Results from the AALL0434 phase III trial evaluating nelarabine in newly diagnosed pediatric and young adult T-ALL

Chemotherapy with nelarabine, a DNA-terminating nucleoside, has been successful in producing partial and complete remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL).¹ Nevertheless, its efficacy in newly diagnosed T-ALL has not been fully evaluated. So far, preliminary results from the AALL00P2 pilot study have shown that nelarabine addition to chemotherapy backbone was safe and led to a 5-year event-free survival (EFS) rate of 73% in patients with high-risk newly diagnosed pediatric T-ALL.

Therefore, Dunsmore et al.¹ investigated the efficacy and safety of nelarabine in children and young adults with newly diagnosed T-ALL during the phase III randomized AALL0434 trial (NCT00408005). The results of the study were published in the Journal of Clinical Oncology and are summarized below.

Study design

• Randomized, phase III trial that enrolled 1,596 patients aged 1–31 with newly diagnosed, untreated (except corticosteroids) T-ALL. All patients participated in a 28-day, prednisone-based, four-drug induction. Following induction, patients underwent risk stratification, and high-risk (HR) and intermediate-risk (IR) patients were included in the efficacy phase, while only HR patients were included in the safety phase.
• In total, 659 HR or IR patients were randomized to receive six 5-day courses of 650 mg/m²/d of nelarabine or not, together with backbone chemotherapy (either pegaspargase + methotrexate [C-MTX] or high-dose methotrexate [HDMTX]):
  • Consolidation phase: Two nelarabine courses on Days 1-5 and Days 43-47.
  • Delayed intensification phase: One nelarabine course on Days 29-33.
  • Maintenance phase: Three nelarabine courses on Days 29-33 of the first three maintenance cycles.
  • All IR and HR patients received prophylactic cranial radiation therapy (12 Gy).

Results

• No differences in baseline characteristics were detected between the nelarabine and no nelarabine arms, as shown in Table 1.

Table 1. Patient characteristics from the phase III AALL0434 trial¹

• The 5-year disease-free survival (DFS) and overall survival for patients receiving ± nelarabine and by arm are shown below in Table 2. Notably, patients receiving nelarabine had greater 5-year DFS but unchanged 5-year overall survival when compared with those without nelarabine treatment. When comparing arms, C-MTX + nelarabine had the best 5-year DFS rate, followed by C-MTX without nelarabine, then HDMTX + nelarabine, and lastly the HDMTX arm (p = 0.01).
• Among 323 patients who received nelarabine, 39 patients had an event, whereas 58 out of 336 patients treated without nelarabine had an event. The most common event was relapse (72.2%). Nelarabine addition to backbone chemotherapy was associated with a decrease in central nervous system relapses (p = 0.0001).

Table 2. Outcomes for patients receiving ± nelarabine and by arm in the phase III AALL0434 trial¹

• Twenty-three out of 917 patients (2.5%) were taken off protocol to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Multivariable Cox regression analysis on this group revealed worse DFS for those who underwent allo-HSCT compared with those receiving protocol chemotherapy, irrespective of their early T-cell precursor status. These results are shown below in Table 3.

Table 3. Multivariable cox regression analyses from the phase III AALL0434 trial¹

• In terms of safety, the rate of overall Grade ³ 3 adverse events were similar between the nelarabine (41.2%) and no nelarabine arms (46.1%) (p = 0.2). Similarly, the incidences of Grade 3-4 neuropathy (motor, p = 0.223; sensory, p = 0.664) and Grade ³ 3 central neurotoxicities (p = 0.298) were not significantly different between the two groups.

• Two patients with induction failure who were assigned to nelarabine (non-randomly) developed signs of central neurocognitive decompensation and died.

Conclusion

The addition of nelarabine to backbone chemotherapy significantly increased the 5-year DFS rate for children and young adults with newly diagnosed T-ALL. More specifically, C-MTX together with nelarabine led to the best overall outcomes when compared with the other arms, which also applied to patients who terminated chemotherapy early to undergo allo-HSCT. Moreover, nelarabine addition to backbone chemotherapy was associated with a significant decrease in the incidence of central nervous system relapses, and no unexpected toxicities were reported. These results indicate that nelarabine is an effective and safe treatment for children and young adults with newly diagnosed T-ALL.