Gemtuzumab Ozogamicin Misses Early EFS Endpoint, as Phase III Study Continues in NPM1+ AML

Gemtuzumab ozogamicin (Mylotarg) in combination with intensive induction therapy was associated with a higher early death rate compared with induction therapy alone in patients with NPM1-mutated acute myeloid leukemia (AML), according to results of the phase III AMLSG 09-09 trial.

However, patients who achieved complete remission (CR) or incomplete hematologic recovery (CRi) after induction therapy experienced fewer relapses in the gemtuzumab ozogamicin arm compared with the standard-of-care arm, which comprised idarubicin, cytarabine, etoposide, and all-trans-retinoic acid (ATRA).

Event-free survival (EFS) in the gemtuzumab ozogamicin arm was not significantly different compared with the standard arm (HR, 0.83; 95% CI, 0.65-1.04; P = .10). The early death rate during induction therapy was 10.3% in the gemtuzumab ozogamicin arm and 5.7% in the standard arm (P = .05). The causes of death in both arms were mainly due to infections.

“On the basis of a meta-analysis, [gemtuzumab ozogamicin] dosages >3 mg/m² per application were associated with a higher early mortality rate,” the authors noted in the trial. “Although we adhered to the 3 mg/m² dosage without capping the dose at 5 mg, we observed a mortality rate of up to 20% in patients older than 70 years. In addition, we combined [gemtuzumab ozogamicin] with the intensive [induction] regimen, which may have contributed further to an unfavorable safety evaluation.”

A total 588 patients with newly diagnosed NPM1-mutated AML were randomly assigned 1:1 to receive either gemtuzumab ozogamicin (n = 292) or the standard arm (n = 296).

Patients were randomized to receive induction chemotherapy with or without gemtuzumab ozogamicin at 3 mg/m² intravenously on day 1. Induction therapy consisted of 2 cycles of idarubicin (12 mg/m² IV on days 1, 3, and 5). For patients >60 years of age the second induction cycle was reduced on days 1 and 3. Induction therapy also consisted of 2 cycles of cytarabine at 100 mg/m² continuously IV on days 1 to 7, and etoposide 100 mg/m² IV on days 1 to 3, which was also reduced for patients >60 years of age on days 1 and 3, plus ATRA at 45 mg/m² orally on days 6 to 8 and 15 mg/m² on days 9 to 21. Etoposide was reduced between 3 to 2 days for all patients in cycle 2 as a result of prolonged hematologic recovery in both arms.

The median age was 58.7 years, and 46.4% of patients were male. The median bone marrow blasts was 73.% and the median peripheral blood blasts was in 26% of patients. The primary endpoint was EFS, and exploratory endpoints were cumulative incidence of relapse, cumulative incidence of death, and toxicity.

The first induction therapy was started in 295 and 290 patients in the standard arm and gemtuzumab ozogamicin arm, respectively. After the first induction therapy, 93.2% and 88.0% of patients responded, respectively, including those who experienced CR, CRi, and partial remission. Overall response to induction therapy in the standard and gemtuzumab ozogamicin arms saw CR/CRi in 88.5% and 85.3%, refractory disease in 5.4% and 4.1%, and death during induction therapy in 5.7% and 10.3% of patients, respectively.

There was no difference between the arms in CR/CRi rate (P = .27), but a higher death rate was observed in the gemtuzumab ozogamicin arm (P = .05). Moreover, more patients >70 years of age died during induction therapy in the gemtuzumab ozogamicin arm (20.4%) compared with the standard arm (4%).

Results also showed that, at a median follow-up time of approximately 40.0 months (95% CI, 35.5-47.0), the median EFS and 2-year EFS rates were 39.4 months (95% CI, 27.1-59.2 months) and 55.3% (95% CI, 51.3%-59.7%), respectively. Moreover, 523 patients achieved CR/CRi and of these patients, 178 relapsed and 48 had died.

Univariable survival analyses showed that the 2-year EFS rates were 52.6% (95% CI, 47.0%-58.9%) in the standard arm and 58.1% (95% CI, 52.5%-64.4%) in the gemtuzumab ozogamicin arm.

Patients with an FLT3-ITD mutation did not show an EFS benefit with the addition of gemtuzumab ozogamicin (HR, 1.53; 95% CI, 0.95-2.48) compared with patients who had FLT3-ITD wild-type disease (HR, 0.72; 95% CI, 0.56-0.95).

However, results showed that female patients had a significant improvement in EFS (HR, 0.67; 95% CI, 0.49-0.92) with the addition of gemtuzumab ozogamicin compared with males (HR, 1.08; 95% CI, 0.77-1.51). In addition, patients >70 years old did not have an EFS benefit from the addition of gemtuzumab ozogamicin (HR, 1.22; 95% CI, 0.76-1.95).

The most common grade ≥3 adverse events in the standard and gemtuzumab ozogamicin arms were blood/bone marrow (83.5% vs 82%, respectively), gastrointestinal issues (30% vs 36%), and infection (59% vs 64%).

“In summary, our study failed to show a significant benefit in EFS by the addition of [gemtuzumab ozogamicin] to intensive therapy in patients with NPM1-mutated AML,” the authors concluded. “There was a significant reduction in CIR with gemtuzumab ozogamicin, providing evidence for antileukemic activity of the antibody-drug conjugate.”

In 2017, gemtuzumab ozogamicin was approved by the FDA for patients with newly diagnosed relapsed/refractory CD33-positive AML.

Schlenk RF, Paschka P, Krzykalla J, et al. Gemtuzumab ozogamicin in NPM1-mutated acute myeloid leukemia: early results from the prospective randomized AMLSG 09-09 phase III study. J Clin Oncol. 2019;38(6):623-639. doi: 10.1200/JCO.19.01406.