This correlative analysis from the Children’s Oncology Group AALL1231 trial suggests that bortezomib may benefit a biologically defined subset of newly diagnosed T-ALL patients rather than all-comers: leukemias with relatively high immunoproteasome and low constitutive proteasome subunit levels showed deeper early responses and better event-free survival when bortezomib was added to augmented BFM chemotherapy. In particular, higher β5i activity and higher immunoproteasome-to-constitutive proteasome ratios were associated with greater bortezomib sensitivity, while low β1/β5 expression also marked favorable outcomes in the bortezomib arm. These findings provide a plausible biomarker-based explanation for why the phase III trial overall was negative and support future prospective validation of proteasome profiling to select T-ALL patients most likely to benefit from frontline proteasome inhibition.
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