Ixazomib with chemotherapy for childhood relapsed acute lymphoblastic leukemia: a TACL consortium report.
This phase 1/2 TACL study of 24 pediatric patients with relapsed/refractory ALL found that ixazomib could be combined with relapse chemotherapy at an RP2D of 2 mg/m², with reported acceptable safety, a 67% complete response rate among evaluable patients, and flow MRD negativity in 9 of 14 responders.
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This phase 1/2 TACL study of 24 pediatric patients with relapsed/refractory ALL found that ixazomib could be combined with relapse chemotherapy at an RP2D of 2 mg/m², with reported acceptable safety, a 67% complete response rate among evaluable patients, and flow MRD negativity in 9 of 14 responders.
Research significance
The study provides early clinical evidence that adding the oral proteasome inhibitor ixazomib to established relapse chemotherapy is feasible and may have antileukemic activity in pediatric relapsed/refractory ALL; whether ixazomib improves response durability or survival beyond chemotherapy alone remains an untested inference requiring controlled trials.
Source abstract
Ixazomib (MLN 9708) is an oral proteasome inhibitor, preclinically more potent than bortezomib, that is currently US Food and Drug Administration-approved for the treatment of multiple myeloma. We conducted a phase 1/2 study to estimate the maximum tolerated dose, recommended phase 2 dose (RP2D), and early efficacy of ixazomib when combined with chemotherapy in pediatric patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Patients aged ≤21 years with R/R ALL/LL (including Down syndrome) were eligible. Ixazomib was combined with up to 3 different 28-day blocks of well-established, relapsed ALL chemotherapy. Ixazomib was tested at 2 dose levels (DL; DL1: 1.6 mg/m2 per dose; DL2: 2 mg/m2 per dose) using a 3+3 design. Dose-limiting toxicities (DLTs) during block 1 were used to make DL escalation decisions. Twenty-four patients enrolled, all with ALL (10 in phase 1, 14 in phase 2). The most common categories of grade ≥3 attributable adverse events were gastrointestinal disorders (n = 12) and febrile neutropenia (n = 9). Two patients experienced a DLT (both treated at DL2 in phase 2), however, DL2 was determined to be the RP2D. The complete response rate for evaluable patients was 67%; 64% (9/14) of whom were also flow minimal residual disease negative. The half-life was consistent across DLs and was comparable with that previously reported in adults. Oral capsule and liquid formulations were determined to be palatable. Ixazomib can be combined with chemotherapy with an acceptable safety profile and an encouraging early efficacy signal in pediatric R/R ALL. This trial was registered at www.clinicaltrials.gov as NCT03817320.