The protocol aims at adding GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) to standard chemotherapy (low-dose cytarabine) to treat patients older than 65 years diagnosed with AML and unfit for intensive chemotherapy.
L-asparaginase (ASNase) holds a key role in chemotherapy for Acute Lymphoblastic Leukemia (ALL) in children and young adults. In elderly patients, its efficacy is counterbalanced by its toxicity, which impairs its use. However, a study conducted with GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) in elderly ALL (study reference "GRASPALL-GRAAL SA2 2008") showed that efficacy/safety profile was positive, paving the way for introducing ASNase benefit into chemotherapy for elderly patients. In adults, Capizzi (1988) reported a significant benefit of ASNase associated with high-dose cytarabine treatment (HiDAC) in Acute Myeloid Leukemia (AML). Indeed, there was an overall statistically superior complete remission rate for HiDAC/ASNase (40%) vs HiDAC (24%) and an overall survival benefit for patients treated with HiDAC/ASNase (19.6 weeks vs 15.9 weeks). Another study in elderly patients also displayed positive results for ASNase treatment (Petti, 1989), as well as recent single case reports that point out the potential benefit of ASNase in different AML or mixed lineage leukemia (Horikoshi, 2009; Rubnitz, 2009). Our preclinical results also showed that an AML cell line and blast cells from the bone marrow of AML patients were sensitive to ASNase in vitro. However, up to now, the toxicity of ASNase for elderly had prevented its use in this population that represents the majority of AML patients. Considering the promising results of ASNase for AML treatment and the better safety profile offered by GRASPA (L-aspariginase encapsulated in red blood cells, erysapase), a multicenter, randomized, controlled IIb trial is open for recruitment. Efficacy and tolerability of GRASPA plus low-dose cytarabine will be evaluated versus low-dose cytarabine alone in treatment of AML patients over 65 year-old, unfit for intensive chemotherapy. One hundred and twenty-three patients (65-85 year-old) newly diagnosed for AML are planned for inclusion in the study. A 2:1 randomization will be respected (82 patients treated with GRASPA® plus low-dose cytarabine and 41 patients treated with low-dose cytarabine alone). Each patient will be followed for 24 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
123
Patients receiving Intervention (experimental group) will be treated with one injection of graspa per cycle of treatment, each cycle during 28 days, for a duration up to 24 cycles maximum
Hôpital l'Archet 1
Nice, Alpes Maritimes, France
Centre Léon Bérard
Lyon, Auvergne-Rhône-Alpes, France
Overall Survival
OS is defined as the time elapsed between randomization and death from any cause.
Time frame: Each patient will be followed for a duration of 24 months.
Response to Treatment
Percentage of patients with Complete remission (CR), Complete remission with incomplete recovery (neutrophil or platelet regeneration, CRi), Partial remission (PR)
Time frame: Each patient will be followed for a duration of 24 months.
Progression Free Survival (PFS)
Defined as the time elapsed between randomization and resistant disease or relapse or death from any cause
Time frame: Each patient will be followed for a duration of 24 months.
Patient Quality of Life
Collecting survey about patients quality of life
Time frame: Each patient will be followed for a duration of 24 months.
Safety of GRASPA Adverse Events and Serious Adverse Events
Number of incidences, type, severity and causality of adverse events / serious adverse events
Time frame: Each patient will be followed for a duration of 24 months.
Relapse Free Survival
Defined only for patients who achieve CR or CRi as the time elapsed between date of CR/CRi and date of disease relapse or death from any cause
Time frame: Each patient will be followed for a duration of 24 months.
Number of Hospitalizations
Hospitalizations (except schedule protocol visit during the study)
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Centre hospitalier Lyon Sud
Pierre-Bénite, Auvergne-Rhône-Alpes, France
Institut Paoli Calmettes
Marseille, Bouche Du Rhone, France
Hôpital JEAN MINJOZ
Besançon, Doubs, France
Hopital Morvan
Brest, Finistere, France
Hôpital Haut-Lévèque
Pessac, Gironde, France
CHRU de Nîmes
Nîmes, Guard, France
Hopital de Hautepierre
Strasbourg, Haut Rhin, France
Hopital De Purpan CHU Toulouse
Toulouse, Haute Garonne, France
...and 11 more locations
Time frame: Each patient will be followed for a duration of 24 months.
Percentage of Patients Who Need Transfusions
Number of transfusions per patient (red blood cells and or platelets)
Time frame: Until patient stops treatment (expected average of 8 months)
Pharmacodynamic and Pharmacokinetic Parameters of GRASPA
Plasma concentrations of asparagine, aspartate, glutamine, glutamate, whole blood L- asparaginase activity
Time frame: Until patient stops treatment (expected average of 8 months)
Immunogenicity
Titer of anti L-asparaginase antibodies
Time frame: Until patient stops treatment (expected average of 8 months)
Asparagine Synthetase (Optional)
Asparagine synthetase and in vitro sensitivity to aspariginase on the harvested bone marrow cells
Time frame: Until patient stops treatment (expected average of 8 months)
Biomarker Cytogenetic Testing (Optional)
Defined as cytogenetic biomarker testing
Time frame: Until patient stops treatment (expected average of 8 months)