Background
Phase III RCT (n=326), Ph-negative or Ph-positive relapsed/refractory CD22-positive B-cell ALL. Randomized 1:1 to the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin vs standard intensive chemotherapy.
Interventions and follow up
Arm A: Inotuzumab ozogamicin x6 cycles — cycle 1 (Q21D) 1.8 mg/m2 split 0.8 mg D1, 0.5 mg D8 and D15; reduced to 0.5 mg D1 after CR/CRi; cycles 2-6 Q28D
Arm B: Investigator-choice chemotherapy (FLAG; cytarabine + mitoxantrone; or high-dose cytarabine)
Primary endpoint: CR/CRi and OS
Median follow-up: NR
Arm B: Investigator-choice chemotherapy (FLAG; cytarabine + mitoxantrone; or high-dose cytarabine)
Primary endpoint: CR/CRi and OS
Median follow-up: NR
Results
CR/CRi: 80.7% vs 29.4% (A vs B), P<.001 (first 218 patients)
MRD-negativity (among responders): 78.4% vs 28.1%
mOS: 7.7 vs 6.7 mo, HR 0.77, 97.5%CI 0.58-1.03, P=.04
mPFS: 5.0 vs 1.8 mo, HR 0.45, P<.001
MRD-negativity (among responders): 78.4% vs 28.1%
mOS: 7.7 vs 6.7 mo, HR 0.77, 97.5%CI 0.58-1.03, P=.04
mPFS: 5.0 vs 1.8 mo, HR 0.45, P<.001
Adverse events
Hematologic/cytopenias (grade ≥3): Thrombocytopenia 37%, neutropenia 49% (inotuzumab); cytopenias common in both arms.
Infections (grade ≥3): Febrile neutropenia 24% vs 49% (A vs B).
Hepatic: Veno-occlusive disease / sinusoidal obstruction syndrome 11% (incl. 5 fatal), especially after subsequent allogeneic HCT (1% in chemo arm).
Other: Any grade ≥3 event 91% vs 95%; fatal AEs 4 vs 2 patients.
Infections (grade ≥3): Febrile neutropenia 24% vs 49% (A vs B).
Hepatic: Veno-occlusive disease / sinusoidal obstruction syndrome 11% (incl. 5 fatal), especially after subsequent allogeneic HCT (1% in chemo arm).
Other: Any grade ≥3 event 91% vs 95%; fatal AEs 4 vs 2 patients.
Conclusions
Inotuzumab ozogamicin produced markedly higher CR/CRi and MRD-negativity rates and improved PFS/OS versus standard chemotherapy in relapsed/refractory B-cell ALL; hepatic VOD, especially peri-HCT, requires monitoring.
Key Limitations
Open-label; heterogeneous comparator. OS benefit modest and of borderline significance. VOD risk (carrying a boxed warning) complicates subsequent allogeneic HCT, particularly with dual alkylator conditioning. Limited follow-up at primary report.
Clinical Context
Pivotal trial supporting FDA (2017) and EMA approval of inotuzumab ozogamicin for relapsed/refractory B-cell precursor ALL. ESMO guidance positions it as preferred salvage and bridge to allogeneic HCT; minimizing peri-transplant VOD risk (e.g., limiting cycles, avoiding dual alkylators) is emphasized.