How to Administer Pegaspargase during Induction Treatment of Acute Lymphoblastic Leukemia in Children and Adolescents? Results of the Caall-F01, a Multicentre Randomized Clinical Trial from the French Pediatric Cancer Society (SFCE)
Year: 2024
Type: conference-abstract
Abstract: CAALL-F01 is a French prospective multicentric cohort study focused on children and adolescents, aged 1-17 years, with acute lymphoblastic leukemia (ALL). Patients with BCP-ALL were initially stratified based on age, white blood cell count, central nervous system (CNS) and/or testis involvement, genetics, and response to a prednisone prephase (PP). This stratification defined three risk groups: standard (B-SR), medium (B-MR), and high risk (B-HR). T-cell ALL patients were stratified into two groups, T-SR and T-HR, depending on CNS status and response to PP. As asparaginase is a major drug for childhood ALL and the pegylated form, pegaspargase (PEG), was not registered in the EU, a two-parallel-arm randomized clinical trial (RCT) was conceived and embedded in the cohort study. Randomization occurred before the first PEG infusion (D12), in the B-SR, B-MR, and T-SR groups. Patients were allocated (1:1) to either receive one infusion of PEG 2500 IU/m² on D12 (Arm A) or two infusions of 1250 IU/m² on D12 and D26 (Arm B) during induction. The dose assigned at randomization was used in subsequent treatment phases. Patients in the B-HR and T-HR groups received two infusions of PEG 2500 IU/m² during induction and 2500 IU/m² per infusion afterwards. The study had two primary objectives: 1) to assess the superiority of the fractionated scheme in terms of pharmacokinetics, 2) to assess the equivalence in tolerance of the two schemes. The co-primary endpoints were: 1) the incidence of adequate (>100 IU/L) asparaginase activity (AA) at the end of induction (D33 ± 1 day), 2) the incidence of severe (CTCAE Grade ≥ 3) asparaginase-related toxicities (CNS thrombosis, pancreatitis, severe allergy/anaphylaxis, and bilirubin elevation) from D12 of induction to D49. Results: From September 2016 to February 2022, 2032 patients (mean age, 5.4 years, 57% male) were included. Among these, 1624 patients in the B-SR (942 pts), B-MR (518 pts), or T-SR (164 pts) groups were randomly allocated to Arm A (814 pts) or Arm B (810 pts). The 2 arms were well balanced for baseline characteristics and prognostic features. The median follow-up was 44.6 months. The D33 AA was evaluable in 1475 (86.7%) randomized patients. The two-infusion arm was superior to the one-infusion arm, as D33 AA was ≥ 100 U/L in 87.9% of the patients in Arm A (653/743) versus 96.6% in Arm B (707/732) (p<.0001). The cumulative incidence of any of the four targeted toxicities was 15.9% in Arm A (129/814 pts) versus 14.1% in Arm B (114/810 pts) (difference, 1.78%, 95% confidence interval (CI) -1.70 to +5.26%); as the equivalence margin was set to 4%, equivalence was not demonstrated. Minimal residual disease levels assessed by clone-specific IG-TCR PCR at the end of induction and consolidation did not differ between the 2 arms, nor did the 48-month event-free survival (EFS, 95.5% CI 95 94.7-97.4 vs 97% CI 95.78-98.12). Post hoc analyses revealed that 48-month EFS in Arms A and B were not significantly different for patients with B-ALL (94.0%, 95CI 92.0-95.9 for Arm A vs 95.8%, 95CI 94.2-97.4 for Arm B, HR= 0.78, 95CI 0.51-1.20, p=0.26), nor for patients with T-cell ALL (88.0%, 95CI 81.2-95.2 for ArmA vs 87.2%, 95CI 80.1-94.9 for Arm B, HR=1.16, 96CI 0.49-2.72; p=0.74). Conclusion: For non-high-risk ALL, representing 80% of the study population, a fractionated scheme of pegaspargase (2 doses of 1250 IU/m²) is at least as well tolerated as a one-infusion scheme (1 dose of 2500 IU/m²) and more effective in terms of maintaining adequate AA throughout induction. However, at the current MFU of 44 months, this did not translate into superior long-term outcomes.
Source: Blood
Authors: Marion Strullu, Arnaud Petit, Carine Halfon-Domenech, Anne-France Ray-Lunven, Paul Saultier, Wadih Abou Chahla, Stéphane Ducassou, Marlène Pasquet, Caroline Thomas, Cécile Pochon, Virginie Gandemer, Catherine Paillard, Alexandre Theron, Claire Pluchart, Pascale Schneider, Damien Bodet, Isabelle Pellier, Pierre Simon Rohrlich, Anne-France Jourdain, Pauline Simon, Frederic Millot, Liana Carausu, Corinne Armari Alla, Camille Leglise, Justyna Kanold, Claire Desplantes, Sandrine Thouvenin, Christophe Piguet, Nicolas Boissel, Wendy Cuccuini, Vahid Asnafi, Aurélie Caye-Eude, Hélène Cavé, Guy Leverger, Jean-François Benoist, Yves Bertrand, Sylvie Chevret, André Baruchel
Institutions: Assistance Publique – Hôpitaux de Paris, Hôpital Robert-Debré, Sorbonne Université, Hôpital Armand-Trousseau, Institut d’Hématologie et d’Oncologie Pédiatrique, Assistance Publique Hôpitaux de Marseille, Centre Hospitalier Universitaire de Lille, Hôpital Pellegrin, Centre Hospitalier Universitaire de Toulouse, Centre Hospitalier Universitaire de Nantes, Centre Hospitalier Régional et Universitaire de Nancy, Hôpitaux Universitaires de Strasbourg, Centre Hospitalier Universitaire de Montpellier, Centre Hospitalier Universitaire de Reims, Hôpital Charles-Nicolle, Centre Hospitalier Universitaire de Caen Normandie, Centre Hospitalier Universitaire d'Angers, Centre Hospitalier Universitaire de Nice, Centre Hospitalier Universitaire de Tours, Centre Hospitalier Universitaire de Besançon, Centre Hospitalier Universitaire de Poitiers, Centre Hospitalier Régional Universitaire de Brest, Hôpital Couple Enfant, Centre Hospitalier Universitaire Amiens-Picardie, Centre Hospitalier Universitaire de Clermont-Ferrand, CHU Dijon Bourgogne, Centre Hospitalier Universitaire de Saint-Étienne, Centre Hospitalier Universitaire de Limoges, Hôpital Saint-Louis, Université Paris Descartes, Hôpital Necker-Enfants Malades
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: Servier
OpenAlex ID: W4405041122