ALCANTARA

Background

Phase 2, multicenter, single-arm trial (ALCANTARA). N=45 adults (≥18 years) with Ph-positive (BCR::ABL1-positive) B-cell precursor ALL who had relapsed after or were refractory to ≥1 second-generation (or later) TKI, or were intolerant to ≥2nd-generation TKIs and intolerant/refractory to imatinib. Blinatumomab was evaluated in this heavily pretreated, TKI-resistant Ph+ ALL population. Published JCO 2017; long-term final analysis published 2021 (PMID 33588145).

Interventions and follow up

Regimen: Blinatumomab 9 µg/d days 1–7, then 28 µg/d days 8–28 (CIV) × 4 induction cycles, then up to 5 consolidation cycles, in R/R Ph+ B-ALL after TKI failure
Primary endpoint: CR/CRh within the first 2 blinatumomab cycles
mFollow up: 25.1 months (final analysis)

Results

CR/CRh within 2 cycles (primary endpoint): 35.6% (16/45; 95% CI 21.9–51.2%)
Molecular response (BCR::ABL1 negativity among CR): 88% (14/16)
Response in T315I-mutant patients: 4 of 10 (40%) achieved CR/CRh despite gatekeeper mutation resistance
mOS (all patients): 9.0 months (95% CI 5.7–13.5)
mOS (CR/CRh responders vs non-responders): 19.8 vs 6.0 months, P<.001

Adverse events

Neurologic: Grade 3–4 neurologic events 20% (encephalopathy, speech disorder, cognitive disturbance) — primary dose-limiting toxicity, managed with corticosteroids and infusion interruption
CRS/infection: Grade ≥3 CRS 4%; grade ≥3 infections 11%
Deaths: 2 treatment-related deaths (1 infection, 1 multiorgan failure)

Conclusions

Blinatumomab achieved CR/CRh in 36% of adults with heavily pretreated TKI-resistant Ph+ ALL, including patients with T315I mutations. Responses were deep (88% molecular response) and associated with significantly improved OS (19.8 vs 6.0 months). This trial supported FDA approval of blinatumomab for R/R Ph+ ALL and established it as a preferred bridge-to-transplant strategy in this setting.

Key Limitations

Small single-arm cohort (N=45) without a randomized comparator. CR/CRh rate of 36% is modest, reflecting the heavily pretreated TKI-resistant population. Survival benefit inferred from responder vs non-responder comparison subject to selection bias. T315I subgroup very small (n=10). No combination with concurrent TKI tested, which has since become a more effective strategy.

Clinical Context

ALCANTARA supported the expanded FDA approval (July 2017) of blinatumomab to include R/R Ph+ B-ALL after TKI failure; EMA approval followed. ESMO and ELN guidance position blinatumomab as a salvage option in TKI-resistant Ph+ ALL, increasingly combined with later-generation TKIs (e.g., ponatinib) and used as a bridge to allo-HSCT.

References