L-Asparaginase-Loaded Red Blood Cells Combined with Standard EWALL Chemotherapy in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (Ph- ALL): First Results of the GRASPALL/GRAALL-SA2-2008 Study

In adults with Ph- ALL, the clinical benefit of L-asparaginase is hampered by its toxicity. With its improved efficacy/tolerability potential, L-asparaginase-loaded red blood cells (GRASPA®) could be a suitable option for combining L-asparaginase with standard chemotherapy, especially in older patients with the disease.

The GRASPALL/GRAALL-SA2-2008 was an open label Phase II dose escalation study conducted by the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) in patients aged >55y with newly diagnosed ALL Ph-. The aim was to determine the optimal dose of GRASPA® that could be combined with the standard EWALL chemotherapy backbone in these patients. The primary composite endpoint included tolerance and efficacy, the latter being defined as the achievement of target asparagine depletion for at least 7 days. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival and anti L-asparaginase antibody titer (Abs), were secondary endpoints. Three doses of Graspa® (50, 100 and 150 IU/kg), infused at d3 and d6 of two successive induction cycles, were investigated, using a Bayesian experimental plan. After each 3-pt cohort, an independent Data Safety Monitoring Board reviewed study drug tolerance before opening the next dose. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone 10 mg/m² d1-2,/8-11, vincristine 1 mg d1,8, and idarubicine 10 mg d1-2/8-9) and induction-2 (cyclophosphamide 500 mg/m² d15-17 and cytarabine 60 mg/m² d16-19/23-26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (1 g/m² d1), E.coli asparaginase (10,000 IU/m² d2) and high-dose cytarabine (1 g/m²/q12 hrs d1,3,5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for a total duration of 2 years. Dose reductions were recommended for pts aged >70y.

Between March 2009 and October 2010, 30 pts were recruited in 20 GRAALL centers. The 50, 100 and 150 dose levels included 3, 13 and 14 pts, respectively. Median age was 67 years (range 59–77). Twenty-six pts had B-lineage ALL and 4 had T-ALL. No differences in baseline characteristics were observed across the 3 dose level groups. Overall, 0 (0%), 2 (15%) and 5 (36%) pts presented limiting toxicities in the 50, 100 and 150 dose level, respectively. Because of insufficient efficacy, only 3 pts received the lower 50 IU/kg dose. At the higher 100 and 150 dose levels, 85% and 71% pts reached target asparagine depletion at d7, respectively. In these two 100 and 150 IU/kg groups, grade 3/4 infections were observed in 69% and 71% pts and invasive fungal infection in 23% and 43% pts, respectively. Incidences of adverse events tended to be lower in the 100 IU/kg group:

Anti L-asparaginase Abs were detected in 0/3, 2/13 and 1/14 pts after induction-1 and 1/2, 3/9 and 5/9 pts after induction-2, in the 50, 100 and 150 dose level group, respectively. Nevertheless, no clinical allergy was observed after the second drug infusion, but allergic reactions to native E-Coli L-asparaginase were observed in 5/19 pts after consolidation 1. Grade 3–4 infections and renal methotrexate toxicities were observed in 11% (11/99) and 10% (11/51) of consolidations courses.

Responses to therapy were as follows:

Two infusions of 100 IU/kg GRASPA® appear to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older pts with Ph- ALL. Larger prospective evaluations of this new L-asparaginase formulation are warranted.

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