Nelarabine Can Be Safely Incorporated into an Intensive, Multiagent Chemotherapy Regimen for the Treatment of T-Cell Acute Lymphocytic Leukemia (ALL) in Children: A Report of the Children’s Oncology Group (COG) AALL00P2 Protocol for T-Cell Leukemia.

Nelarabine(araG), is an agent that has shown significant clinical activity in relapsed T-ALL, but has been associated with increased incidence of neurotoxicity. AALL00P2 was a two-stage pilot study designed to assess the feasibility and safety of adding Nelarabine to an intensive modified BFM chemotherapy regimen in children with T-ALL. Ninety-two patients (89 eligible, 87 evaluable) were accrued from April 2001 to October 2005. In stage 1 of the trial, patients with a slow early response, defined as either (a) ≥ 1000 peripheral blood blasts on day 8 of a prednisone prephase or (b) minimal residual disease (MRD) level ≥1% at day 36 of induction therapy, were assigned to receive chemotherapy that included five 5-day courses of Nelarabine 400mg/m²/day, while other patients received chemotherapy without Nelarabine. After 10 patients were assigned to receive Nelarabine, the study was temporarily halted and post-induction toxicities were compared between the regimens with/without Nelarabine. Of 30 (27 eligible) patients in the first stage, 12 (11 evaluable) were assigned to Nelarabine. Stage 2 of the study was limited to T-ALL patients with NCI high risk features. In stage 2, all patients received chemotherapy with five courses of Nelarabine, at either the phase II recommended dose of 650mg/m²/day (slow early response patients defined above) or 400mg/m²/day (others). After ten patients assigned to receive Nelarabine 650mg/m²/day were accrued, the study was closed and analysis of toxicities was conducted. Stage 2 accrued 61 patients with 10 patients receiving Nelarabine 650mg/m² and 51 receiving Nelarabine 400mg/m². Toxicities were compared between the regimens with (71 evaluable pts) and without Nelarabine (16 evaluable pts). There were no differences in the incidence of pre-defined targeted neurotoxicities of peripheral neuropathy (PNS; 5/71 Nelarabine vs 1/16 no Nelarabine p=1.000) and central neurotoxicity (CNS; 2/71 Nelarabine vs 2/16 no Nelarabine p=0.1526). Additional toxicities including decrease in hemoglobin, platelets and neutropenia (60/71 vs 16/16 p= 0.2043), AST/ALT elevations (29/71 vs 9/16 p=0.2799) and pancreatitis (4/71 vs 1/16 p=1.000) were similar in the regimens with/without Nelarabine. The only difference in toxicities between the regimens was a decrease in neutropenia with infection in the with Nelarabine arms (27/71 vs 13/16 p=0.0021). In comparison between the two different dosing levels (400mg/m² vs. 650mg/m² ) there were no differences in any of the targeted or non-targeted toxicities. Adverse events were reported for 12 of 71 patients on Nelarabine-containing and 5 of 16 patients on the no-Nelarabine regimens. There were two CNS adverse events reported for the 16 patients treated without Nelarabine; CNS hemorrhage and cerebellar infarct. There were 4 CNS adverse events reported among the 71 patients that received Nelarabine: two seizures and one CNS hemorrhage not attributed to Nelarabine and mild leukoencephalopathy possibly attributed to Nelarabine. There were 2 PNS adverse events reported on the Nelarabine regimens, both at 400mg/m². One patient had lower extremity motor weakness and one patient developed ascending polyneuropathy Guillain Barre-like syndrome, both attributed to Nelarabine. In conclusion, it is feasible with acceptable toxicity to add Nelarabine to an intensive chemotherapy regimen for children with T-ALL.