Treating pediatric acute promyelocytic leukemia in india – key challenges and lessons learned

Abstract

Acute promyelocytic leukemia (APML) is an uncommon subtype of acute myeloid leukemia (AML) among children with scarce literature available on treatment outcomes. In this regard, the recent article by Srinivasan et al. published in IJP presents important data on the outcome of pediatric APML treated at a tertiary care centre in India [1]. APML is known to be uniquely sensitive to differentiating agents like all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). The use of ATO in APML has been derived from research conducted based on the traditional knowledge of Chinese medicine. This is one of the examples which highlights how knowledge derived from traditional and complementary medicine may augment modern healthcare research. Systematic and rigorous studies on traditional remedies may open up newer options of treatment in medicine. Indeed, the coronavirus disease-19 pandemic offered a unique situation when research on traditional and complementary medicine was extensively conducted in countries like India and China [2]. Chemotherapy free regimens are often emphasized as the way forward in APML at least in low-risk disease, unlike the traditional chemotherapy-based regimens for AML which use anthracyclines, cytosine arabinoside and/or etoposide [3]. In this study, the authors used ATRA and ATO alternatively along with oral and intravenous chemotherapeutic agents, with uniform use of steroids prophylactically during induction to prevent differentiation syndrome. Even then, the results show that nearly 40% of the children did require anthracyclines as cytoreductive therapy due to the differentiation syndrome. Additionally, the requirement of cytoreductive therapy was expectedly significantly higher (81%) in high-risk disease. Hence, at least for children with high-risk disease, it may be prudent to consider ATRA-chemotherapy based treatment to prevent such higher proportion of differentiation syndrome and related morbidities. Furthermore, the daily administration of ATO needs stringent cardiac and electrolyte monitoring, which remains often challenging in resource-challenged settings. Hence, the appropriate risk-stratification and treatment adaptations needs to be prospectively studied among children, especially in low-middle income countries. APML is notoriously well known to have significantly high proportion of early death even prior to initiation of definitive therapy in the community. This is driven mainly by bleeding manifestations, especially intracranial bleeds. In this study conducted in low-middle income country (LMIC) setting, the observed early mortality rate was 5.5% with the overall mortality rate of 10%. In contrast, the early mortality rate of APML observed in national cancer databases even in resource-rich countries like United States is 7.2%, and other studies conducted in LMICs reporting estimates exceeding 30%. Hence, this study does not capture the true mortality or burden of this disease from a community or epidemiological perspective, and likely underestimates the early mortality of childhood APML in India. The data recorded in cancer registries also does not capture incidence and mortality of this uncommon yet important disease as a separate category [4]. Collaborative research groups like Indian Pediatric Oncology Group (InPOG) working on multi-centre studies on childhood cancer should lead studies to capture treatment patterns and survival outcomes of childhood APML across the country [5].