A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial

Gore, Steven D.; Fenaux, Pierre; Santini, Valeria; Bennett, John M.; Silverman, Lewis R.; Seymour, John F.; Hellström‐Lindberg, Eva; Swern, Arlene S.; Beach, C. L.; List, Alan F.

doi:10.3324/haematol.2012.074831

Cited by 125 publications

(77 citation statements)

References 19 publications

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“…34 Similarly, in a secondary analysis of the AZA-001 trial, 91% of high-risk MDS patients responded to treatment within 6 azacitidine cycles and the continuation of treatment further improved the response rates. 35 In our survey, approximately 42% of patients (41.4% of high-risk MDS or CMML patients and 44.4% of AML patients) achieved a treatment response, which is consistent with findings of the previous Dutch, French, Italian, and Austrian studies, in which the overall treatment responses were 48%, 43%, 50%, and 45%, respectively (Table 3). 28,29,33,34 In our survey, the overall response was higher than that reported in the Scottish study in patients with MDS or AML (31%).…”

Section: Discussionsupporting

confidence: 80%

“…20,28,29,34 The longer med- Furthermore, an additional analysis of the AZA-001 study evaluating the relationship between treatment response and OS revealed that OS of patients with treatment response or HI was significantly improved compared to non-responders; the OS was also significantly higher in patients treated with azacitidine than in those treated with conventional care. 35 The main limitation of our survey is the small number of patients included and a relatively short follow-up period (1 year). Our findings describe the safety and efficacy of azacitidine treatment in this group of patients and must be interpreted cautiously.…”

Section: Discussionmentioning

confidence: 99%

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Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey

Béguin

Selleslag

Meers

et al. 2014

Acta Clinica Belgica

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Objectives: We evaluated azacitidine (Vidaza H ) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed. Methods: This non-interventional, post-marketing survey included 49/50 patients receiving azacitidine at 14 Belgian haematology centres from 2010-2012. Treatment-emergent adverse events (TEAEs), including treatment-related TEAEs, and serious TEAEs (TESAEs) were recorded throughout the study. Treatment response [complete response (CR), partial response (PR), haematological improvement (HI), stable disease (SD), treatment failure (TF)) and transfusion-independence (TI) were evaluated at completion of a 1-year observation period (1YOP) or at treatment discontinuation, and overall survival (OS), at study conclusion. Results: The median age of patients was 74.7 (range: 43.9-87.8) years; 69.4% had MDS, 26.5% had primary or secondary AML, and 4.1% had CMML. Treatment-related TEAEs, grade 3-4 TEAEs, and TESAEs were reported in 67.3%, 28.6%, and 18.4% of patients, respectively. During 1YOP, patients received a median of 7 (1-12) treatment cycles. Treatment response was assessed for 38/49 patients. Among MDS and CMML patients (n529), 41.4% had CR, PR, or HI, 41.4% had SD, and 17.2% had TF. Among AML patients (n59), 44.4% had CR or PR, 33.3% had SD, and 22.2% had TF. TI was observed in 14/32 (43.8%) patients who were transfusion-dependent at baseline. Median (95% confidence interval) OS was 490 (326-555) days; 1-year OS estimate was 0.571 (0.422-0.696). Conclusions: Our data support previous findings that azacitidine has a clinically acceptable safety profile and shows efficacy.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey

Béguin

Selleslag

Meers

et al. 2014

Acta Clinica Belgica

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“…Importantly, the study of azacitidine has revealed nuances of treatment with DNMTi therapy not seen with the use of traditional chemotherapy. These include improved OS, which can occur in the absence of a complete remission (CR),7, 8, 22 a need to treat with as many as 6 treatment cycles prior to achieving maximal response, and hematologic toxicities seen during early treatment tend to decrease if patients can remain on treatment 7, 8, 23…”

Section: Introductionmentioning

confidence: 99%

Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

Savona

Kolibaba²,

Conkling

et al. 2018

American J Hematol

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CC‐486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC‐486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC‐486 300 mg once‐daily for 21 days of repeated 28‐day cycles. Median age was 71 years (range: 53‐93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC‐486 treatment cycles was 4 (range: 1‐32). The most common treatment‐emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3‐4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC‐486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on‐study. No baseline gene mutation was predictive of response/nonresponse. CC‐486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics.KEY POINTSThe safety profile of oral CC‐486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal.Extended (21‐day/cycle) CC‐486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.

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“…Patients who achieved partial remission (PR) and histologic improvement (HI) demonstrated a survival benefit with azacitidine treatment (13). Patients with stable disease had a survival benefit compared with those with progression, but this was seen in those treated with azacitidine or CCR (14). MDS clones can persist in patients who respond to treatment, suggesting that azacitidine can modulate the function of the cytogenetically abnormal clone and act as a biologic response modifier (15).…”

Section: Azanucleosides In the Mdssmentioning

confidence: 99%

Clinical development of demethylating agents in hematology

Navada¹,

Steinmann²,

Lübbert³

et al. 2014

J. Clin. Invest.

133

112

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The term epigenetics refers to the heritable changes in gene expression that are not associated with a change in the actual DNA sequence. Epigenetic dysregulation is linked to the pathogenesis of a number of malignancies and has been studied extensively in myelodysplastic syndromes and acute myeloid leukemia. DNA methylation is frequently altered in cancerous cells and likely results in transcriptional silencing of tumor suppressor genes. Re-expression of these genes by inhibition of the DNA methyltransferases has been successful in the treatment of benign and malignant disease. In this Review, we discuss the clinical development of demethylating agents in hematology, with a focus on azacitidine and decitabine.

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A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial

Cited by 125 publications

References 19 publications

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey

Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

Clinical development of demethylating agents in hematology

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