Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia

Abstract

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.).

Figure 1. Remission (CR/CRi) by Randomization Stratification Factors (A) and Baseline Patient Characteristics (B)

CR=complete remission; CRi=complete remission with incomplete hematologic recovery; DFR=duration of first remission; InO=inotuzumab ozogamicin; SC=standard of care. Analysis of CR/CRi was based on an ITT218 population (InO, n=109; SC, n=109). P values are 2-sided and based on chi-square or Fisher’s exact tests (if any cell count is <5). *Data missing for 1 patient in each InO and SC arm; ^†Data missing for 2 patients in each InO and SC arm ^‡By central laboratory analysis (data missing for 11 and 22 patients receiving InO and SC, respectively); ^§By local laboratory analysis; ^¶The assessment of CR/CRi in patients with normal karyotype required a minimum of 20 analyzed chromosomes; ^||By central/local laboratory analysis or medical history.

Figure 1. Remission (CR/CRi) by Randomization Stratification Factors (A) and Baseline Patient Characteristics (B)

CR=complete remission; CRi=complete remission with incomplete hematologic recovery; DFR=duration of first remission; InO=inotuzumab ozogamicin; SC=standard of care. Analysis of CR/CRi was based on an ITT218 population (InO, n=109; SC, n=109). P values are 2-sided and based on chi-square or Fisher’s exact tests (if any cell count is <5). *Data missing for 1 patient in each InO and SC arm; ^†Data missing for 2 patients in each InO and SC arm ^‡By central laboratory analysis (data missing for 11 and 22 patients receiving InO and SC, respectively); ^§By local laboratory analysis; ^¶The assessment of CR/CRi in patients with normal karyotype required a minimum of 20 analyzed chromosomes; ^||By central/local laboratory analysis or medical history.

Figure 2. Duration of Remission Among Patients with CR/CRi (A), Progression-Free Survival (B), and Overall Survival (C)

Medians were estimated using the Kaplan-Meier method, P values are from stratified log-rank test, and hazard ratio (HR) and corresponding CI were estimated using stratified Cox proportional hazard regression. OS and PFS data represent all 326 patients included in the ITT population (InO, n=164; SC, n=162), and duration of remission is based on the patients with best response of CR/CRi (investigator assessed). Note: because no disease assessments were evaluated by the endpoint adjudication committee after the end of treatment, analysis of DoR was based on the investigator’s assessments. CR=complete remission; CRi=complete remission with incomplete hematologic recovery; InO= inotuzumab ozogamicin; DoR=duration of remission; PFS=progression-free survival; OS=overall survival; SC=standard of care. Data represent the ITT218 population (InO, n=109; SC, n=109).

Figure 2. Duration of Remission Among Patients with CR/CRi (A), Progression-Free Survival (B), and Overall Survival (C)

Medians were estimated using the Kaplan-Meier method, P values are from stratified log-rank test, and hazard ratio (HR) and corresponding CI were estimated using stratified Cox proportional hazard regression. OS and PFS data represent all 326 patients included in the ITT population (InO, n=164; SC, n=162), and duration of remission is based on the patients with best response of CR/CRi (investigator assessed). Note: because no disease assessments were evaluated by the endpoint adjudication committee after the end of treatment, analysis of DoR was based on the investigator’s assessments. CR=complete remission; CRi=complete remission with incomplete hematologic recovery; InO= inotuzumab ozogamicin; DoR=duration of remission; PFS=progression-free survival; OS=overall survival; SC=standard of care. Data represent the ITT218 population (InO, n=109; SC, n=109).