Using an investigational oral form of azacitidine therapy, CC-486, significantly improved overall survival in older patients with newly diagnosed acute myeloid leukaemia (AML) who were in remission following standard induction chemotherapy with or without consolidation therapy, according to a phase III study presented today during the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando.

The drug was found to be safe and researchers say the results are the first to validate the role of maintenance therapy in AML.

“The AML community has been trying to validate the role of maintenance therapies to extend initial treatment responses for many decades and – until now – without success,” said lead study author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital, Melbourne, Australia. “While several agents have been studied and shown to increase relapse-free duration, demonstration of a survival benefit has been elusive. CC-486 is the first therapy to provide statistically significant and clinically meaningful improvement in both overall survival and relapse-free survival in patients with AML in remission following induction chemotherapy, with or without consolidation.”

Based on these findings, Dr Wei said it is reasonable to expect that this therapy will become an integral part of treatment for older people with AML in remission and may help them to defer the need for further AML therapy.

Currently, in the post-remission period after induction and consolidation, management is either observation or stem cell transplant, the latter of which is complex and not viable for everyone.

CC-486 has multiple potential mechanisms of action, including remodelling the epigenetic program in leukaemic blasts.

The oral route of administration, which allows for extended duration dosing (14 days each cycle) over a prolonged period of time (approximately 30% of patients are still on therapy after two years), may be an important factor in explaining the drug’s effectiveness, said Dr. Wei. 

A total of 472 patients with AML, ranging from 55-86 years of age, with either intermediate- or poor-risk cytogenetics were enrolled in the QUAZAR AML-001 trial between May 2013 and October 2017 across 148 centres in 23 countries.

To be included, they had to 1) achieve a complete response or complete response with incomplete count recovery after induction chemotherapy, with or without consolidation, and 2) not be candidates for haematopoietic stem-cell transplant.

Within four months of attaining any complete response, patients were randomised to receive either 300 mg of CC-486 or placebo once daily for 14 days of a 28-day cycle plus best supportive care until disease relapse.

Researchers tracked overall survival, the study’s primary endpoint, as well as relapse-free survival, safety and tolerability, and health-related quality of life.

After a median follow-up of 41.2 months, there was a 31% lower risk of death among patients receiving CC-486 compared with those on placebo; median overall survival was 24.7 months vs. 14.8 months.

The risk of relapse was also significantly lower in those who received the medication (10.2 months in the CC-486 arm vs. 4.8 months for placebo).

Minimal residual disease was also eradicated more frequently in patients receiving the drug.

A striking finding, according to Dr. Wei, was that treatment benefits remained consistent across broad subgroups of patients, including the number of prior [chemotherapy] cycles received, the presence of any measurable residual disease, poor cytogenetic risk, or patients ≥ 65 years.

Self-reported quality of life did not change across treatment groups.

There were significantly more gastrointestinal events among patients receiving the treatment drug, including nausea, vomiting, and diarrhoea, but most of these events occurred in the first two cycles and patients remained on therapy with supportive care.

The most common grade 3-4 adverse events were neutropenia, thrombocytopenia (low blood platelet count), and anaemia; serious adverse events were infrequent, consisting mainly of infections, which occurred in 17% of patients in the CC-486 arm and 8% of patients in the control arm.

Despite these side effects, patients in the treatment group underwent more cycles of treatment than those on placebo (median exposure of 12 vs. six cycles).

Additionally, those who were on placebo were more likely to receive post-trial treatments, including chemotherapy and stem cell transplantation.

“The QUAZAR shows that, rather than observing patients and waiting for them to relapse, we can now actively engage in trying to reduce relapse risk and improve survival in the post-remission phase.”

AML accounts for one out of every three adult leukaemia cases.

Although it can occur in children, it most often strikes older people, who average 68 years of age, when first diagnosed. Fewer than 30% of patients with AML survive five years.

Source: American Society of Hematology

Watch the press conference here.

Watch our interview with Prof Wei here.