Nelarabine May Be Safely Incorporated Into a Phase III Study for Newly Diagnosed T-Lineage Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group

Abstract 865

With dose-intensified, multi-agent therapy, 80 to 85% of patients with T-lineage acute lymphoblastic leukemia (T-ALL) are cured. Nelarabine (Compound 506U78; IND# 52611) has shown impressive single agent clinical activity in relapsed T-ALL, but has been associated with significant neurotoxicity. We previously showed that Nelarabine could be added safely to an intensive multi-agent chemotherapy backbone in the COG AALL00P2 pilot study without excess neurotoxicity. The Phase III AALL0434 T-ALL study was designed to assess the safety and efficacy of adding Nelarabine to a COG-augmented BFM chemotherapy regimen. In the Safety Phase of the study, 600 patients with newly-diagnosed T-ALL were accrued from January 2007 to June 2010. Patients with high-risk T-ALL, defined by bone marrow (BM) minimal residual disease (MRD) level >1% or >5% BM blasts at day 29 of Induction, were randomized to receive backbone chemotherapy +/− five 5-day courses of Nelarabine 650 mg/m²/day once in Consolidation, once in Delayed Intensification and at the start of the first three Maintenance cycles. Patients were also randomly assigned to treatment arms that contained either high-dose methotrexate (HD-MTX) plus leucovorin rescue or Capizzi style escalating intravenous MTX without rescue during Interim Maintenance. Fifty-seven patients were assigned to the High-risk arm and were equally randomized to each of the MTX regimens +/− Nelarabine; their progress was followed for at least 8 weeks after receiving cranial radiation in the Delayed Intensification Phase (week 34) to assess for neurotoxicities. Toxicities were compared between patients who were randomized to regimens with Nelarabine (n= 28) and without Nelarabine (n= 29). There were no differences in the incidence of pre-defined targeted neurotoxicities of peripheral motor neuropathy (10 Nelarabine vs 6 no Nelarabine p= 0.38), sensory neuropathy (10 Nelarabine vs 7 no Nelarabine p = 0.78) and central neurotoxicity (0 Nelarabine vs 3 no Nelarabine; p=0.11 [two-tailed Fisher's Exact Test]). Additional toxicities including febrile neutropenia (24 vs 29 p= 0.058), and AST/ALT elevations (24 vs 20; p=0.36) were similar in the regimens with/without Nelarabine. The only difference in toxicities between the regimens was increased AST and ALT (unrelated to Nelarabine) within the escalating MTX treatment arms, as compared to arms containing HD-MTX (34 vs 10 p=0.003). Adverse events were reported for 8 of 28 patients on Nelarabine-containing and 7 of 29 patients on the non-Nelarabine containing treatment arms. There were two CNS adverse events reported for the 29 patients treated without Nelarabine. There were no CNS adverse events on the Nelarabine treatment arms. There were 3 PNS adverse events reported among the 28 patients that received Nelarabine: two events in the same patient included abdominal pain and constipation, and one patient had a transient Grade 2 motor neuropathy following a course of Nelarabine. These results show that the addition of Nelarabine to the backbone chemotherapy is safe and feasible. The AALL0434 Efficacy phase has now opened, and both intermediate and high-risk patients will be randomly assigned to all four treatment arms. The COG experience with Nelarabine demonstrates that this agent may have significant toxicity in heavily pre-treated T-ALL patients, but may be well-tolerated in newly diagnosed patients. AALL0434 will determine whether or not Nelarabine treatment improves outcome of children, adolescents and young adults with newly diagnosed T-ALL.