Comment on“Venetoclax Alone or in Combination With Chemotherapy in Paediatric and Adolescent/Young Adult Patients With Relapsed/Refractory Acute Myeloid Leukaemia”Dear Editor,With great interest we read the article “Venetoclax Alone or in Combo With Chemotherapy in Paediatric and Adolescent/Young Adult Patients With Relapsed/Refractory Acute Myeloid Leukaemia” by Seth E Karol et al.[1]. The authors addressed a topical and important subject with exceptional clarity and depth. The article provided some wonderful insights into a difficult area while facilitating readable and accessible text. This is a highly commendable didactic effort in paediatric oncology. Nevertheless, a few points require clarification with respect to increased explanation to enable the greatest exposure for clinicians and researchers.Firstly, It’s possible that the study’s follow-up period was insufficiently long to evaluate treatment’s late impacts and long-term results, which are particularly important in paediatric populations.A 2024 systematic review indicated that only 8% of RCTs related to the prevention of preterm birth reported long term outcomes in children, and in 43% of these RCTs the conclusions changed when long term outcomes were evaluated, thus demonstrating how short follow up can affect truly understanding differences in effectiveness or harms in pediatric populations. [2]Secondly,The results’ applicability to the larger community of paediatric children with R/R AML may be impacted by selection bias, given the study had particular eligibility requirements for patient inclusion.In practice, much the majority of oncology patients would probably normally be ruled out under such criteria – many still receive treatment, but with different results.[3]Third,Treatment Regimen Variability: The consistency and dependability of findings may be impacted by differences in the chemotherapy and Venetoclax regimens used by different institutions.A retrospective multi-institutional study from Texas Medical Center noted that the diversity of concurrent regimens (HMAs, chemotherapy, TKIs) used with venetoclax resulted in heterogeneity that limited the comparisons and generalizability of results.[4]Furthurmore,Impact of Previous Treatments, Although this can bring complicating factors for determining efficacy, the study did not address how previous treatment lines may have affected the response to Venetoclax.Previous treatments, consisting of numerous lines of chemotherapy and HSCT, can affect venetoclax response; in adult AML, more prior therapies led to lower response rates and second-line treatment was more predictive of a poor outcome.[5]Moreover,Psychosocial Factors, The study might not have taken into consideration how paediatric patients’ treatment adherence and response may be impacted by psychosocial factors such support networks, socioeconomic position, or mental health.The Pediatric Self-Management Model demonstrated how adherence behaviors in pediatric chronic illness are influenced by family context and other environmental factors.[6]Additionally ,The efficacy and safety of drugs may be impacted by the underrecognized differences in drug metabolism and pharmacokinetics between young children and adolescents.Age-related pharmacokinetic differences (e.g. prolonged half-lives in neonates and increased CYP3A4 metabolism in children) illustrate how uniform dosing could obscure genuine differences in efficacy and safety.[7]Lastly,The absence of a control group makes it difficult to conclusively link observed results to Venetoclax treatment alone rather than to other variables like the course of the disease.Historical control comparisons have a much greater risk of overestimating benefit sometimes as much as 30% than randomized trials.[8]
