Nelarabine

In T‑cell acute lymphoblastic leukemia (T‑ALL), nelarabine resistance was associated with hyperactivation of AKT and MEK/ERK signaling, not with differences in drug transporters or metabolic activators. Combining nelarabine with the pan‑PI3K inhibitor ZSTK‑474 overcame resistance in cell lines and primary patient samples, synergistically reducing survival, inducing apoptosis, and downregulating Bcl2 while dephosphorylating AKT. The combination was more effective than PI3Kγ/δ‑selective inhibitors or Bcl2 inhibition. The authors propose that adding a PI3K inhibitor to nelarabine represents a promising strategy for relapsed/refractory T‑ALL.

Fig. 1 Nelarabine induces cytotoxic effects in T-ALL cell lines. (Lonetti A, et al., 2016)

In the Children’s Oncology Group trial AALL0434 (1,562 patients with newly diagnosed T‑ALL), adding six 5‑day courses of nelarabine to augmented Berlin‑Frankfurt‑Muenster (ABFM) therapy significantly improved 5‑year disease‑free survival (88.2% vs. 82.1%; P=0.029). The best outcome was with escalating‑dose methotrexate plus nelarabine (5‑year DFS 91%). Nelarabine also markedly reduced isolated and combined CNS relapses (1.3% vs. 6.9%, P=0.0001). Toxicities, including neurotoxicity, were acceptable and similar between arms. The authors conclude that nelarabine improves DFS in newly diagnosed T‑ALL without increasing toxicity.

Fig. 2 The 5-year cumulative incidence rates of CNS relapse (isolated and combined) in the nelarabine versus no nelarabine arms were 1.3% ± 0.63% and 6.9% ± 1.4%, respectively. (Dunsmore KP, et al., 2020)