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2814 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)

Program: Oral and Poster Abstracts
Session: 613. Acute Lymphoblastic Leukemias: Therapies Excluding Allogeneic Transplantation: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphoid Leukemias, ALL, Combination therapy, Clinical Research, Diseases, Treatment Considerations, Lymphoid Malignancies
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Marion Strullu1*, Arnaud Petit, MD, PhD2,3*, Carine Halfon-Domenech, MD4*, Anne-France Ray-Lunven, MD1*, Paul Saultier5*, Wadih Abou Chahla, MD6*, Stéphane Ducassou7*, Marlène Pasquet, MD8*, Caroline Thomas, MD9*, Cécile Pochon10*, Virginie Gandemer11*, Catherine Paillard, MD, PHD12*, Alexandre Theron, MD13*, Claire Pluchart, MD14*, Pascale Schneider, MD, PhD15*, Damien Bodet16*, Isabelle Pellier, PhD17*, Pierre Simon Rohrlich18*, Anne-France Jourdain19*, Pauline Simon20*, Frederic Millot21*, Liana Carausu22*, Corinne Armari Alla, PhD23*, Camille Leglise24*, Justyna Kanold25*, Claire Desplantes26*, Sandrine Thouvenin27*, Christophe Piguet28*, Nicolas Boissel, MD, PhD29, Wendy Cuccuini, MD, PhD30*, Vahid Asnafi31*, Aurélie Caye-Eude32*, Hélène Cavé, PhD33*, Guy Leverger, MD, PhD34*, Jean-François Benoist35*, Yves Bertrand, MD36*, Sylvie Chevret37* and André Baruchel, MD, PhD38

1Pediatric Hematology, Hopital Robert Debré, AP-HP, Paris, France
2Hôpital Armand Trousseau, APHP, PARIS, Île-de-France, France
3Sorbonne Université, Paris, France
4Institut D'Hématologie Et D'Oncologie Pédiatrique, Lyon, France
5APHM, Marseille, France
6Department of Pediatric Hematology, Centre Hospitalo-Universitaire de Lille, Lille, France
7Service d'onco-hématologie pédiatrique, Hôpital Pellegrin Tripode, Bordeaux, France
8Department of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France
9Pediatric Oncology, CHU Nantes, Nantes, FRA
10Nancy University Hospital, Pediatric onco-hematology department, Vandoeuvre lès Nancy, France
11Pediatric BMT Unit, Rennes, France
12Pediatric Oncology, CHRU Strasbourg, Strasbourg, FRA
13Pediatric Oncology, CHU Montpellier, Montpellier, FRA
14Pediatric Oncology, CHU de Reims, Reims, France
15Pediatric Hematology, Immunology, Oncology and Stem Cells Transplantation, Rouen University Hospital Charles Nicolle CHU Rouen, Rouen, France
16Pediatric Oncology, CHU De Caen,, Caen, FRA
17Pediatric Oncology, CHU Angers, Angers Cedex, FRA
18Department of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de Nice, Nice, PACA, France
19Pediatric Oncology, CHU de Tours, Tours, France
20Hématologie et oncologie pédiatrique,, CHRU de Besancon, Besancon, France
21Pediatric Oncology, CHU Poitiers, Poitiers, France
22Department of Pediatric Hematology and Oncology,, Centre Hospitalo-Universitaire de Brest, Brest, France, Brest, France
23Pediatric Oncology, CHU Grenoble Hôpital Couple Enfant, GRENOBLE, FRA
24Department of Pediatric Oncology, Hematology, Immunology,, University Hospital of Amiens, Amiens, France
25Pediatric Oncoloy, CHU Clermont Ferrand, Clermontferrand, FRA
26Pediatric Oncology, CHU de Dijon, Dijon, France
27Pediatric Oncology, CHU Saint Etienne, Saint Etienne, FRA
28Pediatric Oncology, CHU Limoges, Limoges, FRA
29Hematology Adolescents and Young Adult Unit, Saint-Louis Hospital, APHP, Paris, France, Paris Cedex 10, Paris, France
30Saint Louis Hospital, Paris, France
31Hematology Department, Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants, Paris, FRA
32Department of Genetics, University Hospital Robert Debré, Assistance Publique Des Hôpitaux, Paris, France
33Department of Genetics, Hôpital Robert Debré, Paris, France
34Pediatric Hematology Oncology Immunology Department, Hôpital Trousseau, Paris, France
35Biochemistry Department, Hôpital Universitaire Necker Enfants Malades, Paris, France
36Pediatric Hematology, Institut d'Hématologie et Oncologie Pédiatrique, Lyon, France
37Biostatistics and Medical Information Department, Saint Louis Hospital, Assistance Publique — Hôpitaux de Paris (AP-HP), Paris, France
38Department of Pediatric Hematology and Immunology,, University Hospital Robert Debré, Assistance Publique des Hôpitaux de Paris (APHP), Paris, France

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 Arm A 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.

Disclosures: Strullu: Clinigen: Membership on an entity's Board of Directors or advisory committees; Servier: Other: symposium. Boissel: Pfizer: Other; Sanofi: Other; Adveysa: Other; Amgen: Other. Baruchel: Jazz: Membership on an entity's Board of Directors or advisory committees; Wugen: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Servier: Other: TRavel Grant, Symposium, Research Funding.

*signifies non-member of ASH