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AbstractMultiple asparaginase products have been approved by the United States (US) Food and Drug Administration (FDA) for the treatment of acute lymphoblastic leukemia in pediatric and adult patients. Hepatic veno-occlusive disease (VOD) is a potentially life-threatening disorder resulting from damage to the liver sinusoidal endothelial cells. To evaluate this safety concern with asparaginase (i.e. Asparlas, Oncaspar, Rylaze, and Erwinaze) use, we performed a postmarketing review of hepatic VOD reports retrieved from the FDA Adverse Event Reporting System database and literature with these four products. We identified 55 cases of hepatic VOD following exposure to asparaginase products. The median time to onset of hepatic VOD from the first dose of asparaginase was 18 days (interquartile range 13-24 days). Notably, 80% (44/55) of cases reported grades 3-5 VOD per the Common Terminology Criteria for Adverse Events. Although patients received asparaginase with standard chemotherapeutic agents known to induce VOD, case-level data indicates that asparaginase products may have contributed to hepatic VOD. Asparaginase products are associated with hepatotoxicity and thrombosis, suggesting a plausible mechanism for asparaginase-induced hepatic VOD. Based on the totality of data, including temporality and biologic plausibility, we determined hepatic VOD to be a class effect with asparaginase products. These data contributed to the addition of hepatic VOD to the hepatoxicity warning in the US Prescribing Information for asparaginase class products. [ABSTRACT FROM AUTHOR]

Simple Summary: Berlin–Frankfurt–Münster (BFM) protocols are widely used outside clinical trials to treat pediatric acute lymphoblastic leukemia patients. However, local specificities might demand treatment adaptations, like the reduction of high-dose methotrexate due to lack of pharmacokinetic monitoring, the substitution of conventional asparaginase for peg-asparaginase because of the unavailability of the latter, or flow-cytometry-based measurable residual disease instead of a PCR-based one. Here, we report the results of a 22-year period of children treated with BFM protocols in a developing country. The results were somewhat comparable to the BFM reports, and we conclude that BFM protocol adaptations can be safely implemented in developing countries, accounting for local specificities. Introduction: The objective of the current study was to determine the survival probabilities of children and adolescents with acute lymphocytic leukemia treated with adapted Berlin–Frankfurt–Münster (BFM) protocols and compare our results with the original BFM reports. Methods: This retrospective study included 695 patients up to 19 years old treated with adapted BFM protocols between 1997 and 2018 in four hospitals in Rio de Janeiro. The 1997–2007 and 2008–2018 cohorts were analyzed separately. Results: More than half of the patients were stratified into the high-risk BFM classification. Overall and event-free survivals were, in the 1997–2007 period, respectively, 88% and 80% (BFM standard risk group—SRG), 75% and 67% (intermediate risk group—IRG), and 48% and 33% (high-risk group—HRG). The corresponding numbers for the 2008–2018 period were 93% and 84% (SRG), 75% and 63% (IRG), and 64% and 57% (HRG). In the second period, both the OS (HR = 0.71, p = 0.011) and EFS (HR = 0.62, p < 0.001) were higher. Except for the intermediate-risk group, the latter results are comparable to the BFM. Conclusion: The BFM protocol adaptations can be safely implemented in developing countries, accounting for local specificities. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Survival rates for children with ALL have improved, and today, more than 90% of children with ALL can be successfully treated. Acute pancreatitis (AP), which develops during chemotherapy for ALL can be a serious and fatal complication. It is a widely known toxicity, and several reports indicate that AP occurs with an incidence of 2–10% in patients treated for leukemia. It is mainly, but not exclusively, associated with the administration of asparaginase (ASP), which is one of the key components of multiagent chemotherapy used in ALL. The development of AP usually delays subsequent courses of chemotherapy and is the most common reason for the discontinuation of ASP, thus increasing the potential risk of leukemia relapse in children with ALL. Therefore, both the pathogenesis of AP in ALL and its impact on long-term outcomes remain to be thoroughly investigated. Purpose: This study aimed to identify the risk factors for acute pancreatitis (AP) and its impact on outcomes in Polish children treated for ALL. Methods: The study group included 2303 children receiving intensive chemotherapy for ALL. The group was divided into patients with at least one episode of AP and those who did not develop AP after treatment for ALL. Results: The cumulative incidence of AP in the study group was 4.08%. Older age was an independent risk factor for the development of AP (OR = 1.05; 95%CI = 1.006–1.098; p = 0.03). The overall mortality associated with AP was 2.13%. The probabilities of disease-free survival (p-DFS) and event-free survival (p-EFS) in both subgroups were 0.84 vs. 0.86, log-rank p = 0.65 and 0.75 vs. 0.80, log-rank p = 0.12, respectively. A total of 22 out of 94 patients (23.4%) with AP were re-exposed to asparaginase (ASP) during the subsequent treatment phases. Only one patient re-exposed to ASP (4.5%) developed a second episode of AP. There were no significant differences in p-DFS and p-EFS between patients re-exposed and not re-exposed to asparaginase (0.78 vs. 0.86, log-rank p = 0.27 and 0.63 vs. 0.79, log-rank p = 0.09, respectively). Conclusions: The incidence of AP in children with ALL is low and related to patients' age. The development of AP does not seem to influence p-DFS and p-EFS in children with ALL. Recurrence of AP after re-exposure to asparaginase in patients with ALL and a history of AP is low (4.5%). Re-exposure to asparaginase after the first episode of AP does not improve either p-DFS or p-EFS in children with ALL. [ABSTRACT FROM AUTHOR]