Summary
An investigational oral form of azacitidine therapy significantly improved overall survival (OS) in older patients with newly diagnosed acute myeloid leukemia (AML) who were in remission following standard induction chemotherapy, with or without consolidation therapy, according to results of a new study (Abstract LBA-3).
Standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60-80 percent of patients aged 60 years and under and in 40-60 percent of patients aged more than 60 years. The majority of patients who attain CR with induction chemotherapy will eventually relapse, and relapse is the primary obstacle to long-term survival. The goals of AML maintenance therapy are to decrease the likelihood of disease relapse and prolong OS, without causing undue toxicity or compromising health-related quality of life (HRQoL), said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital, Melbourne, Australia, at a press briefing at the 2019 ASH Annual Meeting.
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Original Article
Maintenance Therapy Markedly Improves Overall Survival in AML Patients in Remission
Oncology Times
By Mark L. Fuerst
An investigational oral form of azacitidine therapy significantly improved overall survival (OS) in older patients with newly diagnosed acute myeloid leukemia (AML) who were in remission following standard induction chemotherapy, with or without consolidation therapy, according to results of a new study (Abstract LBA-3).
Standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60-80 percent of patients aged 60 years and under and in 40-60 percent of patients aged more than 60 years. The majority of patients who attain CR with induction chemotherapy will eventually relapse, and relapse is the primary obstacle to long-term survival. The goals of AML maintenance therapy are to decrease the likelihood of disease relapse and prolong OS, without causing undue toxicity or compromising health-related quality of life (HRQoL), said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital, Melbourne, Australia, at a press briefing at the 2019 ASH Annual Meeting.
“To date, no AML maintenance therapy has shown clear improvements in OS. CC-486 is an oral hypomethylating agent with demonstrated clinical activity in patients with hematologic malignancies. Oral dosing of CC-486 allows for extended drug exposure during each treatment cycle to prolong therapeutic activity. We hypothesized that prolonged treatment with CC-486 could be effective as post-remission maintenance in AML,” said Wei.
He added: “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. 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 (RFS) in patients with AML in remission following induction chemotherapy, with or without consolidation.”
Based on these findings, 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. Not all patients are eligible for transplant.
CC-486 has multiple potential mechanisms of action, including remodeling the epigenetic program in leukemic blasts. The oral route of administration, which allows for extended duration dosing (14 days each cycle) over a prolonged period of time may be an important factor in explaining the drug’s effectiveness, said Wei. He noted that about 30 percent of patients are still on therapy after 2 years.
In the phase III international, randomized, double-blind, placebo-controlled QUAZAR AML-001 trial, 472 AML patients, ranging from 55 to 86 years of age, with either intermediate-risk or poor-risk cytogenetics were enrolled between May 2013 and October 2017 across 148 centers in 23 countries. The patients had to achieve a complete response or complete response with incomplete count recovery after induction chemotherapy, with or without consolidation, and not be candidates for hematopoietic stem cell transplant. Within 4 months of attaining any complete response, patients were randomized 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.
After a median follow-up of 41.2 months, median OS was prolonged by 9.9 months with CC-486 (24.7 months) versus placebo (14.8 months). Median RFS was more than doubled with CC-486 (10.2 months) versus placebo (4.8 months). Minimal residual disease was also eradicated more frequently in patients receiving the drug.
OS benefits with CC-486 were observed across subgroups of patients defined by pre-specified baseline characteristics, which was a “striking finding,” said Wei. The baseline characteristics included the number of prior chemotherapy cycles received, the presence of any measurable residual disease, poor cytogenetic risk, or patients 65 years and older. Self-reported quality of life did not change across treatment groups.
The safety and tolerability profile of CC-486 was comparable to injectable azacitidine, with no unexpected events. Most adverse events were gastrointestinal, including nausea, vomiting, and diarrhea, or hematologic events, and occurred in the first 2 cycles. “Treatment discontinuation due to adverse events was infrequent, suggesting CC-486 was manageable in the maintenance setting,” he said.
The most common grade 3-4 adverse events were neutropenia, thrombocytopenia, and anemia. Serious adverse events were infrequent, consisting mainly of infections, which occurred in 17 percent of patients in the CC-486 arm and 8 percent of patients in the control arm.
Despite these side effects, patients in the treatment group underwent more cycles of treatment (median exposure of 12 cycles) than those on placebo (median exposure of 6 cycles). Additionally, those who were on placebo were more likely to receive post-trial treatments, including chemotherapy and stem cell transplantation.
“The QUAZAR trial 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,” said Wei. “Oral CC-486 has a manageable safety profile and represents a new therapeutic standard for patients with AML in remission.”
Mark L. Fuerst is a contributing writer.