Global Challenges in Paediatric Acute Lymphoblastic Leukaemia

Abstract

Background

Acute lymphoblastic leukaemia (ALL) is the commonest paediatric cancer and represents a fifth of adult leukaemias. Global outcome disparities are linked to variations in socio-demographic indices (SDIs).

Summary

In high-SDI regions, established collaborative groups report cure rates surpassing 90% in paediatric ALL. The focus is on reducing treatment toxicity using chemotherapy-free strategies, principally T-cell-directed immunotherapies and targeted small molecules, as exemplified in adult Philadelphia-chromosome-positive ALL. High cure rates limit testing of novel approaches outside niche subgroups, while high costs preclude wider real-world adoption of these advances. Mid-SDI regions (50–80% cure) face challenges in fully implementing contemporary risk-adapted therapy to improve outcomes and reduce costs. This necessitates collaborative practice, standardised high-quality risk-stratification diagnostics, and access to quality-assured generic cytotoxics. Low-SDI regions (<50% cure) report rising disease burden and face more fundamental challenges, including timely diagnosis, access to treatment and expertise, and minimising toxicity and abandonment. Solutions require locally adapted protocols, collaborative partnerships, and sustained patient-support programmes.

Key Message

Global partnerships across SDI regions are crucial to address shared challenges in ALL, including access to affordable quality therapeutics, continuing refinement of established treatment elements, tailoring biomarkers for diverse populations, and collaborative frameworks to evaluate new treatments, technologies, and treatment paradigms.

Introduction

Childhood cancer, though relatively rare, is collectively the 6th leading cause of cancer and the 9th leading cause of childhood disease burden globally [1]. Worldwide, other than in sub-Saharan Africa (SSA), acute lymphoblastic leukaemia (ALL) is the commonest paediatric cancer, also affecting adults who have a less favourable prognosis. At the start of this millennium, long-term survival rates in childhood ALL approached 90% in high socio-demographic index (SDI) countries. This was achieved by an iterative process. Multicentre clinical trials progressively intensified combination chemotherapy using agents available since the 1970s. Over time, varying prognostic combinations of clinical risk features and genetic characteristics led to risk-stratified therapy, starting at diagnosis. Patients at higher relapse risk received further intensification and for some, remission was consolidated with allogeneic haematopoietic stem/progenitor cell transplantation (allo-HSCT). With increasing intensity of therapy for all risk groups, deaths due to toxicity approached those due to disease recurrence. With the introduction of methods to assess measurable residual disease (MRD) after blocks of therapy, it became possible to de-intensify therapy for those with early clearance of disease and decrease the need for allo-HSCT. Focus in high-SDI countries progressively moved towards preventing recurrence in those with suboptimal response to therapy and developing successful strategies for relapsed disease. In the last 2 decades, use of targeted therapies such as tyrosine kinase inhibitors for Philadelphia-positive (Ph+) and Ph-like ALL and T-cell-directed immunotherapies such as the bispecific T-cell-engaging antibody, blinatumomab, and chimeric antigen receptor T cells (CAR-T) are now entering mainstream therapy. Recently, adults with Ph+ ALL have been treated successfully with a chemotherapy-free combination of tyrosine kinase inhibitors and blinatumomab with minimal toxicity [2], and this may be further potentiated by addition of an allosteric ABL1 inhibitor [3]. Adults with Ph-negative ALL, given blinatumomab as consolidation therapy, achieved MRD negativity and 93% 3-year survival without allo-HSCT [4]. This heralds a switch from combination chemotherapy to targeted agents and immuno-therapy in the near future. Reflecting these improvements, the global burden of ALL in high-SDI countries, as measured by incidence, deaths, and disability-adjusted life years (DALYs), has declined, though prevalence has increased [5]. Conversely in low-SDI regions, prevalence, incidence, deaths, and DALYs are on the rise. In low- and low-mid SDI regions, childhood cancers collectively rank first in terms of DALY contribution among all cancer types [1]. In the case of ALL, 5-year survival estimates range from 10% to 90% worldwide [6]. Thus, the single most important determinant of outcome is the country where the child is treated. For the purposes of this review, we have categorised the world into 3 regions. Region 1 includes countries with ALL treatment outcomes higher than 80%, e.g., North America, Western Europe, Japan, China, Korea, Malaysia/Singapore, some of the Gulf states, Australia, and New Zealand; region 2, with outcomes between 50 and 80%; and region 3, where outcomes are below 50%, mostly countries of SSA [5, 7]. The challenges for each of these regions are different and are discussed separately.

