A phase III trial evaluating the addition of gemtuzumab ozogamicin to intensive chemotherapy in patients with NPM1-mutated acute myeloid leukemia (AML) did not meet its primary endpoints.
Hartmut Döhner, MD, of Ulm University Hospital, and collaborators from the German–Austrian AML Study Group conducted the trial and published their findings in the Lancet Haematology.
The open-label trial evaluated intensive chemotherapy with or without the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin in adults with newly diagnosed, NPM1-mutated AML. The researchers conducted the trial at 56 hospitals in Germany and Austria.
They randomly assigned 588 patients to receive intensive chemotherapy alone (n=296) or with gemtuzumab ozogamicin (n=292).
All patients received two cycles of induction therapy with idarubicin, cytarabine, and etoposide plus all-trans retinoic acid followed by three consolidation cycles of high-dose cytarabine or an intermediate dose for those older than 60 years and all-trans retinoic acid. Patients randomized to receive gemtuzumab ozogamicin in addition to intensive chemotherapy received a dose of gemtuzumab ozogamicin 3 mg/m2 intravenously on day one of induction cycles one and two, and consolidation cycle one.
The primary endpoints were short-term event-free survival (EFS) and overall survival (OS) in the intention-to-treat population.
There was no difference in short-term EFS or OS between the treatment groups. The short-term EFS was 53% in the patients receiving intensive chemotherapy and was 58% in those receiving gemtuzumab ozogamicin in addition to intensive chemotherapy (hazard ratio [HR], 0.83; 95% CI, 0.65-1.04; P=.10). The two-year OS rate was 69% in patients receiving intensive chemotherapy and was 73% in those receiving gemtuzumab ozogamicin in addition to intensive chemotherapy (HR, 0.90; 95% CI, 0.70-1.16; P=.43).
The complete remission rate was 58% in the group receiving intensive chemotherapy and was 47% in the group receiving gemtuzumab ozogamicin in addition to intensive chemotherapy (odds ratio [OR], 0.63; 95% CI, 0.45-0.80; P=.0068).
However, the cumulative incidence of relapse was significantly reduced by gemtuzumab ozogamicin. The cumulative incidence of relapse was 37% in the group receiving intensive chemotherapy and was 25% in the group receiving gemtuzumab ozogamicin in addition to intensive chemotherapy (HR, 0.65; 0.49-0.86; P=.0028). There was no difference in the cumulative incidence in death between groups (P=.91).
The most common treatment-related adverse events of grade 3 and 4 were febrile neutropenia, occurring in 47% of patients receiving gemtuzumab ozogamicin in addition to intensive chemotherapy and 41% of patients receiving intensive chemotherapy alone and thrombocytopenia in 90% of patients from both treatment groups.
Treatment-related deaths occurred in 25 patients, including eight who were receiving intensive chemotherapy and 17 who were receiving gemtuzumab ozogamicin in addition to intensive chemotherapy. Most deaths were due to sepsis and infections, the researchers reported.
The primary endpoints of EFS and OS were not met, but the researchers concluded that the “antileukemic efficacy” of gemtuzumab ozogamicin in NPM1-mutated AML “is shown by a significantly lower cumulative incidence of relapse rate, suggesting that the addition of gemtuzumab ozogamicin might reduce the need for salvage therapy in these participants.”
Döhner H, Weber D, Krzykalla J, et al. Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09–09): a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2023;10(7):e495-e509. doi:10.1016/s2352-3026(23)00089-3