Health-related quality of life was sustained in patients taking oral azacitidine (also known as CC-486) compared with placebo in patients with acute myeloid leukemia (AML), according to results of the phase III QUAZAR AML-001 trial reported at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposion.1 These findings come on the heels of the primary analysis of the trial showing improved relapse-free survival and overall survival with oral azacitidine.2
“Effective, well-tolerated maintenance treatments are needed for older patients with AML in first remission to reduce the risk of relapse and reemergence of symptoms and to prolong overall survival without compromising health-related quality of life or worsening fatigue. Oral azacitidine is approved for continued treatment of adults with AML in first remission post induction therapy who are not able to complete curative therapy,” explained Gail J. Roboz, MD, Professor of Medicine, Weill Cornell College of Cornell University, NewYork-Presbyterian Hospital.
“We have incredibly few quality-of-life data in AML. One of the exciting things about this study is that we now have, and our data include older patients as well.”— Gail J. Roboz, MD
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“Our analysis found that patients in first remission had low levels of fatigue and favorable health-related quality of life at baseline. Health-related quality of life was preserved in patients who received maintenance therapy with oral azacitidine over the entire duration of treatment. Longitudinal analyses supported the noninferior health-related quality of life in the oral azacitidine arm. Oral azacitidine significantly improved overall survival and relapse-free survival while maintaining health-related quality of life comparable to placebo,” she told listeners.
Health-related quality of life in patients with AML is often compromised by fatigue, and no existing therapies have been able to show efficacy and safety without reducing health-related quality of life, providing the rationale for this analysis of QUAZAR AML-001.
“We have incredibly few quality-of-life data in AML. One of the exciting things about this study is that we now have it, and our data include older patients as well. Oral azacitidine was able to be used in older patients, and it is tolerable across the ages we looked at in the study, which is very exciting,” Dr. Roboz noted.
Two different instruments were used to assess health-related quality of life in this study: Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and the EuroQol-5 Dimension (EQ-5D-3L).
FACIT-Fatigue is a self-assessment tool to report the level of fatigue from 1 week to the next using a survey of 13 questions, with a scale of 0 to 4 to indicate fatigue levels (with 0 meaning lack of fatigue and 4 meaning high levels of fatigue). The total score on FACIT-Fatigue could range from 0 to 52. Three points were deducted from the score if patients had worsening minimally important differences, and 3 points were added if minimally important differences were improving.
EQ-5D-3L is a standardized self-assessment tool that assesses patients’ current overall health-related quality of life. This measurement tool looks at five dimensions (including mobility, self-care, usual activities, pain, and anxiety or depression) scored according to a visual analog scale (VAS), ranging from 0 for worst possible health to 100 for best possible health. Eleven points were deducted for worsening of minimally important differences and 11 points were added for improvement in minimally important differences.
QUAZAR AML-001 randomly assigned a total of 472 patients who achieved complete response or complete response with incomplete count recovery after AML induction chemotherapy 1:1 to receive either oral azacitidine at 300 mg once daily for 14 days or matching placebo in repeating 28-day cycles. Patients found to have 5% to 15% of bone marrow blasts at follow-up assessments were eligible to receive oral azacitidine or matching placebo for 21 of 28 days. Treatment was continued until more than 15% blasts were present or unacceptable adverse effects occurred. Enrollment criteria included age of at least 55 years, de novo AML or AML secondary to myelodysplastic syndromes, or chronic myelomonocytic leukemia with intermediate or poor-risk cytogenetics, and not candidates for hematopoietic stem cell transplant (HSCT).
Patients were assessed at the time of their first complete response or complete response with incomplete hematologic recovery after induction chemotherapy with or without consolidation therapy. Other enrollment criteria were ECOG performance status of 0 to 3 and adequate laboratory values including absolute neutrophil count > 500 K/μL and platelet count > 20 K/μL.
Low Fatigue Levels, Good Health-Related Quality of Life
Overall, 95% of the oral azacitidine population and 94% of the placebo population were evaluable for health-related quality of life. Health-related quality of life was comparable in both study arms, as assessments showed low fatigue levels and overall good health-related quality of life. In the oral azacitidine group, mean FACIT-Fatigue score was 40.8 compared with a mean of 40.7 in the placebo arm.
The EQ-5D-3L score for the oral azacitidine arm was 0.80 vs 0.79 in the placebo arm. Finally, the EQ-5D VAS score was 74.6 in patients treated with oral azacitidine compared with 75.4 for the placebo-treated group.