Region 1

Region 1 represents countries with a high SDI, where cure rates for children with ALL exceed 90% [8]. Here, patients are treated at specialist centres and are often enrolled in clinical trials. The primary objective of these trials is to evaluate novel therapies that either improve or maintain existing cure rates while reducing treatment-related morbidity, thereby enhancing patients’ quality of life. Recent clinical trials in region 1 centres have demonstrated the benefits of blinatumomab, in both newly diagnosed [9] and relapsed ALL [10, 11]. Similarly, CD19-targeting CAR-T therapy is increasingly used in relapsed ALL [12]. Nevertheless, outcome disparities persist within high SDI countries. While some of these disparities may be attributed to differences in genetic ancestry that influence treatment outcomes [13], other systemic and potentially remediable factors contribute significantly. Access to newer therapies is often inequitable [14], frequently observed along racial and ethnic lines [15], and is further limited by income disparities and health insurance availability [16]. Furthermore, a “geographical lottery” disadvantages patients residing far from specialised treatment centres that offer these advanced therapies [17]. These newer treatments are expensive, and scaling them for all patients, as in the case of CAR-T therapies, presents formidable implementation challenges. Consequently, not all patients are enrolled in clinical trials that offer access to these novel treatments [14]. Addressing these disparities requires broader infrastructure investments coupled with outcome-based price negotiations for newer therapies. Additionally, long-term outcome data and potential toxicities of these newer treatments are still being compiled. Given the high cure rates for ALL in region 1, conventional early-phase evaluation of novel candidate agents in patients with relapsed/refractory disease is increasingly a challenge, and enrolment in such trials, even international collaborative ones, is often slow and prolonged. Furthermore, given the cost of bringing a new product to market, pharmaceutical companies are primarily interested in developing “blockbuster” drugs and not necessarily drugs for a rare cancer that occurs primarily in children.

Region 2

The bulk of the world’s children live in this region, which includes most of Asia and countries in South and Central America. This region also contributes to the highest number of deaths and DALYs due to childhood ALL [5]. Many of these countries have well-established paediatric cancer centres with high-quality facilities, often with strong links to centres in region 1. Most centres employ protocols used in Europe (e.g., from the United Kingdom ALL group or the Berlin Frankfurt Münster group) or the USA (e.g., protocols developed by St. Jude Children’s Research Hospital, the Children’s Oncology Group, or the Dana Farber Cancer Institute). Patients often have access to funding for treatment either from government or non-government sources as well as support for out-of-pocket expenses such as for accommodation. Nevertheless, outcomes at the major centres are relatively inferior and have stagnated for decades at between 58% and 78% [18–25]. Most centres use locally altered “modified” or “adapted” versions rather than the original protocols. Reports present historical observations from single centres collected over extended periods and reflect results of all-purpose treatment rather than contemporary risk-stratified therapy, changing practices are not recorded, and events are not scrutinised with the rigour of a clinical trial. This wide variation in practice, coupled with missing data typical for retrospective audits, make it difficult to analyse comparative data, but common to all were high treatment-related deaths (TRDs), ranging from 10 to 25% [20, 22, 24, 26–29].

Risk-stratified therapy decreases morbidity, mortality and is very cost-effective [30]. TRD and increased morbidity from infections [31] are associated with treatment intensity in region 2 countries. The principal adverse effect of intensive therapy is myelosuppression leading to infections during the neutropenic phase. Antibiotics, antifungals, and antivirals used to treat febrile neutropenic episodes are expensive and can significantly increase costs that match or surpass the cost of chemotherapy [30]. Appropriate risk stratification can identify those who can be cured with the least intensive therapy, significantly decreasing TRD and treatment costs [26, 32–35]. Progress in decreasing TRDs and improving outcomes has come from risk-stratified therapy tailored to regional needs [34], with prospective collection of data through multicentre clinical trials run by cooperative groups [18, 25, 35–37]. Risk stratification in ALL requires genetic analyses and MRD assessment. Fluorescence in situ hybridisation (FISH) [35] along with flow cytometry have been used successfully to identify genetic risk groups and quantify MRD [18, 35]. While decreasing treatment intensity reduces TRD, the strategy fails if this comes at the cost of increased relapse rates. In our experience, families will accept more intensive treatment rather than face a higher risk of relapse. It is therefore imperative to accurately identify low-risk patients to ensure that treatment can be de-intensified for this cohort without increasing the risk of relapse. This approach needs to be implemented uniformly across all centres to ensure equitable benefit. Region 2 centres usually have access to point-of-care tests for diagnosis and routine management of cancer patients. Each centre has also used existing laboratory equipment innovatively to develop immunophenotyping and MRD assays. With FISH not always available, some cooperatives have used molecular screening for genetic risk stratification. [18], This approach is insufficient as it primarily targets identification of fusion transcripts. Standardisation of tests across all centres poses practical difficulties. As a result, there is considerable variability between centres in how patients are categorised and stratified [35]. Many centres are simply unable to do all the tests required to run a cooperative study. The Bridge Project in Mexico involves 14 centres located in 12 states and has centralised immunophenotyping, FISH, and MRD. With the regularisation of standardised testing, the proportion of patients classified as high risk at individual centres decreased from approximately 50% to around 30% [38]. Centralisation allows standardisation and economies of scale and are easier to sustain when resources are limited. Newer sequencing technologies offer rapid and cost-effective approaches to risk stratification [39] but require expertise and optimal environments. This is achievable with a centralised model. Extending the twinning approach [40], the Indian Collaborative Childhood Leukaemia (ICiCLe) Group has implemented a hub-and-spoke model where experienced centres are linked to less experienced centres to aid knowledge transfer (CTRI/2023/12/060828). A centralised clinical trial unit coordinates data collection using a remote entry database. Site compliance is monitored with the help of the National Cancer Grid [41]. To deliver equitable care across all participating centres, comprehensive networks will be required to facilitate standardisation of diagnosis and monitoring by centralising expertise and resources. Centralisation of the independent review and ethical board would greatly benefit the development of these networks.

