Ixazomib (MLN9708) Proteasome Inhibitor + Salvage Chemo Delivers 67% CR in Pediatric R/R ALL

Ixazomib is an oral proteasome inhibitor (more potent than bortezomib preclinically; FDA-approved in multiple myeloma) evaluated in a TACL Phase 1/2, 3+3 dose-escalation study combining ixazomib with established 28-day relapsed ALL chemotherapy blocks in patients ≤21 years with relapsed/refractory ALL/LL (n=24 enrolled; all had ALL; Phase 1 n=10, Phase 2 n=14; NCT03817320). Ixazomib 2.0mg/m² (DL2) was declared the RP2D despite 2 DLTs at DL2 in Phase 2; the most common grade ≥3 attributable AEs were GI disorders (n=12) and febrile neutropenia (n=9). In evaluable patients, CR was 67% with 64% (9/14) achieving flow MRD-negativity—numerically in the same ballpark as proteasome-inhibitor–augmented pediatric relapse regimens like bortezomib + VPLD reported CR2 rates around ~73% in first relapse settings, and higher than historical chemotherapy-only salvage in multiply relapsed/refractory disease (often ~40–56% CR depending on regimen and risk group).