Editorial theme | Management of treatment-related toxicities for oral azacitidine in AML patients: An update on the phase III QUAZAR AML-001 trial

Acute myeloid leukemia (AML) is a progressive, molecularly heterogenous hematologic malignancy originating from a rare population of leukemic stem cells. The use of combination chemotherapy, hypomethylating agents (HMAs) and/or hematopoietic stem cell transplantation (HSCT) are the current standard of treatment for AML.¹ However, despite the many clinical benefits conferred by treatments for AML, health practitioners are facing challenges in managing associated toxicities that impact on the quality of life of patients. Treatment-related adverse events (TAEs) such as cardiotoxicity, hepatotoxicity, gastrointestinal toxicity, hematologic toxicity, immunological and pulmonary toxicity are common in patients with AML and contribute to treatment discontinuation and failure.² Read more here.

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition (ASH 2020), Ravandi et al.³ provided updates on the phase III QUAZAR AML-001 trial, with a focus on onset of treatment-related gastrointestinal (GI) adverse events (AEs) in older patients with AML in first remission receiving oral azacitidine (AZA), along with the toxicity management criteria.

Methods

Eligibility

Eligible patients were:

• ≥55 years
• newly diagnosed AML
• Intermediate- or poor-risk cytogenetics at diagnosis
• Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤3
• not candidates for HSCT (Table 1)

Patient distribution

• Patients were randomized 1:1 into the oral azacitidine cohort (300 mg for 14 days/28-day treatment cycle) or placebo cohort for the same duration (within a 4-month period of attaining first complete remission).

• Safety assessment was done by monitoring AEs in the ‘safety population’, in patients who received ≥1 dose of the study drug, from the date of first dose through 28 days after the last dose.

Table 1. Patient baseline characteristics*

AML, acute myeloid leukemia; AZA, azacitidine; CR, complete remission; CRi, CR with incomplete blood count recovery; ECOG PS, Eastern Cooperative Oncology Group performance status; IC, induction chemotherapy; MRD, minimal residual disease; NCCN, National Comprehensive Cancer Network; WHO, World Health Organization. *Adapted from Ravandi et al.3
Characteristic	Oral AZA (n = 236)	Placebo (n = 233)
Median age, years	68	68
ECOG PS score, %
0	49.2	47.6
1	41.9	45.1
2−3	8.9	7.3
de novo AML, %	89.4	92.3
WHO AML classification, %
Myelodysplasia-related changes	20.8	18.0
Recurrent genetic abnormalities	16.1	19.7
Therapy-related	0.8	0
Not otherwise specified	62.3	61.8
NCCN cytogenetic risk at diagnosis, %
Intermediate	85.6	86.7
Poor	14.4	13.3
Response after induction, %
CR	78.4	84.5
CRi	21.6	15.5
Received consolidation, %	78.0	82.0
Median time from IC to randomization, months	3.9	4.0
Median time from CR/CRi to randomization, days	84	86
Median bone marrow blast %	2	2
MRD-positive at randomization, %	43.2	49.4

Results

Major findings included:

• significant prolonged overall survival and relapse-free survival in the azacitidine cohort (12 treatment cycles [range, 1−80]) versus placebo (6 cycles (1−73])
• most common TAEs included low-grade GI events

Other details of the phase III QUAZAR AML-001 trial can be found on our hub.

Treatment-related toxicities

Common TAEs were low grade. Serious events were reported in only 6% of patients in the oral azacitidine arm, at any time on-study (Table 2). Most common Grade 3 events were nausea, vomiting, or diarrhea, and only one Grade 4 event was reported.

Table 2. Treatment-related GI AEs in the oral azacitidine cohort (n= 236)*

AE, adverse event; AZA, azacitidine; GI, gastrointestinal; TAE, treatment-related adverse event. *Adapted from Ravandi et al.3
GI TAE	Total, %	TAE based on grades, %
		1	2	3	4
Any	91.1	26.7	50.0	12.7	1.7
Nausea	64.8	34.3	28.0	2.5	0
Vomiting	59.7	34.3	22.5	3.0	0
Diarrhea	50.4	26.3	19.1	4.7	0.4
Constipation	38.6	22.0	15.3	1.3	0
Abdominal pain	13.1	8.1	4.2	0.8	0
Upper abdominal pain	8.9	5.9	2.1	0.8	0
Flatulence	5.5	3.8	1.7	0	0

Toxicity management

 Most common concomitant GI medications during oral azacitidine treatment that were given to a percentage of patients, were as follows:

• Ondansetron, 77%
• Metoclopramide, 25%
• Pantoprazole, 24%
• Omeprazole, 21%
• Lactulose, 17%
• Potassium chloride, 16%
• Granisetron, 14%
• Loperamide, 13%

Dose modifications due to TAEs were infrequent but some adjustments were made to manage toxicities (Table 3).

Table 3. Toxicity management via dose reduction and treatment discontinuation in AML patients with GI AEs*

AE, adverse event; GI, gastrointestinal. *Adapted from Ravandi et al.3
GI AE	Treatment interruption, %	Dose reduction, %	Treatment discontinuation, %
Any	13.1	5.5	4.7
Nausea	5.5	1.7	2.1
Diarrhea	4.2	3.4	1.7
Vomiting	3.8	0.8	1.3
Constipation	1.3	0.4	0.4
Abdominal pain	1.7	0	0
Upper abdominal pain	0.4	0	0.8

In most patients, after the initial treatment cycles (1−2), there was a reduction in TAEs as well as in the use of GI medications, which suggests progressive tolerance to oral azacitidine with continued therapy. It was suggested that prophylaxis and symptomatic intervention may facilitate treatment adherence to promote better outcomes.

Conclusion

Awareness about the possibility for GI events during early oral azacitidine treatment will facilitate patients and clinicians to pre-plan and introduce prophylaxis and symptomatic interventions, which in turn will increase treatment adherence and better outcomes.