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.

Inclusion criteria:

• Patient > 65 years old and < 85 years old
• Newly diagnosed Acute Myeloid Leukemia (AML) or post myelodysplastic syndrome diagnosed within 6 months prior to study enrollment
• Unfit for intensive chemotherapy (at risk to suffer treatment related pejorative toxicities /early death) due to the presence of one or more of the following criteria: Dependence in activities of daily living owing to the presence of comorbidities other than those resulting from the deterioration caused by the neoplastic disease. Presence in the patient's medical history of three or more of the following comorbidities, even if they are under control with proper treatment: Congestive heart failure, other chronic cardiovascular diseases, chronic obstructive pulmonary disease, cerebrovascular disease, peripheral neuropathy, chronic kidney failure, hypertension, diabetes mellitus, systemic vasculitis, severe arthritis
• Presence of geriatric syndromes such as fecal or urinary incontinence, spontaneous bone fractures, mild and moderate dementia, or patients who fall repeatedly, or, patient unwilling to receive intensive chemotherapy
• Eligible to receive low-dose cytarabine treatment
• ECOG performance status ≤ 2
• Female patients of childbearing potential and males must agree to use adequate contraception (e.g., hormonal or barrier method of birth control; abstinence) for the duration of study treatment and for 6 months after the last dose of Cytarabine or 3 months after last dose of GRASPA (whichever is the longest).
• Negative serum pregnancy test at study entry for female subjects of childbearing potential
• Subscription to social security insurance (if applicable, in accordance with local regulations)
• Ability to understand, and willingness to sign, a written informed consent document and to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

Exclusion criteria:

• Patients with M3 AML of FAB classification (APL, acute promyelocytic leukemia)
• Patients with AML involving chromosome 16 abnormalities or translocation (8:21) (CBF-AML)
• Patient with secondary AML subsequent to prior malignant blood disorder such as: Myelodysplastic syndrome diagnosed more than 6 months before study entry or Myeloproliferative syndrome
• Prior therapy to AML (standard therapy or investigational agents)
• Inadequate organ function : Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis, Serum creatinine concentration > 2 x ULN (Upper Limit of Normal), AST or ALT levels > 3.5xULN or 5xULN if related to AML, Total bilirubin > 2 x ULN, INR > 1.5, unless patient under chronic treatment with anticoagulants (in this case, INR should be within expected ranges for the specific condition), Insulin-dependent or uncontrolled diabetes mellitus
• Concurrent malignancies other than AML requiring chemotherapy
• Severe active infection, HIV seropositivity, or known active type B or C viral hepatitis
• Known or suspected hypersensitivity or intolerance to mannitol
• Breastfeeding or lactating women

Adverse events were collected from signature of the informed consent from first patient and until 4 months after last GRASPA/ low-dose cytarabine administration of last patient i.e. up to 28 months for the longuest study drug exposure and on a total of 46 months of AE collection period throughout the study.