The most common approach to decreasing the intensity of treatment is to reduce the use of anthracyclines, cyclophosphamide, and high-dose methotrexate. It is vital then that the necessary drugs are available to all patients and that they are of the highest quality. In most countries in this region, even where treatment costs are subsidised or completely supported, procurement of drugs remains the responsibility of each hospital. This means that local hospitals are often dependent on regional suppliers and can procure only from those who offer the lowest price. More expensive drugs are either obtained through non-governmental organisations/donors or directly sourced by patient families. In either scenario, there is no guarantee of the availability of drugs, or of their quality. The Global Platform for Access to Childhood Cancer Medicine [42], a partnership between the World Health Organisation (WHO), UNICEF, the Pan American Health Organisation Strategic Fund, and St. Jude Children’s Research Hospital, is aiming to address this. This ambitious and much needed project is aiming to address equity of care for children with cancer by ensuring that quality-assured drugs are available uniformly at the point of care. This is a considerable challenge. Chemotherapy drugs are in short supply even for countries in region 1. The bulk of common cytotoxic agents are manufactured and packaged in India and China and then marketed by other companies. Often, the source of the active pharmaceutical ingredient is not clear. An example is the drug l-asparaginase (ASNase), a critical drug for patients with ALL; it comes either in its native form or conjugated to polyethylene glycol to increase its half-life. The former is cheaper but requires more frequent administration at a higher dose, while the latter is less toxic but far more expensive. Countries in region 1 use polyethylene glycol-ASNase, mostly Oncaspar™, which is marketed by Servier at a cost of around USD 2,500 a vial. Most children will need at least 3 vials (USD 7,500). In contrast native ASNase is available for around USD 15 a vial. With patients requiring at least 10 vials (USD 150), the native product has been the drug of choice in most centres in region 2, until recently. Many native ASNase biogenerics are available on the market. For many, the active pharmaceutical ingredient is sourced from China and is then packaged (in some cases further processed) and marketed by Indian companies across countries in region 2. The primary source of ASNase is Escherichia coli, so it is important to remove bacterial impurities and recognise that different strains have different potencies. We and others have reported on the poor quality of generic native ASNases marketed in India [43–45] and South America [46] and its adverse impact on outcomes [47]. It has only been possible to identify this issue because centres set up assays to assess ASNase activity and then extended these observations to identify the reasons for the suboptimal activity. Along with ensuring the availability of quality drugs to centres in all countries, we recommend that reference centres are equipped to monitor the quality of each drug, as in our opinion the issue of quality extends to other essential anti-cancer drugs as well. Another problem is drug contamination. At least two recent reports have highlighted bacterial contamination of methotrexate [48], used intrathecally as well as intravenously – resulting in meningitis and septicaemia [49]. While the companies identified to have suboptimal/contaminated drugs have usually withdrawn their products, globalisation of the pharmaceutical industry can affect supply chains even in region 1. In situations where injectables are expensive, it is not uncommon for patients to share a vial or for a single-dose vial to be stored and re-used, increasing the risk of contamination and/or compromising drug activity. This usually occurs when vial sizes are designed for adults and considerable drug is left over when used for a child. Designing vials for use in children at an affordable cost can help resolve this problem.

