From Lab to Life: Insights & Innovations from Malaysia-Singapore (MaSpore) Childhood Acute Lymphoblastic Leukaemia Clinical Trials
The treatment of acute lymphoblastic leukaemia (ALL), the commonest childhood malignancy, involves administering different blocks of chemotherapy with varying intensities depending on risk stratification outcomes of patients across numerous cycles over a period of 2 years.
Choices of chemotherapy drugs and risk stratification criteria that guide the treatment of Malaysian patients have been based on local protocols developed since 2003. The Malaysia-Singapore (MaSpore) ALL2020 is the latest of three multi-institutional collaborative clinical trials between Universiti Malaya (UM) and the National University of Singapore (NUS) which aim to improve survival outcomes and reduce treatment-related complications among ALL patients. The lead researchers are Professor Hany Ariffin of UM and Associate Professor Allen Yeoh of NUS.
Prof. Hany shared that the initial goals were to improve survival rates which the MaSpore ALL2003 trial has achieved - from 56% to 81%. However, the latter protocols were more ambitious, such as replicating these stellar results whilst reducing acute toxicities as well as late effects of chemotherapy.
“In MaSpore ALL2010, we are the pioneers to demonstrate that complete removal of anthracyclines such as daunorubicin - one of the old, generational chemotherapy drugs that are still used in ALL treatments worldwide with debilitating late-effects to patients - does not jeopardise survival rates among non-high-risk patients. Approximately 40% of children can be spared from exposure to anthracyclines and yet be cured.
“This is a significant milestone as we have removed a major component of ALL treatment that has been proven to increase the risk of stroke, cardiomyopathy, hypertension, diabetes and second neoplasms among childhood cancer survivors during adulthood,” she said.
Prof. Hany further explained that cancer therapies, especially radiation and anthracyclines, increase cellular senescence, leading to chronic inflammation which accelerates the ageing process, subsequently leading to an increase in chronic health problems suffered at a younger age.
Her study, titled “Anthracycline-Free Protocol for Favourable-Risk Childhood ALL”, was published on 10 July 2023 in the prestigious Journal of Clinical Oncology which has an impact factor of 45.3, placing it at the top 1% of journals worldwide.
“ALL is a very heterogeneous disease with great patient variability. If we can select patients who are destined to do well, essentially standard-risk patients who comprise 40% of our study cohort, we can reduce the cost of managing anthracycline-related acute toxic effects as well the enormous economic burden of managing childhood cancer survivors who develop a host of chronic health issues,” she said.
Morning ward rounds in the paediatric transplant unit
To precisely select which patients could be managed without anthracyclines, the MaSpore team conducted extensive lab studies on the biology of leukaemia cells and molecular responses of patients as well as determining risk assignment criteria such as sequential minimal residual disease levels, IKZF1 gene aberration and RNA- sequencing. They were able to accurately identify which patients could be ‘safely’ treated with an attenuated regimen.
“There is a saying that goes, ‘Don’t throw the baby out with the bathwater’! While we want to eliminate the side effects of chemotherapy, we cannot reduce therapy intensity to such an extent till the patients are inadequately treated and instead, relapse. Clearly, further research is required to achieve this balance where treatment for childhood cancer is effective, yet patients manage to survive to adulthood in a healthy state,” she shared, adding it is clear that robust laboratory output which translates to real-life data application for improvements in patient survival rates and quality of life is the main basis of her research, hence the title ‘From Lab to Life’.
Professor Hany infusing cryopreserved blood stem cells into her patient
Like many researchers working with limited resources, Prof. Hany has had her fair share of challenges to overcome. When the first MaSpore study commenced in 2003, there was no dedicated lab for pediatric oncology research or to support the need for an investigator-initiated clinical trial; hence one had to be developed from scratch.
“It was a vicious cycle where to obtain a research grant, you would need to produce some form of results to earn a track record. But to produce such results, you would need a grant. Fortunately, we managed to secure our first capital investment through charitable support from several local companies and individual donations, which eventually led to more funding towards our project,” she shared.
To date, the UM/UMMC Paediatric Oncology Research Laboratory has managed to secure competitive grants from within and outside Malaysia.
“Even the best treatment protocol in the world cannot succeed if patients are not compliant, so we need to address these challenges as well – which include lack of parental knowledge, poverty, and inadequate social support,” Prof Hany said. Working together with well-wishers, non-governmental organizations, and corporate citizens, a charitable fund was established within Universiti Malaya Medical Centre to help patients overcome financial and logistical barriers.
Over the last 20 years, charity projects by Prof Hany and her team have raised approximately RM4,000,000 to aid patients from poor families, ensuring these children can receive treatment till completion.
Whilst a 100% survival rate for ALL remains an unrealistic target, Prof Hany envisions that in the not-too-distant future, all paediatric malignancies will have therapeutic approaches determined by biologically defined subtypes. By exploiting distinctive characteristics of each cancer subtype, new modalities such as immunotherapy or cellular therapy can hit these precise targets.
To all budding researchers, Prof Hany cites a quote attributed to Charles Darwin, ‘It is not the strongest of the species that survives, nor the most intelligent that survives. It is the one that is most adaptable to change.
“I was trained as a clinician, but I learned wet lab work required for my research because I needed to. I hung around labs in UM/UMMC and NUS and learned to isolate and grow cells, perform PCR, and so forth.
“To be a successful researcher here, you need to be a Jack of all trades, and this includes finding sources of funding,” she said.
Prof. Hany also emphasized the importance of networking to secure meaningful collaborations.
“I am grateful to the many people who supported my journey. One overseas researcher sent us cell lines, and another shared detailed assay methodology. A renowned European professor provided airfare and a stipend for my research assistant to learn a new technique in his lab.
Prof. Dr. Hany binti Mohd Ariffin,
Senior Consultant Paediatric Oncologist,
Universiti Malaya Medical Centre
“Be focused on what you want and never shy away from asking for help as there are many generous people in the scientific community. We just need to reach out and find them,” she shared.
Author:
Mr. Wong Zhi Yong is a passionate medical student who seeks the balance between science and writing. From dissecting the intricacies of the human body to weaving narratives, He is intrigued by both medicine and the written word.
E-mail: wong.zhiyong1@gmail.com
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