Management of Adverse Effects During Maintenance Treatment of AML Patients
The randomized phase III study QUAZAR AML-001 evaluated the maintenance treatment of acute myeloid leukemia (AML) in patients after first remission. The following text summarizes the findings regarding the most common adverse events (AEs) in this therapy and practical recommendations for managing side effects based on guidelines from professional societies.
Methodology and Progress of the QUAZAR AML-001 Study
For most AML patients, relapse occurs sooner or later after achieving morphological remission, and the prognosis in these cases is not favorable. The pivotal QUAZAR AML-001 study focused on the maintenance treatment of AML with oral azacitidine (AZA p.o.) showed a significant prolongation of overall survival (OS: by 9.9 months; p < 0.001) and relapse-free survival (RFS: by 5.3 months; p < 0.001) compared with placebo in AML patients in first remission after intensive chemotherapy (IC) who were not indicated for transplantation.
QUAZAR AML-001 is an international double-blind randomized phase III study with placebo control, enrolling patients aged ≥ 55 years with AML and intermediate or high cytogenetic risk. These patients achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) within 4 months before entering the study. Subsequently, they were randomized in a 1:1 ratio to receive AZA at a dose of 300 mg p.o. or placebo once daily for 14 days in repeated 28-day cycles. Safety was evaluated in all patients who received ≥ 1 dose.
A total of 469 patients participated in the study (236 in the AZA p.o. arm, 233 in the placebo arm), with a median age of 68 years and a median treatment duration of 12 cycles (range 1–80) in the azacitidine arm and 6 cycles (1–73) in the placebo arm.
Most Common Adverse Events Observed
Gastrointestinal AEs were common in both arms and typically of low grade (1–2). The median duration of nausea, vomiting, and diarrhea was 10, 2, and 6 days, respectively. Antiemetic prophylaxis was not indicated during the study but could be administered if needed.
The most common grade 3–4 AEs occurring during oral AZA treatment were hematologic events. Cytopenias were reported in both treatment arms – primarily neutropenia (41% in AZA p.o., compared with 24% in the placebo arm), thrombocytopenia (22% compared with 21%), and anemia (14% compared with 13%).
Reported AEs rarely required permanent discontinuation of AZA p.o. treatment (13%), suggesting effective management with concomitant medication and dose adjustments of oral AZA.
Management of Gastrointestinal AEs
These AEs were primarily managed with standard measures of supportive pharmacological medication, dose adjustments, or interruptions of AZA administration. The most common pharmacological interventions in the AZA p.o. arm were serotonin receptor antagonists 5-HT3, specifically ondansetron (83%), metoclopramide (34%), or granisetron (18%), and proton pump inhibitors (PPI) pantoprazole (30%) or omeprazole/esomeprazole (29%). Uncomplicated diarrhea can often be managed with fluid and electrolyte replacement and antidiarrheal medications (e.g., loperamide, lactulose, basic bismuth subsalicylate). Intravenous electrolytes were administered in approximately 10% of patients in each arm during the QUAZAR study.
National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend prophylactic administration of 5-HT3 receptor antagonists before initiating moderately or highly emetogenic therapy.
Although higher-grade GI events are not common, oral azacitidine treatment should be interrupted in patients who develop grade 3–4 nausea, vomiting, or diarrhea. Treatment can resume once toxicity decreases to grade ≤ 1. Upon reoccurrence of grade 3–4 events, treatment should again be interrupted until toxicity decreases to grade ≤ 1, and then resumed at a lower dose (200 mg/day) and potentially with a shortened administration period of 7 days.
If diarrhea severity is ≥ 3, oral AZA administration should be interrupted until it subsides to grade ≤ 1, and then continue at the recommended initial dose if there is no reoccurrence – in such a case, the dose should be reduced (200 mg/day), or a shorter treatment period should be considered (e.g., 7 days/cycle).
Management of Hematologic AEs
Hematologic AEs were primarily managed by dose adjustments of AZA or treatment interruptions (n = 3).
Professional recommendations suggest prophylactic administration of granulocyte colony-stimulating factor (G-CSF) filgrastim in case of an overall risk of febrile neutropenia in ≥ 20% of patients with the given therapy. However, the frequency of febrile neutropenia during oral azacitidine treatment (12%) did not meet this threshold.
Guidelines from the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) indicate that erythropoiesis-stimulating agents (ESA) may benefit patients with hemoglobin (Hb) levels ≤ 100 g/l. NCCN guidelines recommend administering ESA for chemotherapy-induced anemia in symptomatic patients with Hb ≤ 110 g/l. For patients with significant chemotherapy-induced thrombocytopenia, these guidelines recommend dose adjustments, platelet transfusions, and the use of romiplostim.
Conclusion
The safety profile of oral azacitidine was generally favorable in the observed patients in maintenance treatment. Effective prophylaxis with antiemetics and monitoring of blood counts (every other week during the first 2 cycles and then as needed) appeared beneficial. Awareness of the onset and duration of common side effects and the implementation of effective management can maximize treatment adherence and optimize the benefits of AZA p.o. therapy in the indication of AML maintenance treatment.
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Source: Ravandi F., Roboz G. J., Wei A. H. et al. Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial. J Hematol Oncol 2021; 14 (1): 133, doi: 10.1186/s13045-021-01142-x.
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2011-CZ-2300022
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