Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia

BACKGROUND: The prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy. METHODS: In this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival. RESULTS: Of the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80. 7% 95% confidence interval CI, 72. 1 to 87. 7 vs. 29. 4% 95% CI, 21. 0 to 38. 8, P<0. 001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0. 01% marrow blasts) (78. 4% vs. 28. 1%, P<0. 001) ; the duration of remission was longer in the inotuzumab ozogamicin group (median, 4. 6 months 95% CI, 3. 9 to 5. 4 vs. 3. 1 months 95% CI, 1. 4 to 4. 9; hazard ratio, 0. 55 95% CI, 0. 31 to 0. 96; P=0. 03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5. 0 months 95% CI, 3. 7 to 5. 6 vs. 1. 8 months 95% CI, 1. 5 to 2. 2; hazard ratio, 0. 45 97. 5% CI, 0. 34 to 0. 61; P<0. 001) ; the median overall survival was 7. 7 months (95% CI, 6. 0 to 9. 2) versus 6. 7 months (95% CI, 4. 9 to 8. 3), and the hazard ratio was 0. 77 (97. 5% CI, 0. 58 to 1. 03) (P=0. 04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy. CONCLUSIONS: The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. (Funded by Pfizer; INO-VATE ALL ClinicalTrials. gov number, NCT01564784. ).