A Phase 2 study of L-asparaginase encapsulated in erythrocytes in elderly patients with Philadelphia chromosome negative acute lymphoblastic leukemia: The GRASPALL/GRAALL-SA2-2008 study

Mathilde Hunault-Berger (1) , Thibaut Leguay (2) , Françoise Huguet (3) , Stéphane Leprêtre (4) , Eric Deconinck (5, 6, 7) , Mario Ojeda-Uribe , Caroline Bonmati , Martine Escoffre-Barbe (8) , Pierre Bories (9) , Chantal Himberlin , Patrice Chevallier (10) , Philippe Rousselot , Oumedaly Reman (11) , Marie-Laure Boulland (12) , Séverine Lissandre (13) , Pascal Turlure (14) , Didier Bouscary (15, 16) , Laurence Sanhes (17) , Olivier Legrand (18) , Marina Lafage-Pochitaloff (19) , Marie C. Béné , David Liens , Yann Godfrin , Norbert Ifrah (20, 1) , Hervé Dombret (21, 22)

1 CRCINA-ÉQUIPE 7 - Innate Immunity and Immunotherapy
2 CHU Bordeaux
3 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
4 GPL - Groupe d'étude des proliférations lymphoïdes
5 RIGHT - Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098)
6 Service d'hématologie
7 IBCT (ex IFR133) - Ingénierie et biologie cellulaire et tissulaire
8 Service d'hématologie clinique
9 Service Hématologie
10 CHU Nantes - Centre Hospitalier Universitaire de Nantes
11 Laboratoire d'Hématologie Biologique [CHU Caen]
12 HITC - Service d'Hématologie, Immunologie et de Thérapie Cellulaire
13 Service d'hématologie [Tours]
14 Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges]
15 Ligue Nationale Contre le Cancer - Paris
16 IC UM3 (UMR 8104 / U1016) - Institut Cochin
17 Hôpital de Perpignan
18 CHU Saint-Antoine [AP-HP]
19 APHM - Assistance Publique - Hôpitaux de Marseille
20 CHU Angers - Centre Hospitalier Universitaire d'Angers
21 Lymphocyte et cancer
22 Hôpital Saint-Louis

PURPOSE: The GRASPALL/GRAALL-SA2-2008 Phase II trial evaluated the safety and efficacy of L-asparaginase encapsulated within erythrocytes (GRASPA®) in patients ≥ 55 years with Philadelphia chromosome-negative acute lymphoblastic leukemia. FINDINGS: Thirty patients received escalating doses of GRASPA® on Day 3 and 6 of induction Phases 1 and 2. The primary efficacy endpoint was asparagine depletion \textless 2 µmol/L for at least 7 days. This was reached in 85 and 71% of patients with 100 and 150 IU/kg respectively but not with 50 IU/kg. Grade 3/4 infection, hypertransaminasemia, hyperbilirubinemia and deep vein thrombosis occurred in 77, 20, 7, and 7% of patients, respectively. No allergic reaction or clinical pancreatitis was observed despite 17% of Grade 3/4 lipase elevation. Anti-asparaginase antibodies were detected in 50% of patients and related to a reduction in the duration of asparagine depletion during induction Phase 2 without decrease of encapsulated L-asparaginase activity. Complete remission rate was 70%. With a median follow-up of 42 months, median overall survival was 15.8 and 9.7 months, in the 100 and 150 IU/kg cohorts respectively. CONCLUSIONS: The addition of GRASPA®, especially at the 100 IU/kg dose level, is feasible in elderly patients without excessive toxicity and associated with durable asparagine depletion. (clinicaltrials.gov identifier NCT01523782)

Mots clés: Aged; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Asparagine; Drug Carriers; Drug Compounding; Erythrocytes; Female; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Mycoses; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Survival Analysis

Domaines: Sciences du Vivant [q-bio]

Mathilde Hunault-Berger, Thibaut Leguay, Françoise Huguet, Stéphane Leprêtre, Eric Deconinck, et al.. A Phase 2 study of L-asparaginase encapsulated in erythrocytes in elderly patients with Philadelphia chromosome negative acute lymphoblastic leukemia: The GRASPALL/GRAALL-SA2-2008 study. American Journal of Hematology, 2015, 90 (9), pp.811--818. ⟨10.1002/ajh.24093⟩. ⟨hal-01237093⟩