Median number of cycles of therapy was 12 cycles with oral azacitidine and 7 with placebo. Both baseline and postbaseline health-related quality-of-life compliance rates were high, suggesting the results were a true reflection of patients’ health-related quality of life.
In terms of the first secondary endpoint of the study, there was no meaningful difference in changes from baseline between the oral azacitidine arm and the placebo arm. However, the difference in EQ-5D-3L at cycles 22 (P = .048) and 23 (P = .033) were considered statistically significant.
The longitudinal analysis did not show a statistically significant difference between the treatment arms on the FACIT-Fatigue scale over time. There was also no difference in the overall change for the FACIT-Fatigue or EQ-5D-3L scores, and scores did not exceed the prespecified thresholds of minimally important differences.
“These results support the initial hypothesis that health-related quality of life is not inferior in patients who received oral azacitidine compared with those who are given a placebo,” Dr. Roboz said.
Clinical deterioration rates were low and similar between the two treatment arms. There was no statistically significant difference shown in the time to definitive health-related quality-of-life deterioration on any scale.
“These results support the initial hypothesis that health-related quality of life is not inferior in patients who received oral azacitidine compared with those who are given a placebo.”— Gail J. Roboz, MD
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Primary Analysis of QUAZAR AML-001
The primary analysis of QUAZAR AML-001 demonstrated an improvement in overall survival and relapse-free survival with oral azacitidine vs placebo in patients with AML aged 55 or older in first remission following induction chemotherapy.2 Based on these results, the U.S. Food and Drug Administration approved oral azacitidine for continued treatment of adults with AML in first remission post-induction chemotherapy who are not able to undergo a curative therapy like HSCT.
At a median follow-up of 41.2 months, median overall survival was 24.7 months in the oral azacitidine arm compared with 14.8 months in the placebo arm, for an absolute improvement of 9.9 months favoring oral azacitidine (P = .0009). In addition, relapse-free survival was 10 months with oral azacitidine vs 4.8 months with placebo (P = .0001).
Taken together, the primary analysis and health-related quality-of-life analysis data on patients with AML from the QUAZAR AML-001 showed that those with complete remission/complete remission with incomplete hematologic recovery had low levels of fatigue and favorable health-related quality-of-life outcomes, with no deterioration from baseline after treatment with oral azacitidine. Oral azacitidine was noninferior to placebo based on changes from baseline on two validated quality-of-life scoring systems: FACIT-Fatigue and EQ-5D-3L.
DISCLOSURE: Dr. Roboz has served as a consultant or advisor to AbbVie, Actinium Pharmaceuticals, Agios, Amgen, Amphivena, Argenx, Array BioPharma, Astellas Pharma, Astex Pharmaceuticals, Bayer, Bristol Myers Squibb, Celgene, Celltrion, Daiichi Sankyo, Eisai, Genentech/Roche, Genoptix, GlaxoSmithKline, Helsinn Therapeutics, Janssen, Jazz Pharmaceuticals, MedImmune, MEI Pharma, Mesoblast, Novartis, Orsenix, Otsuka, Pfizer, Roche, Sandoz, Takeda, and Trovagene; has received institutional research funding from AbbVie, Agios, Amphivena, Astex Pharmaceuticals, Celgene, Cellectis, CTI, Janssen, Karyopharm Therapeutics, MedImmune, MEI Pharma, Moffitt, Novartis, Onconova Therapeutics, Pfizer, Sunesis Pharmaceuticals, and Tensha Therapeutics; and has been reimbursed for travel, accommodations, or other expenses by AbbVie, Agios, Amgen, Amphivena, Array BioPharma, Astex Pharmaceuticals, Bayer, Celgene, Celltrion, Clovis Oncology, Eisai, Janssen, Jazz Pharmaceuticals, Novartis, Pfizer, Roche/Genentech, Sandoz, and Sunesis Pharmaceuticals.
1. Roboz G, Döhner H, Pocock C, et al: Health-related quality of life with CC-486 in patients with acute myeloid leukemia in first remission following induction chemotherapy: Results from the phase III QUAZAR AML-001 maintenance trial. 2020 ASH Annual Meeting & Exposition. Abstract 214. Presented December 6, 2020.
2. Wei AH, Döhner H, Montesinos P, et al: The QUAZAR AML-001 maintenance trial: Results of a phase III randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia in first remission. Blood 134(suppl 2):LBA-3, 2019.
Commenting on this trial, Marlise Luskin, MD, of Dana-Farber Cancer Institute, Boston, explained that the treatment of AML in older adults remains a particular challenge for leukemia clinicians.
“Although many older patients eligible for intensive induction chemotherapy achieve complete remission, ...