifically, in MASPORE ALL2020, Standard Risk patients will not
receive any anthracyclines and only receive two blocks of high-dose
and those with CNS3 status will have options for CAR-T cell therapy
as consolidation.
In conclusion, the MASPORE ALL Study Group has successfully
focused on using MRD to de-intensify therapy. The successful
collaboration has come from dedicated investigators focusing on
improving patient outcomes, funded by both competitive grants
and charity. This collaboration of neighbours has shown that it is
possible to develop local cost-effective protocols that are tailored to
Asian biology.
Acknowledgements
HA, SAR and SHL acknowledge funding from Ministry of Higher
Education, Malaysia (UM.C/HIR/MOHE/Med-12 and IIRG-021-2019)
and Ministry of Science and Technology, Malaysia (IF1019-Q1148).
AEJY, EKHC and TCQ would like to thank Singapore National Med-
ical Research Council Clinician Scientist Investigator Awards
(NMRC/CSA/0053/2013); Cancer Science Institute, Singapore; VIVA
Foundation for Children with Cancer; Children’s Cancer Founda-
tion; Singapore Tote Board and Goh Foundation.
References
[1] The World Bank. Data. Available from: https://data.worldbank.org/indicator/
NY.GDP.PCAP.CD. [Accessed 28 December 2019].
[2] The World Bank. Data. Available from: https://data.worldbank.org/indicator/
SH.XPD.CHEX.PC.CD. [Accessed 28 December 2019].
[3] Ng SM, Lin HP, Ariffin WA, Zainab AK, Lam SK, Chan LL. Age, sex, haemoglobin
level, and white cell count at diagnosis are important prognostic factors in
children with acute lymphoblastic leukemia treated with BFM-type protocol.
J Trop Pediatr 2000;46(6):338e43.
[4] Li CK, Chik KW, Ha SY, Lee ACW, Yuen HL, Ling SC, et al. Improved outcome of
acute lymphoblastic leukaemia treated by delayed intensification in Hong
Kong children: HKALL 97 study. Hong Kong Med J 2006;12(1):33e9.
[5] Ribeiro RC, Antillon F, Pedrosa F, Pui CH. Global Pediatric Oncology: lessons
from partnerships between high-Income countries and low to middle coun-
tries. J Clin Oncol 2016;34:53e61.
16 H. Ariffin et al. / Pediatric Hematology Oncology Journal 5 (2020) 11e16
[6] Tubergen DG, Gilchrist GS, O’Brien RT, Coccia PF, Sather HN, Waskerwitz MJ,
et al. Improved outcome with delayed intensification for children with acute
lymphoblastic leukemia and intermediate presenting features. J Clin Oncol
1993;11:527e37.
[7] Ariffin H, Chen SP, Wong HL, Yeoh A. Validation of a multiplex RT-PCR assay
for screening significant oncogene fusion transcripts in children with acute
lymphoblastic leukaemia. Singap. Med. J. 2003;44(10):517e20.
[8] Ariffin H, Ariffin WA, de Bruyne JA, Lee CL, Peng LH. Belief in traditional
healers amongst Malaysian parents of children with cancer. J Trop Paediatr
1997;43:375e6.
[9] Yeoh AE, Ariffin H, Chai EL, Kwok CS, Chan YH, Ponnudurai K, et al. Minimal
residual disease-guided treatment deintensification for children with acute
lymphoblastic leukemia: results from the Malaysia-Singapore acute lympho-
blastic leukemia 2003 study. J Clin Oncol 2012;30(19):2384e92.
[10] Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating
childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J
Med 2009;360:2730e41.
[11] Veerman AJ, Kamps WA, van den Berg H, van den Berg E, Bo € kkerink JP,
Bruin MC, et al. Dexamethasone-based therapy for childhood acute lympho-
blastic leukaemia: results of the prospective Dutch Childhood Oncology Group
(DCOG) protocol ALL-9 (1997-2004). Lancet Oncol 2009;10(10):957e66.
[12] Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB, et al. Deletion of
IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med
2009;360(5):470e80.
[13] Boer JM, van der Veer A, Rizopoulos D, Fiocco M, Sonneveld E, de Groot-
Kruseman HA, et al. Prognostic value of rare IKZF1 deletion in childhood B-cell
precursor acute lymphoblastic leukemia: an international collaborative study.
Leukemia 2016;30(1):32e8.
[14] Yeoh AEJ, Lu Y, Chin WHN, Chiew EKH, Lim EH, Li Z, et al. Intensifying
treatment of childhood B-lymphoblastic leukemia with IKZF1 deletion re-
duces relapse and improves overall survival: results of Malaysia-Singapore
ALL 2010 study. J Clin Oncol 2018;36(26):2726e35.
[15] Weinshilboum RM, Sladek SL. Mercaptopurine pharmaco- genetics: mono-
genic inheritance of erythrocyte thiopurine methyltransferase activity. Am J
Hum Genet 1980;32:651e62.
[16] McLeod H, Krynetski E, Relling MV, Evans WE. Genetic polymorphism of
thiopurine methyltransferase and its clinical relevance for childhood acute
lymphoblastic leukemia. Leukemia 2000;14:567e72.
[17] Krynetski EY, Evans WE. Genetic polymorphism of thiopurine S-methyl-
transferase: molecular mechanisms and clinical importance. Pharmacology
2000;61:136e46.
[18] Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited
NUDT15 variant is a genetic determinant of mercaptopurine intolerance in
children with acute lymphoblastic leukemia. J Clin Oncol 2015;33(11):
1235e42.
[19] Moriyama T, Yang YL, Nishii R, Ariffin H, Liu C, Lin TN, et al. Novel variants in
NUDT15 and thiopurine intolerance in children with acute lymphoblastic
leukemia from diverse ancestry. Blood 2017;130(10):1209e12.
[20] Oeffinger KC, Mertens AC, Sklar AC, Kawashima T, Hudson MM, Meadows AT,
et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J
Med 2006;355(15):1572e82.
[21] Ariffin H, Azanan MS, Abd Ghafar SS, Oh L, Lau KH, Thirunavakarasu T, et al.
Young adult survivors of childhood acute lymphoblastic leukemia show evi-
dence of chronic inflammation and cellular aging. Cancer 2017;123(21):
4207e14.
[22] Ness K, Kirkland J, Gramatges MM, Wang Z, Kundu M, McCastlain K, et al.
Premature physiologic aging as a paradigm for understanding increased risk
of adverse health across the lifespan of survivors of childhood cancer. J Clin
Oncol 2018;36(21):2206e15.
[23] Mulrooney DA, Hyun G, Ness KK, Bhakta N, Pui CH, Ehrhardt MJ, et al. The
changing burden of late health outcomes in adult survivors of childhood acute
lymphoblastic leukaemia: a report from the St Jude Lifetime Cohort Study.
Lancet Haematol 2019;6(6):306e16.