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There was bad news and good news in a phase III trial evaluating intensive chemotherapy with or without gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia (AML) patients with newly diagnosed, NPM1-mutated disease.

For the primary endpoints of event-free survival (EFS) and overall survival (OS), the gemtuzumab ozogamicin-treated group experienced no benefit, but addition of the monoclonal antibody significantly cut the cumulative incidence of relapse compared with chemotherapy alone:

• EFS at 6 months: 58% vs 53%, respectively (HR 0.83, 95% CI 0.65-1.04, P=0.10)
• OS at 2 years: 73% vs 69% (HR 0.90, 95% CI 0.70-1.16, P=0.43)
• Cumulative relapse at 2 years: 25% vs 37% (HR 0.65, 95% CI 0.49-0.86, P=0.0028)

Despite the negative trial, the anti-leukemic efficacy of gemtuzumab ozogamicin, as evidenced by the lower relapse rate, suggests that addition of the drug to standard chemotherapy "might reduce the need for salvage therapy in these participants," according to Hartmut Döhner, MD, of Ulm University Hospital in Germany, and colleagues.

"The results from this study provide further evidence that gemtuzumab ozogamicin should be added in the standard of care treatment in adults with NPM1-mutated acute myeloid leukemia," the team wrote in .

Gemtuzumab ozogamicin -- an antibody-drug conjugate targeting CD33 -- currently holds an indication for treating CD33-positive AML, and the current study is the first randomized trial involving patients with mutated NPM1, a group with high CD33 expression, the study authors said.

Döhner's group observed that the EFS endpoint was not met primarily because of an increased early death rate in the gemtuzumab ozogamicin group among participants over 70 years of age, a population "for whom the chemotherapy backbone and the repetitive administration of gemtuzumab ozogamicin might have been too intensive." Specifically, 30-day mortality in this group was 20% in the gemtuzumab ozogamicin arm versus 8% in the control arm.

The researchers urged caution when administering the therapy to older patients with NPM1-mutated AML.

Age played a role in relapse rates as well. Döhner and colleagues noted that the significant effect of gemtuzumab ozogamicin on relapse was driven by the benefit in patients ages 60 and under, with rates of 18% at 2 years in the combination group and 35% in the standard chemotherapy group (P=0.0015), with no significant effect observed in patients over 60.

At 5 years, the cumulative incidence of relapse in the overall population was 32% versus 45%, respectively.

In an , Richard Dillon, MA, PhD, and Jad Othman, MBBS, both of King's College London, agreed that the reduction in relapse and subsequent avoidance of salvage and allogeneic transplantation, "would likely be considered a meaningful benefit by patients."

"Although the dosing schedule and chemotherapy backbone require careful thought, gemtuzumab ozogamicin has clear activity in NPM1-mutated acute myeloid leukemia," they wrote. "The challenge ahead is to integrate it with the increasingly crowded therapeutic landscape for this disease subtype."

The open-label phase III trial () was conducted at 56 hospitals in Germany and Austria and included 588 adults with newly diagnosed NPM1-mutated AML and an ECOG performance status of 0-2. Participants were randomly assigned in a 1:1 ratio to chemotherapy with or without gemtuzumab ozogamicin, with age as a stratification factor (18-60 vs >60 years). Median patient age was 59 years, 54% were women, and 98% were white.

Participants received two cycles of induction therapy (idarubicin, cytarabine, and etoposide) plus all-trans retinoic acid (ATRA) followed by three consolidation cycles of ATRA and high-dose cytarabine (or an intermediate dose for those over 60). Gemtuzumab ozogamicin (3 mg/m²) was given intravenously on day 1 of the first two induction cycles, and with the first consolidation cycle.

The most common treatment-related grade 3/4 adverse events in the study were febrile neutropenia (47% in the gemtuzumab ozogamicin group vs 41% in the standard group), thrombocytopenia (90% in both groups), pneumonia (25% vs 22%), and sepsis (29% vs 25%). Treatment-related deaths were documented in 6% and 3% of the two groups, respectively, with most due to sepsis or infections.

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