Finally, age limits in paediatric wards also affect outcomes. In some hospitals, children older than 10 years may be treated on adult wards where clinical teams are more familiar with protocols designed for older adults [50]. Yet as in region 1, the evidence supports that adolescents and young adults with ALL do better on paediatric protocols [51].

Region 3

Region 3 is exemplified by the countries of SSA and includes countries in Asia and South America. While ALL is a significant paediatric cancer in SSA, its reported prevalence is lower than that of the other childhood cancers such as Burkitt lymphoma, Wilms tumour, and retinoblastoma [52]. Data registries in these countries may not accurately reflect the true incidence [53] and it is possible that at least 50% of cases are simply not diagnosed [54, 55]. Currently almost 90% of children with cancer in SSA do not survive, and the region bucks the worldwide trend with an increase in deaths and DALYs for ALL [5], jeopardising the WHO’s goal of a minimum 60% cure for ALL worldwide by 2030 [56]. By 2050, a billion children will live in SSA. As the population at risk increases and diagnosis improves, so will the number of cases [53]. ALL is not a preventable cancer and unless we can remedy this now, in the future most deaths due to ALL worldwide will be in SSA.

Limited centres, resources, and personnel in a region roughly 15% of the world’s landmass means that some patients do not survive long enough to reach a centre for diagnosis. Others reach late and do not survive [57]. Abandonment of treatment after diagnosis is seen in region 2 countries but is highest in region 3 where rates range from 6 to 43%. Abandonment occurs early as well as during the maintenance phase of therapy [27, 58–65]. The cost of therapy is a major factor leading to abandonment. National initiatives like the Seguro Popular Fund/Protection Against Catastrophic Expenditures in Mexico and free cancer treatment for children under 14 years old at select public hospitals in Nepal are steps in the right direction. Many centres across regions 2 and 3 use a combination of government and non-government agencies to fund treatment for children with cancer. Funding for treatment alone is insufficient to prevent abandonment [34, 59]. Common to centres of this region are also high TRD and relapse rates. Families are unsure whether the disease is curable, worry about the toxicities, are confused about the role of complementary/alternative medicines, and are influenced by relatives and friends. Increasing distance from the treating centre has been reported in the Honduras [66] but did not appear to have the same impact in El Salvador [67] and India (region 2) [68]. A systematic approach to providing financial support for treatment, travel, and accommodation during hospital stays, along with regular counselling, follow-up, and tracking, has significantly reduced abandonment [40, 63, 67, 69]. Arguably in region 3, prevention of abandonment along with reducing TRD using the lessons learnt from region 2 should be of the highest priority to meet the WHO 2030 deadline.

A major hurdle is in ensuring that centres have the necessary equipment, resources, and trained staff. Some centres even lack point-of-care tests required to manage sick children. Many regional and worldwide partnerships have stepped in to close the gap. Texas Children’s Hospital Global Hematology Oncology Pediatric Excellence (Global HOPE) initiative has partnered with national as well as other philanthropic organisations to build capacity. This includes a comprehensive training programme for doctors (including subspecialities), nurses, and other required disciplines such as surgery, pathology, radiology, and radiation oncology. Along with these, centralised laboratories that can perform genetic and MRD analyses required for risk stratification have been established [55]. The Aslan Project in Ethiopia has been building capacity, providing comprehensive family support and building essential infrastructure. This initiative has built global partnerships with donor organisations as well as paediatric oncology centres in regions 1 and 2 [70]. Both these programmes have a strong focus in leadership training. Similar to the Aslan Foundation, World Child Cancer also partners with a number of organisations and hospitals to improve outcomes in region 3 countries [71]. The International Society of Paediatric Oncology (SIOP)’s Collaborative African Network for Childhood Cancer Care and Research (CANCaRe Africa) has a major focus on addressing abandonment and improving supportive care at SSA centres [72].

Finally, as for region 2, treatment regimens need to be adapted for local regions. This may include using combinations of drugs that are easy to obtain, adjusting doses based on ethnic differences, and ensuring that drugs are administered correctly. An example of the latter is the appropriate dilution of intrathecal methotrexate and not over-rescuing those receiving high-dose methotrexate.

A Common Problem for all Regions

Treatment of ALL spans 2–3 years, with an initial predominantly hospital-based intensive phase of 6–9 months, followed by an outpatient maintenance treatment phase lasting 2, sometimes 3, years. The primary components of the maintenance phase include oral daily 6-mercaptopurine (6MP) combined with weekly oral methotrexate, together with regular intrathecal methotrexate (typically every 3 months) and infection prophylaxis with oral trimethoprim-sulphamethoxazole. 6MP is a prodrug, metabolised within the body to 6-thioguanine triphosphate nucleotides (6TGN). These active metabolites are subsequently incorporated into DNA and RNA, leading to DNA strand breaks and apoptosis [73]. Multiple enzymes participate in the degradative pathways of 6MP. Germline polymorphisms in these enzymes result in significant inter-individual variability in drug metabolism and elimination rates, necessitating individualised dose titration of 6MP.

