Acute myeloid leukaemia (AML) is the most common leukaemia in adults and makes up 32% of all adult leukaemia cases.1 It is generally lethal, in both older and younger patients. With a median age at diagnosis of 67 years, this disease is far more common in the elderly. Many patients respond to intensive induction chemotherapy, but responses are often short lived and overall survival (OS) is poor particularly in patients aged over 60 years, in whom 5-year survival is less than 10%.2 The epigenetic modifier CC-486 is an oral formulation of azacitidine, which has shown promising clinical activity in patients with AML.
In an expert interview, Dr Gail Roboz, professor of medicine and director of the Clinical and Translational Leukaemia Program at the Weill Medical College of Cornell University and the New York-Presbyterian Hospital in New York City, US, discusses the findings of the QUAZAR AML study (NCT01757535), which investigated the efficacy and safety of CC-486 for patients aged ≥55 years with AML in first complete remission.3,4
Q. What are the major challenges associated with maintaining remission in patients with acute myeloid leukaemia?
Although current therapies are good at getting patients into remission, there is inevitably measurable residual disease. These are fractions of leukaemic cells including leukaemic stem cells that are not eradicated by current therapies. These are not visible under the microscope after initial therapies and build back, leading to relapse. Relapsed AML is a deadly situation. Current therapies are not effective and the majority of relapsed patients have a very poor survival rate. It is very important, therefore, to figure out new strategies to maintain and prolong remission in AML. In acute lymphoblastic leukaemia (ALL), treatment with ongoing cycles of low-intensity, post-remission chemotherapy, called maintenance, transformed survival rates and became part of the standard of care both for children and adults. Unfortunately, past trials of post-remission maintenance chemotherapy in AML did not improve overall survival, and the treatments were difficult to tolerate and unpleasant for patients.
Q. Could you tell us a little about CC-486 and its mechanism of action?
CC-486 is an oral hypomethylating agent, similar to azacitidine, which has been available for a long time for the treatment of myelodysplastic syndromes (MDS) and AML. However, CC-486 has a pharmacokinetic and pharmacodynamic profile that is very distinct from injectable azacitidine.5 It can be given orally in an extended dosing manner so its action can be sustained. Hypomethylating agents in AML are generally considered more effective if there is prolonged exposure to the drug, and the ability to use 14- or 21-day schedules is believed to be one of the major advantages of CC-486.
Q. What are the aims and design of the QUAZAR AML-001 study?
The QUAZAR study was a multicentre, international, placebo-controlled double-blind randomised phase III study.3 The goal of the study was to determine whether CC-486 was effective as a post-remission or maintenance therapy in patients aged over 55 years who were in remission (complete remission [CR] or incomplete count recovery [Cri]) after initial intensive induction. These were patients who were deemed ineligible for allogeneic stem cell transplantation (SCT). Until now, allogeneic SCT has been the only hope of cure or long-term disease-free survival, and ineligible patients have a high chance of relapse.2 Patients were randomised to receive CC-486 or placebo in 14-day dosing schedules and each cycle was 28 days, so they were treated for 14 out of the 28 days. Patients carefully monitored for toxicity and adverse events and, importantly we also followed the patients’ health-related quality of life using detailed, validated questionnaires. The key primary endpoint was overall survival and secondary endpoints included relapse-free survival, tolerability and health-related quality of life.
