Sequential Addition of Gemtuzumab Ozogamicin to Standard Chemotherapy of No Benefit in Older Patients With Newly Diagnosed AML
In a phase III trial (EORTC [European Organisation for Research and Treatment of Cancer]/GIMEMA [Gruppo Italiano Malattie Ematologiche dell’Adulto] consortium AML-17 trial) reported in the Journal of Clinical Oncology, Sergio Amadori, MD, of Tor Vergata University Hospital in Rome, and colleagues evaluated the sequential addition of gemtuzumab ozogamicin (Mylotarg) to standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML). They found no survival benefit of gemtuzumab ozogamicin and excessive toxicity in patients aged ≥ 70 years.
Study Details
In the trial, 472 patients aged 61 to 75 years were randomly assigned to receive induction chemotherapy with mitoxantrone, cytarabine, and etoposide (MICE) with (n = 236) or without (n = 236) a prior course of gemtuzumab ozogamicin at 6 mg/m2 on days 1 and 15. Patients in remission received two consolidation courses with or without gemtuzumab ozogamicin at 3 mg/m2 on day 0. The primary endpoint was overall survival.
The gemtuzumab ozogamicin and control groups were generally balanced for age (median, 67 and 68 years; 35% and 36% 70–75 years), sex (61% and 53% male), Eastern Cooperative Oncology Group performance status (0 in 42% and 48%, 1 in 48% and 41%), white blood cell count at diagnosis (< 30×109/L in 73% in both), type of AML (de novo in 70% and 74%), cytogenetic risk group (intermediate in 35% and 38%, poor in 17% and 14%), CD33 expression (20%–80% in 48% in both, > 80% in 39% in both), and contributing study group (EORTC for 52% in both).
Overall Survival Outcome
The overall response rate was comparable in the gemtuzumab ozogamicin and control groups (45% vs 49%), but induction (17% vs 12%) and 60-day (22% vs 18%) mortality rates were higher in the gemtuzumab ozogamicin group. After median follow-up of 5.2 years, median overall survival was 7.1 vs 10 months (hazard ratio [HR] = 1.20, P = .07). The treatment effect remained the same on multivariate analysis adjusting for cytogenetics, age, contributing group, performance status, and baseline white blood cell count (HR = 1.19, P = .08).
Age and Disease Type
Overall survival was comparable in both groups among patients aged < 70 years, but was significantly worse in gemtuzumab ozogamicin patients aged ≥ 70 years due to the combined effect of increased induction mortality and poorer overall survival in those who did not achieve complete remission or complete platelet recovery (HR = 1.79, P = .009). Patients with de novo AML had significantly shorter overall survival with gemtuzumab ozogamicin, whereas a nonsignificant trend for longer overall survival was seen in those with secondary AML.
The magnitude of treatment effect according to type of disease was age dependent; overall survival was consistently shorter in the gemtuzumab ozogamicin group among patients aged ≥ 70 years regardless of type of disease, whereas a survival benefit was observed in the younger patients with secondary AML (HR = 0.57, P = .02).
There were no significant differences between groups in event-free survival or disease-free survival.
Toxicities
Grade 3 or 4 hematologic and liver toxicities were greater in the gemtuzumab ozogamicin group. There was little difference between groups in adverse events occurring after MICE, but a greater frequency (15%) of grade 3 or 4 liver toxicity was observed during gemtuzumab ozogamicin treatment, with two fatalities resulting from veno-occlusive disease. Treatment-related toxicities led to death during induction in 35 patients in the gemtuzumab ozogamicin group (19 after gemtuzumab ozogamicin, 16 after MICE) and 27 patients in the control group.
Infection was the primary cause of death resulting from toxicity, accounting for 66% and 85% of fatal events, respectively. The duration of neutropenia was significantly prolonged in the gemtuzumab ozogamicin group after the first consolidation course, but platelet recovery was significantly delayed after all courses of therapy.
The investigators concluded: “Treatment with [gemtuzumab ozogamicin] provided no benefit in any prognostic subgroup, with the possible exception of patients aged < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality…. As used in this trial, the sequential combination of [gemtuzumab ozogamicin] and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those aged ≥ 70 years.”
The study was supported by Wyeth (Pfizer) and the EORTC Charitable Trust.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
