Gemtuzumab Ozogamicin Plus Intensive Chemotherapy Reduces Cumulative Incidence of Relapse Among Patients With NPM1-Mutated AML

Results from an Open-Label Phase 3 Trial

The addition of anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin to intensive chemotherapy demonstrated anti-leukemic efficacy by reducing the cumulative incidence of relapse among patients with newly diagnosed nucleophosmin (NPM1)-mutated acute myeloid leukemia (AML), according to findings from a phase 3 trial. 

“Acute myeloid [leukemia] with mutated NPM1 is associated with high CD33 expression and intermediate-risk cytogenetics,” Hartmut Döhner, MD, Ulm University Hospital, Ulm, Germany, and coauthors stated. This study aimed to investigate the efficacy of intensive chemotherapy with or without gemtuzumab ozogamicin among patients with newly diagnosed NPM1-mutated AML, to evaluate its potential as an addition to standard-of-case treatment. 

The primary end points were short-term event-free survival and overall survival in the intention-to-treat population. Secondary end points included long-term event-free survival, rates of complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete hematologic recovery (CRi), cumulative incidences of relapse and death, and the number of days spent in the hospital. 

This phase 3 trial consisted of 588 patients with newly diagnosed NPM1-mutated AML and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients were randomized 1:1 into the standard group (n = 296) or the gemtuzumab ozogamicin group (n = 292). The standard group received 2 cycles of induction therapy consisting of idarubicin, cytarabine, and etoposide, plus all-trans retinoic acid (ATRA), followed by 3 consolidation cycles of high-dose cytarabine and ATRA. The gemtuzumab ozogamicin group received the same treatment as the standard group, with the addition of 3 mg/m2 gemtuzumab ozogamicin on day 1 of induction cycles 1 and 2 and consolidation cycle 1. 

There was no statistically significant difference in short-term event-free survival at the 6-month follow-up between the standard group (53% [95% confidence interval [CI], 47 to 59) and the gemtuzumab ozogamicin group (58%, 53 to 64) (hazard ratio [HR] 0.83; 95% CI, 0.65 to 1.04, p = 0.10). Likewise, there was also no statistically significant difference in overall survival at 2 years between the standard group (69%) and the gemtuzumab ozogamicin group (73%). The primary end points of the trial—event-free survival and overall survival—were not met.

The trial did not demonstrate significant differences in CR or CRi rates between the standard versus gemtuzumab ozogamicin groups (90% versus 86%) or complete remission or CRh rates (72% versus 67%). However, the complete remission rate was lower with gemtuzumab ozogamicin versus standard treatment (58% versus 47%). Notably, gemtuzumab ozogamicin was associated with a reduced cumulative incidence of relapse at 2 years (37%) compared to standard treatment (25%), with no observable effect on the cumulative incidence of death (7% in the standard group versus 6% in the gemtuzumab ozogamicin group.) The number of days in the hospital did not differ across groups. 

In terms of safety, the most common grade 3 to 4 treatment-related adverse events included febrile neutropenia, thrombocytopenia, pneumonia, and sepsis. Treatment-related deaths occurred in 25 patients, and were mainly attributed to sepsis and infections.

Dr Döhner et al concluded, “an anti-[leukemic] efficacy of gemtuzumab ozogamicin in participants with NPM1-mutated acute myeloid [leukemia] 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.” 

“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],” they added. 

Source: 

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. The Lancet Haematol. Published online May 12, 2023. doi: 10.1016/S2352-3026(23)00089-3