Two Years Follow-up Results of Graspall/Graall-SA2–2008 Study: L-Asparaginase-Loaded Red Blood Cell Combined with Standard EWALL Chemotherapy in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (Ph-ALL)

L-asparaginase-loaded red blood cells (GRASPA®) has been shown to be a new available option for combining L-asparaginase with standard chemotherapy in different ALL population, including older patients with the disease. Tolerability and preliminary results of efficacy of GRASPA® in GRASPALL/GRAALL-SA2–2008 study have already been presented. We report below the 2-year follow-up efficacy results of this study.

GRASPALL/GRAALL-SA2–2008 study aimed at determining optimal dose of GRASPA® that could be combined with standard EWALL chemotherapy backbone in patients aged >55y with newly diagnosed Ph-ALL. It was an open label Phase II dose escalation study. Primary endpoint combined tolerance and efficacy (asparagine depletion ≥7 days). Three doses of L-Asparaginase-Loaded Red Blood Cells (50, 100 and 150 IU/kg), infused twice during induction cycles, were investigated. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone d1–2/8–11, vincristine d1,8, and idarubicine d1–2/8–9) and induction-2 (cyclophosphamide d15–17 and cytarabine d16–19/23–26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (d1) / E.coli asparaginase (d2) and high-dose cytarabine (d1, 3, 5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for 2 years. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival were secondary endpoints.

Between March 2009 and October 2010, 30 patients were recruited in 20 centres in France by the GRAALL network. The 50, 100 and 150 dose levels included 3, 13 and 14 patients, respectively. Median age was 67 years (range 59–77). No differences in baseline characteristics were observed across the 3 dose level groups.

The tolerability with L-Asparaginase-related side effects is reported below:

Overall L-asp expected adverse events tended to be lower in the 100 UI/kg group.

Regarding the efficacy and benefit/risk, asparagines depletion, remission rate, EFS and OS are reported below:

Three patients received the dose of 50 UI/kg but this dose was insufficient to reach a 7-day asparagine depletion.

Survival analysis showed that the dose of 100IU/kg was associated with median OS of 15.6 months an absolute value that compared favorably with historical controls: 8,8 mo (Rousselot et al. Drugs Aging,2011) and 10,5 mo (Hunault et al. Haematologica,2011)

GRASPA® at a dose of 100 UI/kg appears to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older patients with Ph- ALL with a sustained asparagine depletion and a good efficacy/safety profile.

Godfrin:ERYTECH Pharma: COO Other.