EHA 2016

SGN-CD33A combined with HMA therapy produces high remission rates among older patients with AML

Dr Amir Fathi, Massachusetts General Hospital, Boston, USA

We will be presenting some data from an ongoing phase I trial evaluating SGN-CD33A, also known as vadastuximab talirine, in combination with hypomethylating agents among older patients with acute myeloid leukaemia. Acute myeloid leukaemia, also known as AML, is a lethal disease of the bone marrow and blood. It is particularly difficult to treat with generally poor outcomes for the majority of patients. This is particularly so for older patients in whom traditional cytotoxic chemotherapy, which is conventional, is harder to administer because of compromised functional status and comorbidities. In recent years there has been an emergence, however, of hypomethylating agents, azacitidine and decitabine, as options for more gentle forms of treatment that can be administered on the outpatient side in the clinic and which can provide some transient responses although rates of remission with these modalities of treatments ranges between 18-28%.

The majority of leukemic cells in AML express a protein on their surface called CD33. Vadastuximab talirine, which from this point on I’ll be referring to as 33A, is a highly potent antibody-drug conjugate designed to deliver a cytotoxic agent directly to the myeloid leukaemia cells by engaging CD33 at the surface of the cells. In preclinical studies the cell-killing activity of hypomethylating agents and 33A is enhanced when these two modalities are provided in combination.

To date 53 AML patients with a median age of 75 have been treated on this study with this combination. The key eligibility criteria are provided here, generally speaking these are older patients who have declined intensive chemotherapy or have not been candidates for intensive chemotherapy and who have CD33 expressing AML. Again, the majority of patients have CD33 expressing AML. Upon screening and enrolment patients can receive up to four cycles of treatment with the combination, receiving the hypomethylating agent first for a defined course, as per the specific HMA agent, followed on the last day by administration of the 33A compound. If the patients have achieved a response or are deriving benefit clinically during the four week cycle they can continue to receive treatment thereafter with follow up and assessment every three months.

During the course of this study we determined that the combination of 33A and HMA was well tolerated. The most common adverse events were related to on-target effects of the drug which manifested as low blood counts or cytopenias; these also included febrile neutropenias. There were few off-target non-hematologic side effects. The early mortality rate was low: 2% 30 day mortality and 8% 60 day mortality.

Quite intriguing was the high response rate seen with the combination. 33A plus HMA therapy led to a remission rate, a composite remission rate, of 71%, the majority of which were complete remissions at 41%. The median time to remission was two cycles.

In conclusion, 33A and HMA provide a favourable balance of safety, tolerability and activity among older patients with AML. This higher remission rate in this traditionally high risk group and difficult to treat population is very compelling. Response rates were higher and achieved more quickly than would be expected from historical data associated with HMA therapy alone. Overall survival data will be presented this afternoon. These are promising and continue to evolve. A phase III trial, randomised placebo controlled, of 33A plus HMA versus HMA plus placebo in older AML patients is currently enrolling. Thank you very much for your attention.