Childhood ALL in Low- and Middle-Income Countries: Achievements and Challenges

In the article that accompanies this editorial, Duffy et al 1 report a systematic review on treatment regimens for pediatric ALL used in low-and middle-income countries 1-10 (LMICs) and on their outcomes and perspectives.We congratulate the authors for this impressive work, with a wealth of data, demonstrating the complexity of pediatric oncology in LMICs because of multiple factors, such as the socioeconomical situations, health systems, diagnostic approaches, international cooperation, health professional availability, government and charity support, quality and access to health care facilities, drug access, drug quality, cultural approaches, treatment abandonment or refusal, treatment adherence, and differences in drug regimens.Of 163 regimens, 138 were derived from different protocols used in high-income countries (HICs).The comparison between the outcomes for the three most used backbones, that is, Berlin Frankfurt M ¨ unster (BFM), UK-ALL, and St Jude Children's Research Hospital (SJCRH) ALL protocols, is skewed as the authors conclude in the discussion: the populations served differ quite a bit.The statistically significant differences among different backbones, which were found for relapse rate (P 5 .020),death in induction (P 5 .003),death in remission (P 5 .002),and abandonment rate (P 5 .002),might have been due to the populations served rather than to the protocols.The UK-ALL backbone was associated with the highest death and abandonment rates, indicating that this backbone was used in the poorest populations, whereas the SJCRH backbone was associated with the lowest death and abandonment rates, possibly because it was used in more affluent populations (including China).Despite these differences, however, no relevant differences in ≥5-year event-free survival (EFS) and overall survival (OS) are found among the most used backbones.This is not surprising since, as observed by the authors, "modern ALL treatment regimens share the same core medications, with modest variations in formulation, dosing, and schedule optimization, with remarkably similar outcomes in HIC."Of the 138 HIC backbone regimens, 104 were adapted (modified) with an overall improvement of OS when compared with those unmodified (≥5 year OS 79% v 67%).For a correct interpretation of these findings, however, factors mentioned above that can affect outcome should be carefully investigated, but this is rarely feasible, as recognized by the authors.In our personal experience, some groups declare using the UKALL 11 or the BFM-ALL 95 protocols, but stratification may be different because of lack of diagnostic and monitoring tools, some drugs such as pegylated L-asparaginase may be unavailable, and treatment intensity may be markedly decreased because of unplanned shortage of drugs, inadequate support therapy, low treatment adherence, or use of drugs with decreased activity.The quality of drugs in LMICs, where drug supply often depends on cost, is not always guaranteed, implying a risk of using formulations with lower activity, higher contaminating proteins, and possibly more frequent side effects as reported for L-asparaginase.2 Difficulties in the assessment of pediatric oncology in LMICs are also due to low quality and bias in the publications; the survey shows that the median number of patients in the eligible reports was rather small (N 5 158) and that 84% of them were from a single institution with a short follow-up, that is, with EFS and OS estimated at 2 or 3 years only, thus providing a modest contribution.In addition, the countries with higher numbers of patients were China, India, and Brazil.In these large countries, some centers have the most advanced diagnostics and treatments available, the same as in HICs, as opposed to centers in other LMICs where diagnostic