Robin Q H Kloos1, Rob Pieters2, Florine M V Jumelet1, Hester A de Groot-Kruseman2,3, Cor van den Bos2,4, Inge M van der Sluis1,2. 1. Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands. 2. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. 3. Dutch Childhood Oncology Group, Utrecht, the Netherlands. 4. Pediatric Oncology and Hematology, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, the Netherlands.
Abstract
PURPOSE: In the DCOG ALL-11 protocol, polyethylene glycol-conjugated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase treatment of pediatric acute lymphoblastic leukemia are individualized with therapeutic drug monitoring (TDM). The efficacy of TDM and its effect on asparaginase-associated toxicity are reported. PATIENTS AND METHODS: After induction with 3 fixed intravenous doses of 1,500 IU/m2 PEGasparaginase, medium-risk patients (n = 243) received 14 individualized doses that targeted trough levels of 100-250 IU/L, standard-risk patients (n = 108) received 1 individualized dose, and high-risk patients (n = 18) received 2-5 fixed administrations (1,500 IU/m2). After a neutralizing hypersensitivity reaction, patients were started with 20,000 IU/m2 Erwinia asparaginase 3 times per week, and l-asparagine was measured to monitor asparaginase efficacy. Several asparaginase-associated toxicities were studied. RESULTS: The final median PEGasparaginase dose was lowered to 450 IU/m2. Overall, 97% of all trough levels of nonallergic patients were > 100 IU/L. Asparagine was < 0.5 μM in 96% and 67% of the PEGasparaginase and Erwinia asparaginase levels > 100 IU/L, respectively. Ten percent developed a neutralizing hypersensitivity reaction to PEGasparaginase, of which 40% were silent inactivations. The cumulative incidence of grade 3-4 pancreatitis, central neurotoxicity, and thromboses was 12%, 4%, and 6%, respectively, and not associated with asparaginase activity levels. During medium-risk intensification, 50% had increased ALT and 3% hyperbilirubinemia (both grade 3/4 and correlated with asparaginase activity levels), and 37% had grade 3/4 hypertriglyceridemia. Hypertriglyceridemia occurred less in intensification compared with ALL-10 (37% v 47%), which is similar to ALL-11 but with higher asparaginase levels during intensification. CONCLUSION: TDM of asparaginase results in a significant reduction of the PEGasparaginase dose with adequate asparaginase activity levels and sufficient asparagine depletion. In addition, with TDM, silent inactivation and allergic-like reactions were identified. However, the effect of reduced asparaginase activity levels on toxicity is limited.
PURPOSE: In the DCOG ALL-11 protocol, polyethylene glycol-conjugated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase treatment of pediatric acute lymphoblastic leukemia are individualized with therapeutic drug monitoring (TDM). The efficacy of TDM and its effect on asparaginase-associated toxicity are reported. PATIENTS AND METHODS: After induction with 3 fixed intravenous doses of 1,500 IU/m2 PEGasparaginase, medium-risk patients (n = 243) received 14 individualized doses that targeted trough levels of 100-250 IU/L, standard-risk patients (n = 108) received 1 individualized dose, and high-risk patients (n = 18) received 2-5 fixed administrations (1,500 IU/m2). After a neutralizing hypersensitivity reaction, patients were started with 20,000 IU/m2 Erwinia asparaginase 3 times per week, and l-asparagine was measured to monitor asparaginase efficacy. Several asparaginase-associated toxicities were studied. RESULTS: The final median PEGasparaginase dose was lowered to 450 IU/m2. Overall, 97% of all trough levels of nonallergic patients were > 100 IU/L. Asparagine was < 0.5 μM in 96% and 67% of the PEGasparaginase and Erwinia asparaginase levels > 100 IU/L, respectively. Ten percent developed a neutralizing hypersensitivity reaction to PEGasparaginase, of which 40% were silent inactivations. The cumulative incidence of grade 3-4 pancreatitis, central neurotoxicity, and thromboses was 12%, 4%, and 6%, respectively, and not associated with asparaginase activity levels. During medium-risk intensification, 50% had increased ALT and 3% hyperbilirubinemia (both grade 3/4 and correlated with asparaginase activity levels), and 37% had grade 3/4 hypertriglyceridemia. Hypertriglyceridemia occurred less in intensification compared with ALL-10 (37% v 47%), which is similar to ALL-11 but with higher asparaginase levels during intensification. CONCLUSION: TDM of asparaginase results in a significant reduction of the PEGasparaginase dose with adequate asparaginase activity levels and sufficient asparagine depletion. In addition, with TDM, silent inactivation and allergic-like reactions were identified. However, the effect of reduced asparaginase activity levels on toxicity is limited.
Authors: Anjali S Advani; Eric Larsen; Kristina Laumann; Selina M Luger; Michaela Liedtke; Meenakshi Devidas; Zhiguo Chen; Jun Yin; Matthew C Foster; David Claxton; Kristin Coffan; Martin S Tallman; Frederick R Appelbaum; Harry Erba; Richard M Stone; Stephen P Hunger; Jennifer L McNeer; Mignon L Loh; Elizabeth Raetz; Naomi Winick; William Carroll; Richard A Larson; Wendy Stock Journal: Blood Adv Date: 2021-01-26
Authors: Leonard A Mattano; Meenakshi Devidas; Kelly W Maloney; Cindy Wang; Alison M Friedmann; Patrick Buckley; Michael J Borowitz; Andrew J Carroll; Julie M Gastier-Foster; Nyla A Heerema; Nina S Kadan-Lottick; Yousif H Matloub; David T Marshall; Linda C Stork; Mignon L Loh; Elizabeth A Raetz; Brent L Wood; Stephen P Hunger; William L Carroll; Naomi J Winick Journal: J Clin Oncol Date: 2021-03-19 Impact factor: 44.544
Authors: Yiwei Liu; John C Panetta; Wenjian Yang; Seth E Karol; Cheng Cheng; Jun J Yang; William E Evans; Hiroto Inaba; Ching-Hon Pui; Sima Jeha; Mary V Relling Journal: Blood Date: 2020-12-17 Impact factor: 22.113
Authors: André Baruchel; Patrick Brown; Carmelo Rizzari; Lewis Silverman; Inge van der Sluis; Benjamin Ole Wolthers; Kjeld Schmiegelow Journal: ESMO Open Date: 2020-09