Abstract

Background: The phase III AZA-001 trial showed AZA is the first treatment to significantly extend OS in higher-risk MDS pts, who received a median of 9 treatment cycles (range 1 to 39) (

Fenaux,
Blood
2007
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110
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817
). Management of AEs is important to prevent early discontinuation of AZA, before therapeutic benefit may be achieved. This analysis evaluated the frequency of the most commonly reported (≥20% of pts) AEs with AZA by cycle, and the supportive care measures used to ameliorate AEs.

Methods: Pts with higher-risk MDS (FAB-defined RAEB, RAEB-T, or CMML and IPSS Int-2 or High) were enrolled in the AZA-001 study. Pts were randomized to AZA 75 mg/m2/d SC × 7d q 28 days or to a conventional care regimen. AZA dosing cycles could be delayed based on hematologic recovery and AEs. Prophylactic G-CSF and erythropoietin were not allowed.

Results: Of 179 pts randomized to AZA, 175 received the drug and were evaluable for safety. Most patients (86%) remained on the initial dose of 75mg/m2 and did not require dose adjustments for AEs. Of the patients requiring dose reduction, 71% were managed with a single dose reduction primarily for neutropenia or thrombocytopenia. Median cycle length was 34 days (range: 15 – 92); 50% of AZA cycles were administered with no delays (at 28 days), 27% at 35 days, and 23% at >35 days. The majority of the most common AEs (≥20%), which included non-hematologic administration-related (injection site reactions, gastrointestinal) and hematologic events, were transient (median duration 13 days), nonserious, and resolved during the study. Less than 1% of AEs resulted in discontinuation of AZA and instead were commonly managed with delays in the next AZA cycle, concomitant medications, transfusions, and other measures. The median duration of injection site reactions was 12 days; none resulted in adjustment in AZA and <15% required treatment with concomitant medications (typically corticosteroids and/or antihistamines). The majority (95%) of gastrointestinal events were transient with a median duration of 1–4 days (diarrhea, nausea, vomiting) or approximately 1 week (constipation). No gastrointestinal events resulted in discontinuation of AZA and were more commonly managed (72%) with concomitant medications (eg, anti-emetics, laxatives). Most hematologic AEs were transient (>86%), occurred during the first 1–2 cycles and were mainly grade 3 or 4; however, £10% of pts experienced neutropenia, anemia, or thrombocytopenia that required hospitalization. For patients remaining on therapy, hematologic AEs decreased with subsequent cycles, paralleling response. The majority of hematologic events were managed with delays in the next AZA cycle (99%) or transfusions for anemia (87%) or thrombocytopenia (29%); <5% of pts discontinued due to a hematologic event. The median duration of fatigue and pyrexia was approximately 1 week; none of the events resulted in discontinuation or dose decrease of AZA and instead were managed by delay in the next AZA cycle in approximately 5% of patients. There were no cumulative or delayed toxicities.

Conclusions: The majority of the most common AEs (≥20%) in the AZA-001 study were transient (median duration 13 days), nonserious, and were managed by either dose delays for hematological events or supportive care measures. Clinicians should be alert to the onset, duration, and management of these events to allow patients to achieve maximum therapeutic benefit.

Table. Most Frequent (≥20% of Patients) Treatment-Emergent Adverse Events With Azacitidine in AZA-001 Study

 Percent of Patients Per Cycle 
System Organ Class Preferred Term * Cycles 1–2 (N=175) Cycles 3–4 (N=147) Cycles 5–6 (N=130) Cycles 7–8 (N=107) Cycles 9–10 (N=89) 
*Multiple reports of the same preferred term for a patient are counted only once. 
Patients with at least 1 individual AE occurring in ≥20% of patients in the AZA group (%) 94 79 65 65 65 
Blood and lymphatic system disorders (%) 75 54 42 36 36 
Anemia 33 18 14 11 14 
Neutropenia 50 31 28 19 20 
Thrombocytopenia 54 30 25 20 21 
Gastrointestinal disorders (%) 62 42 25 27 30 
Constipation 35 20 13 17 
Diarrhea 12 
Nausea 36 19 12 14 11 
Vomiting 18 11 
General disorders & administration site conditions (%) 62 44 32 32 28 
Fatigue 13 10 
Injection site erythema 35 21 18 16 11 
Injection site reaction 21 13 
Pyrexia 16 
 Percent of Patients Per Cycle 
System Organ Class Preferred Term * Cycles 1–2 (N=175) Cycles 3–4 (N=147) Cycles 5–6 (N=130) Cycles 7–8 (N=107) Cycles 9–10 (N=89) 
*Multiple reports of the same preferred term for a patient are counted only once. 
Patients with at least 1 individual AE occurring in ≥20% of patients in the AZA group (%) 94 79 65 65 65 
Blood and lymphatic system disorders (%) 75 54 42 36 36 
Anemia 33 18 14 11 14 
Neutropenia 50 31 28 19 20 
Thrombocytopenia 54 30 25 20 21 
Gastrointestinal disorders (%) 62 42 25 27 30 
Constipation 35 20 13 17 
Diarrhea 12 
Nausea 36 19 12 14 11 
Vomiting 18 11 
General disorders & administration site conditions (%) 62 44 32 32 28 
Fatigue 13 10 
Injection site erythema 35 21 18 16 11 
Injection site reaction 21 13 
Pyrexia 16 

Disclosures: Santini:Celgene: Honoraria; Novartis: Honoraria; J&J: Honoraria. Fenaux:Celgene: Consultancy, Honoraria, Research Funding; Ortho Biotech: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding. Mufti:Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Hellström-Lindberg:Celgene: Consultancy, Research Funding. Silverman:Celgene: Speakers Bureau. List:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gore:Celgene: Consultancy, Equity Ownership, Research Funding. Seymour:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Backstrom:Celgene: Employment. McKenzie:Celgene: Employment. Beach:Celgene: Employment.

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