Acute myeloid leukaemia (AML) harbouring NPM1 mutations is associated with high CD33 expression and intermediate-risk cytogenetics. The study at hand compared the efficacy of intensive chemotherapy alone or in combination with the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin, to treat individuals with newly diagnosed NPM1-mutated AML. The results of this trial, recently published in The Lancet Haematogy, show that the addition of gemtuzumab ozogamicin to chemotherapy significantly reduces the cumulative incidence of relapse, suggesting it might reduce the need for salvage therapy in these patients.
Mutations in the nucleophosmin-1 (NPM1) gene are found in approximately 20%-33% of adults diagnosed with acute myeloid leukaemia (AML). AML patients harbouring this mutation often exhibit high CD33 expression and have intermediate-risk cytogenetics. Gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, is approved by the FDA and EMA to treat newly diagnosed CD33-positive AML patients in combination with induction and consolidation therapy. This study compared the efficacy of intensive chemotherapy alone or in combination with gemtuzumab ozogamicin, to treat individuals with newly diagnosed NPM1-mutated AML.
This open-label, phase 3 trial was conducted at 56 hospitals in Germany and Austria. Eligible participants were ≥18 years and had newly diagnosed NPM1-mutated AML. In total, 588 participants were randomly assigned (1:1) to receive two cycles of induction therapy (idarubicin, cytarabine, and etoposide) plus all-trans retinoic acid (ATRA) followed by three consolidation cycles of high-dose cytarabine (or an intermediate dose for those older than 60 years) and ATRA, without (n=296) or with gemtuzumab ozogamicin (n=292).The primary endpoints were short-term event-free survival (EFS) and overall survival (OS). The secondary endpoints were EFS with long-term follow-up, rates of complete remission, complete remission with partial haematological recovery (CRh), and complete remission with incomplete haematological recovery (CRi), cumulative incidences of relapse and death, and number of days in hospital.
The study results, after a 6-month follow-up period, did not reveal any significant differences in short-term EFS between the standard treatment and gemtuzumab ozogamicin (53% vs. 58%, respectively; HR[95%CI]: 0.83[0.65-1.04]; p=0.10). In addition, there were no significant disparities in the 2-year OS rates between the treatment groups (69% vs. 73%; HR[95%CI: 0.90[0.70-1.16; p=0.43).
Regarding secondary endpoints, no significant differences were observed in the CRi (90% vs. 86% in the standard and gemtuzumab ozogamicin groups, respectively; OR[95%CI]: 0.67[0.40-1.11; p=0.15) and CRh rates (72% vs. 67%; OR[95%CI]: 0.77[0.54-1.10]; p=0.18) between the groups. In contrast, the complete remission rate was lower in the gemtuzumab ozogamicin group (58% vs. 47% in the standard and gemtuzumab ozogamicin groups, respectively; OR[95%CI]: 0.63[0.45-0.80; p=0.0068). At 2 years, the cumulative incidence of relapse was significantly reduced by gemtuzumab ozogamicin (37% vs. 25% in the standard and gemtuzumab ozogamicin groups, respectively; HR[95%CI]: 0.65[0.49-0.86]; p=0.0028), and there was no difference in the cumulative incidence of death (6% vs. 7%; HR[95%CI]: 1.03[0.59-1.81]; p=0.91). There were no differences in the number of days in hospital across all cycles between treatment groups. The most common treatment-related grade 3-4 adverse events were febrile neutropenia (41% vs. 47% in the standard and gemtuzumab ozogamicin groups, respectively), thrombocytopenia (90% each), pneumonia (22 vs. 25%) and sepsis (25% vs. 29%). Treatment-related deaths were documented in 4% vs. 6% of patients in the standard and gemtuzumab ozogamicin groups, respectively, mostly due to sepsis and infections.
Although the study did not meet its primary endpoints of short-term EFS and OS, the findings showed an anti-leukaemic effect of gemtuzumab ozogamicin in individuals with NPM1-mutated AML. The significantly lower cumulative incidence of relapse suggests that adding gemtuzumab ozogamicin may reduce the need for salvage therapy in these patients. These results provide further support for the incorporation of gemtuzumab ozogamicin into the standard treatment of adults with NPM1-mutated AML.
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;S2352-3026(23)00089-3.