About 25% of patients do not tolerate the standard 6MP dose, which, if administered, can lead to myelosuppression and treatment discontinuation in these patients. Conversely, a proportion of patients require higher doses. Clinical outcomes demonstrate an association with levels of intracellular 6-thioguanine triphosphate nucleotides incorporated into DNA [74], a state best achieved through sustained uninterrupted 6MP exposure. In practice, dose titration requires, at minimum, fortnightly blood counts to maintain the absolute neutrophil count (ANC) within a target therapeutic range, effectively “dosing to tolerance” [73]. An excessively low ANC poses a risk of sepsis, whereas an overly high ANC may indicate inadequate dosing or non-adherence. Children also require monitoring for other side effects, such as 6MP-associated hypoglycaemia.

Several factors influence treatment efficacy and safety. In region 1, both non-adherence [75] and dosing beyond tolerance [76] have been identified as factors adversely affecting survival. We have previously reported that a third of TRDs in India (region 2) occur during the maintenance phase [35]. Consequently, clinicians in this region hesitate to dose to tolerance, despite evidence suggesting that doses can often be significantly increased without adversely affecting the ANC or increasing febrile neutropenic episodes [68]. However, given that the frequency of genetic polymorphisms and baseline ANCs vary across ethnic groups, population-specific ANC ranges and recommended starting doses need to be identified.

During maintenance therapy, children typically return home and, ideally, to school. A significant challenge during this period is the requirement for periodic blood counts and ongoing monitoring to titrate doses and assess for toxicity. Traditionally, this necessitates fortnightly clinic visits, which can be arduous for patients requiring lengthy, often overnight, travel. While care can be transferred to reliable satellite centres or shared-care units where available [77], this option is not feasible for most centres in regions 2 and 3. The availability of reliable local blood count services can enable the use of e-clinics [68], potentially with automated drug dosing based on serial blood counts [78], to effectively deliver optimal maintenance therapy.

Regions 2 and 3 also contend with issues of drug quality and the availability of paediatric-suitable formulations. In India, until very recently, only 50-mg tablets of 6MP were available, and 6-thioguanine remains unavailable. The low cost of these drugs and their small market volume offer limited incentive for pharmaceutical manufacturing. As with ASNase, clinicians have collaborated with pharma to introduce 10-mg 6MP tablets and, more recently, a suspension formulation designed for stability in tropical climates [79]. This suspension formulation is crucial for children unable to swallow tablets and for those who only tolerate very small doses of 6MP.

Conclusion

As summarised in Table 1, the goals and challenges are different for the different regions. Region 1 has demonstrated that combination chemotherapy can cure most children with ALL. Progressive intensification has improved survival rates with toxicities acceptable in region 1, but these are unaffordable and associated with mortality in regions 2 and 3. Cooperative groups in regions 2 and 3 that have indigenised protocols based on local experiences have successfully decreased TRD. Thus, priorities and strategies are different for countries within each region and solutions need to be optimised for local health systems. Nevertheless as discussed, globalisation impacts all regions. Collaboration between groups in all 3 regions can improve the quality of drugs, standardise diagnostics, decrease the costs for all patients worldwide, and result in significant improvements in outcomes for children with ALL in regions 2 and 3. Working together, it should be possible for all children with ALL with suboptimal response to therapy to have access to experimental therapies. This has the advantage of rapid identification of active agents, benefiting all patients. If it takes a village to treat a child with cancer, it will take the world to deliver to all children with cancer. We have the knowledge, skills, and resources to make ALL a curable disease worldwide within the next 2 decades.

Table 1.

Goals and challenges in the management of ALL in the different regions

Goal	Region 1	Region 2	Region 3
	prevent recurrence	prevent treatment deaths	prevent abandonment
Challenges	Racial and ethnic disparities	Standardise care across centres	Improve access for patients
	Lack of equity in recruitment to clinical trials	Centralise critical laboratory tests to maintain uniformity	Comprehensive funding for care
	Increasing cost of therapy	Improve quality of drugs	Capacity building
	Slow pace of drug development	Affordability	​
		Paediatric suitable formulations
		Enable multicentre clinical trials
		Central ethical approval
		Clinical trials unit

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

S.K. and V.S. drafted, wrote, and reviewed the paper and jointly submitted for publication.

Funding Statement

This study was not supported by any sponsor or funder.