Approximately 15 percent of acute myeloid leukaemia (AML) patients harbour a mutation of the IDH2 gene, a genetic abnormality that leads to increased production of an oncometabolite known as 2-hydroxyglutarate (2-HG) that prevents immature white blood cells from developing into healthy adult infection-fighting white cells.

This allows immature leukaemic white cells to accumulate and crowd out normal red cells (causing anaemia) and platelets, leading to the development of AML.

By inhibiting this mutated IDH2 enzyme, AG-221 has shown efficacy in treating IDH-2 positive AML and myelodysplastic syndromes.

In an ongoing Phase I study to evaluate the safety and maximum tolerated dose of the IDH2 inhibitor AG-221, 45 patients with IDH2 mutant AML or pre-leukaemia (including myelodysplastic syndromes, chronic myelomonocytic leukaemia, and myeloproliferative neoplasms) received the agent once or twice daily at escalating doses up to 150 mg and 200 mg, respectively and were evaluable for efficacy; as of the most recent safety and efficacy analysis of trial data the maximum tolerated dose had not yet been reached.

Responses were observed in 25 patients (56%), including complete remissions in 15, and partial remission in 10 additional patients.

Further, responses have been durable, as participants have experienced complete remissions lasting as long as eight cycles of treatment to date, and many patients continue to be treated with AG-221.

Overall, this agent has been better tolerated than conventional chemotherapy for relapsed leukaemia.

“These early results in this hard-to-treat population demonstrate that when we inhibit mutant IDH2, we can transform leukaemia cells into healthy, normal adult white blood cells and eradicate disease without the use of traditional chemotherapy,” said lead study author Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Centre in New York.

"These data provide continued validation of mutant IDH2 as a therapeutic target in AML and MDS".

“This approach to treat leukaemia is revolutionary and represents the future of treatment for hematologic diseases. Our goal is to treat patients with therapy that is targeted to the specific genotype of their disease, thereby increasing efficacy, extending patients’ life spans, and minimising toxicity.”

Watch the press conference and the interview for more.

Source: ASH