Prof Hartmut Döhner

Targeted therapies for genetically-defined leukaemias were a major theme amongst the top abstracts at the 63rd ASH Annual Meeting and Exposition.

Professor Hartmut Döhner presented results from the AGILE study which found ivosidenib and azacitidine significantly improved outcomes compared to azacitidine and placebo in patients with newly diagnosed AML and an isocitrate dehydrogenase 1 (IDH1) mutation.

Professor Döhner , from Ulm University Hospital in Germany, said ivosidenib was a first-in-class, potent, oral targeted inhibitor of the mutant IDH1 enzyme. A recently published phase 1b trial had shown the combination treatment had a favourable safety profile and encouraging clinical activity.

The phase 3 AGILE study, which randomised 148 patients from sites in 20 countries including Australia, found ivosiderin plus azacitidine significantly improved event-free survival (EFS) (HR 0.33; p =0.0011).

The EFS benefit was consistent across major sub-groups based on factors such as de novo status, age, sex, baseline ECOG score, cytogenetic risk status, and % bone marrow blasts.

Professor Döhner said overall survival was also significantly improved with the combination treatment (24 v 7.9 months; HR 0.44; p = 0.0005) and again, the benefit was consistent across clinical and disease subgroups.

Ivosidenib plus azacitidine also significantly improved clinical and haematologic responses.

For example, the CR rates were 47.2% versus 14.9% (OR 4.8; p <0.0001) and ORR rates were 62.5% versus 18.9%, with IVO+ AZA compared to azacitidine and placebo, respectively.

“Among patients with bone marrow samples available, the mutant IDH1 clearance rate as assessed by digital PCR in those patients achieving CR was 48.3% with IVO+AZA and 20% with placebo plus azacitidine,” Professor Döhner said.

Health-related quality of life results favoured ivosidenib plus azacitidine across all subscales.

Treatment-emergent adverse events of special interest included grade ≥2 differentiation syndrome (14.1% v 8.2%) and grade ≥3 QT prolongation (9.9% v 4.1%). Fewer infections were reported in the ivosidenib group than the placebo group.

“These data demonstrate the clinical benefit of IVO + AZA in this difficult to treat mIDH1 AML population,” he concluded.

Ivosidenib is currently FDA approved as monotherapy for patients with relapsed or refractory AML or for newly diagnosed AML in patients from 75 years of age or with comorbidities precluding the use of intensive induction chemotherapy.

The study was funded by Agios Pharmaceuticals.