Q. What have been the major efficacy and safety findings of the QUAZAR AML-001 study?
At a median follow up of 41.2 months, there was a clinically and statistically significant overall survival benefit of 9.9 months (14.8 versus 24.7 months). This was a very striking finding that we expect will be practice-changing in AML; it was the first time that a maintenance therapy in AML had been associated with a significant improvement in overall survival. The relapse-free survival was also prolonged. Every subgroup, including cytogenetics, performance status, and whether patients received consolidation therapy, favoured the investigational drug.4 Follow-up data have recently been presented and showed that patients who were aged over 75 years appeared to particularly benefit from CC-486.6 This comprises the majority of patients with AML; the median age is 67–70 years old and the much older patients have the most difficulty tolerating any therapy, particularly SCT.2 The safety profile was reasonable: there were some gastrointestinal events (e.g. nausea and vomiting) in early cycles, which decreased as patients learned to manage these symptoms.4 The longest patient on therapy in the US happens to be my patient; she has been taking CC-486 for 7 years and she has worked out her own eating and scheduling strategies to avoid nausea and vomiting during treatment days. Myelosuppression was also observed on the trial, but did not result in discontinuation of therapy. In further analysis of the data, it seems myelosuppression was more prominent in later cycles among patients with relapsing disease, when haematological toxicity is more expected. The median was 12 cycles of therapy in CC-486 patients, indicating that the therapy can be safely administered in an ongoing manner.4 Health-related quality of life outcomes were comparable to placebo, and not adversely affected by treatment with CC-486.7
Q. In which other treatment settings might CC-486 be successfully used?
Based on the current data, CC-486 was shown to be beneficial for AML patients aged over 55 years who are in remission and are ineligible for allogeneic SCT. Of course, we are hoping and planning for further studies to study whether CC-486 could be effective in other settings where azacitidine is used. For example, the new standard of care for frontline therapy for older patients with AML is azacitidine plus venetoclax.8 We would love to know whether CC-486 could be a better substitute for injectable azacitidine in this setting. We also know that azacitidine can be used successfully in some patients after allogeneic SCT to maintain remission and CC-486 might also be an option for these patients. While we don’t know at the moment where CC-486 could replace standard azacitidine, the success of the QUAZAR trial opens up new and exciting areas for additional study.
1. Cancer.Net. Leukemia – Acute Myeloid – AML: Statistics 2020. Available at: www.cancer.net/cancer-types/leukemia-acute-myeloid-aml/statistics (Accessed 26 June 2020).
2. Almeida AM, Ramos F. Acute myeloid leukemia in the older adults. Leuk Res Rep. 2016;6:1–7.
3. Roboz GJ, Montesinos P, Selleslag D, et al. Design of the randomized, phase III, QUAZAR AML maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia. Future Oncol., 2016;12:293–302.
4. Weil AH, Döhner H, Pocock C, et al. The QUAZAR AML-001 maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) in first remission Blood. 2019;134(Suppl 2):LBA-3.
5. Laille E, Savona MR, Scott BL, et al. Pharmacokinetics of different formulations of oral azacitidine (CC-486) and the effect of food and modified gastric pH on pharmacokinetics in subjects with hematologic malignancies. J Clin Pharmacol. 2014;54:630–9.
6. Ravandi F, Wei A, Döhner H, et al. J Clin Oncol. 2020;38(Suppl 15):7530.
7. Roboz GJ, Döhner H, Pocock C, et al. Health-related quality of life with CC-486 in patients with acute myeloid leukemia (AML) in first remission following induction chemotherapy (IC): results from the phase 3 QUAZAR AML-001 trial. J Clin Oncol. 2020;38(15 Suppl):7533.
8. AbbVie Inc. Prescribing Information. Venclexta® (venetoclax tablets) for oral use. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2018/208573s009lbl.pdf (Accessed 29 June 2020).
Author profile: Gail J. Roboz, M.D. is a professor of medicine and director of the Clinical and Translational Leukemia Programs at the Weill Medical College of Cornell University and the New York Presbyterian Hospital in New York City, US.
Disclosure: Dr Gail J Roboz has provided consultancy or sits on the Advisory Board or Data and Safety Monitoring Committee for AbbVie, Actinium, Agios, Amphivena, Argenx, Array Biopharma, Astex, Astellas, AstraZeneca, Bayer, Celgene, Celltrion, Daiichi Sankyo, Eisai, Epizyme, Helsinn, Janssen, Jasper Therapeutics, Jazz, MEI Pharma (IDMC Chair), Novartis, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda (IRC Chair), Trovagene. has received research Support from Cellectis. Dr Roboz does not perform any promotional activities, does not serve on speaker’s bureaus, is not a member of the board of directors of any company and doe not hold stocks or patents in any healthcare-related company.
Support: Commissioned, edited and supported by Touch Medical Media, who commissioned the interview in liaison with BCW Global. The QUAZAR AML-001 study was supported by Bristol-Myers Squibb.
Published: 6 July 2020