Development of an Adapted Resource and Implementation Application (ARIA) global guideline for the treatment of children with acute lymphoblastic leukemia

Abstract While cure rates for acute lymphoblastic leukemia (ALL) have improved significantly over the last few decades, there remain major disparities in survival outcomes between children in high-income countries (HICs) and those in low- and middle-income countries (LMICs). Using HIC treatment protocols in LMICs without adequate resources for safe administration and supportive care often leads to excessive treatment-related morbidity, mortality, and abandonment, outweighing the anti-cancer benefit. Conversely, over adaptation of protocols to lessen toxicity may significantly reduce treatment efficacy. The Adapted Resource and Implementation Application (ARIA), is a joint initiative between the St. Jude Children's Research Hospital (SJCRH) Department of Global Medicine and the International Society of Paediatric Oncology (SIOP) in partnership with the Paediatric Radiation Oncology Society (PROS), the International Society of Paediatric Surgical Oncology (IPSO), and Childhood Cancer International (CCI), to develop trusted, safe, and effective treatment guidelines for children and adolescents with cancer in all resource settings. These evidence-based global guidelines, incorporating adaptations for local context, are freely available for healthcare providers on a web-based portal which may be used off-line for those with limited internet access. Development of an adapted management guideline (AMG) for ALL involved a rigorous process, starting with a systematic literature search of all publications between January 2000- January 2021 involving treatment of ALL in LMICs, with ongoing alerts for relevant papers subsequently published. A 24-person working group (WG) of pediatric hematologists-oncologists, radiation oncologists, pharmacists, surgeons, and a hematopathologist, from diverse geographic and income level settings was then assembled. WG members attended 27 2-hour meetings between 2023-2024, culminating in an initial guideline draft. Evidence-based recommendations were stratified based upon local resources including presence/absence of blood products, broad-spectrum antimicrobials, radiologic testing modalities, advance intensive care including ventilatory and vasopressor support, and availability of hematopoietic stem cell transplant. Guidance was developed for management of B-cell ALL and T-cell ALL, including the special categories of Philadelphia-chromosome positive ALL, Down syndrome, and infants. A risk classification algorithm was created for assigning risk group based upon whatever diagnostic tests a treating institution has available. Providers can choose between recommendations adapted from a Children's Oncology Group (COG)-backbone or a Berlin-Frankfurt-Münster (BFM)-backbone. Additional treatment modification strategies were generated to address specific chemotherapy unavailability, radiotherapy inaccessibility, malnutrition, and other local challenges. Pharmacy instructions for drug administration, toxicities, and dose adjustments were included. Additional information was provided for general issues of ALL management, important treatment-related complications, and supportive care. Following development by the WG, the AMG draft underwent additional review by a 75-member global representative panel (GRP) of disease experts from 44 countries representing each World Health Organization region and World Bank income level (11 high-income; 12 upper-middle-income; 18 lower-middle-oncome; 3 low-income). Initial feedback from GRP members yielded 603 comments for consideration A modified Delphi method consensus process was employed for issues without sufficient evidence to make solely evidence-based recommendations. For the first iterative review, 24 Delphi statements were distributed to all GRP members with 66 GRP members providing input. In the first round, 17 of 24 statements achieved ≥ 70% agreeance (defined as a score ≥ 7 on a 9-point Likert scale). Full analysis and preparation for the 2nd Delphi round is underway. Following 3 rounds of GRP iterative review, additional external expert input, and patient/family focus group feedback, the final AMG will be made available on the ARIA web-based portal. We anticipate the guideline will be an important tool, helping to maximize survival outcomes for all children with ALL, regardless of where they live.