Background
Phase 2, open-label, randomized controlled trial (BRIGHT AML 1003). N=132 patients with newly diagnosed AML or high-risk MDS unfit for standard induction chemotherapy (age ≥75 or age 55–74 with comorbidities). Glasdegib is a selective oral Smoothened (SMO) inhibitor that blocks the Hedgehog signaling pathway, which is aberrantly activated in AML stem cells and contributes to treatment resistance and cancer stem cell maintenance. The rationale was that inhibiting Hedgehog signaling might sensitize AML blasts to cytarabine. Randomized 2:1 to glasdegib+LDAC vs LDAC alone. Published Leukemia 2019.
Interventions and follow up
Arm A: Glasdegib 100 mg PO once daily + low-dose cytarabine (LDAC) 20 mg SC twice daily days 1–10 of each 28-day cycle
Arm B: Low-dose cytarabine (LDAC) 20 mg SC twice daily days 1–10 of each 28-day cycle alone
Primary endpoint: OS
mFollow up: 20 month
Arm B: Low-dose cytarabine (LDAC) 20 mg SC twice daily days 1–10 of each 28-day cycle alone
Primary endpoint: OS
mFollow up: 20 month
Results
mOS: 8.8 vs 4.9 months (glasdegib+LDAC vs LDAC), HR 0.46 (95% CI 0.30–0.71), P=.0002
CR rate: 17.2% vs 2.3%, P=.0142
1-yr OS: 35.3% vs 11.4%
Benefit in AML subgroup: mOS 8.3 vs 4.3 months (HR 0.46); MDS subgroup: too few for separate analysis
CR rate: 17.2% vs 2.3%, P=.0142
1-yr OS: 35.3% vs 11.4%
Benefit in AML subgroup: mOS 8.3 vs 4.3 months (HR 0.46); MDS subgroup: too few for separate analysis
Adverse events
Overall: Grade ≥3 AEs 87% (glasdegib+LDAC) vs 90% (LDAC); discontinuation due to AEs 8% vs 8%.
Hematologic: Anemia grade ≥3 38% vs 47%, thrombocytopenia 35% vs 43%, neutropenia 35% vs 42% — similar or lower with glasdegib.
Hedgehog class effects: Muscle spasms 38% vs 8%; dysgeusia 20% vs 2%; alopecia 12% vs 0%.
Cardiac: QTc prolongation grade ≥3 4% — ECG monitoring required.
Gastrointestinal: Nausea any grade 36% vs 13%.
Hematologic: Anemia grade ≥3 38% vs 47%, thrombocytopenia 35% vs 43%, neutropenia 35% vs 42% — similar or lower with glasdegib.
Hedgehog class effects: Muscle spasms 38% vs 8%; dysgeusia 20% vs 2%; alopecia 12% vs 0%.
Cardiac: QTc prolongation grade ≥3 4% — ECG monitoring required.
Gastrointestinal: Nausea any grade 36% vs 13%.
Conclusions
Glasdegib + LDAC demonstrated a statistically significant OS improvement over LDAC alone (mOS 8.8 vs 4.9 months, HR 0.46, P=.0002) with higher CR rates (17% vs 2%), supporting FDA approval for newly diagnosed AML unfit for intensive therapy. Muscle spasms and QTc prolongation are the characteristic toxicities of glasdegib.
Key Limitations
Phase 2 trial with N=132 — modest sample size; not powered for OS subgroup analyses. The clinical benefit of glasdegib + LDAC appears lower than venetoclax + azacitidine (VIALE-A: mOS 14.7 vs 9.6 months, HR 0.66) or ven + LDAC (VIALE-C CR+CRi 48%), making glasdegib+LDAC a third-choice option in most patients. Muscle spasms (38%) are common and sometimes limiting. QTc monitoring needed. LDAC is a weak cytotoxic backbone; the Hedgehog rationale for AML remains mechanistically plausible but not robustly validated. Limited data in IDH- or FLT3-mutated subgroups where targeted agents are strongly preferred.
Clinical Context
FDA approved glasdegib (Daurismo) + LDAC for newly diagnosed AML unfit for intensive induction in November 2018. In current practice, glasdegib + LDAC has been largely displaced by venetoclax + azacitidine (VIALE-A) and venetoclax + LDAC (VIALE-C) as the preferred non-intensive AML regimens, given stronger efficacy data with venetoclax combinations. Glasdegib + LDAC may be considered when venetoclax is contraindicated (severe cytopenias requiring monitoring, TLS risk, drug interactions) or unavailable. IDH-mutated patients should receive targeted therapy (ivosidenib+aza, enasidenib). ESMO-MCBS: not assigned.