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.

— Hagop M. Kantarjian, MD, and colleagues

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In a phase III trial reported in The New England Journal of Medicine, Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center, and colleagues found that treatment with the antibody-drug conjugate inotuzumab ozogamicin resulted in a greater complete remission rate and improved overall survival vs standard therapy in patients with relapsed/refractory acute lymphoblastic leukemia (ALL).¹ The conjugate consists of an anti-CD22 monoclonal antibody linked to the cytotoxic antibiotic calicheamicin. CD22 is expressed in more than 90% of patients with B-cell ALL.

Study Details

In the open-label trial, a total of 326 adult patients with relapsed/refractory ALL from 18 countries were randomized beginning in August 2012 to receive inotuzumab ozogamicin (n = 164) or standard intensive therapy (n = 162). The first 218 patients randomized (109 in each group) were included in the primary intention-to-treat analysis of complete remission. A total of 259 patients (139 in the inotuzumab ozogamicin group and 120 in the standard-therapy group) who received at least one dose of study treatment were included in the safety population. Survival was analyzed in the entire population of 326 patients.

Inotuzumab ozogamicin was given intravenously (IV) at a starting dose of 1.8 mg/m² per cycle, with 0.8 mg on day 1 of each cycle and 0.5 mg on days 8 and 15; cycle 1 was 21 days, and subsequent cycles were 28 days, with treatment continued for up to 6 cycles. In patients who achieved complete remission or complete remission with incomplete hematologic recovery, the day 1 dose for each cycle was reduced to 0.5 mg.

Standard therapy consisted of investigator’s choice of FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) for up to four 28-day cycles; cytarabine plus mitoxantrone for up to four 15- to 20-day cycles; or high-dose cytarabine for up to one 12-dose cycle. The primary endpoints were complete remission (including complete remission with incomplete hematologic recovery) and overall survival.

Complete Remission and Survival

Among the 109 inotuzumab ozogamicin patients and 109 standard-therapy patients in the complete remission analysis, rates of complete remission or complete remission with incomplete hematologic recovery were 80.7% (95% confidence interval [CI] = 72.1%–88.7%) vs 29.4% (95% CI = 21.0%–38.8%; P < .001), with complete remission in 35.8% vs 17.4% (P = .002). Among patients with complete remission or complete remission with incomplete hematologic recovery, a higher percentage in the inotuzumab ozogamicin group had results below the 0.01% marrow blasts threshold for minimal residual disease (78.4% vs 28.1%, P < .001). Median duration of remission was 4.6 months (95% CI = 3.9–5.4 months) vs 3.1 months (95% CI = 1.4–4.9 months; hazard ratio [HR] = 0.55, P = .03).

Subgroup analysis showed a significant benefit of inotuzumab ozogamicin for nearly all factors examined, including according to peripheral blast count, bone marrow blast percentage, CD22 expression level, and previous stem cell transplantation. Improvements were not significant according to baseline Philadelphia (Ph)-positive or t(4;11)-positive status.

Median progression-free survival was 5.0 months (95% CI = 3.7–5.6 months) vs 1.8 months (95% CI = 1.5–2.2 months; HR = 0.45, P < .001). Median overall survival was 7.7 months (95% CI = 6.0–9.2 months) vs 6.7 months (95% CI = 4.9–8.3 months; HR = 0.77, P = .04).

Adverse Events

In the safety population, the most frequent grade ≥ 3 nonhematologic adverse events in the inotuzumab ozogamicin group were liver-related events, including increased aspartate transaminase (5%), hyperbilirubinemia (4%), and increased alanine transaminase (3%). Veno-occlusive liver disease of any grade occurred in 11% (9% grade ≥ 3) of the inotuzumab ozogamicin group vs 1% of the standard-therapy group. Grade ≥ 3 hematologic adverse events were more common in the standard-therapy group, including thrombocytopenia (37% vs 59%), platelet transfusion (64% vs 95%), and febrile neutropenia (24% vs 49%). Serious adverse events occurred in 48% vs 46% of patients, with the most common in the inotuzumab ozogamicin group being febrile neutropenia (12%) and veno-occlusive disease (11%).

The investigators concluded: “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.” ■

Disclosure: The study was funded by Pfizer. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Kantarjian HM, DeAngelo DJ, Stelljes M, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. June 12, 2016 (early release online).