Treatment of acute myelogenous leukemia with outpatient azacitidine

Sudan, N; Rossetti, James M.; Shadduck, Richard K.; Latsko, Joan; Lech, John; Kaplan, Robert; Kennedy, Margaret; Gryn, Jeffrey; Faroun, Yacoub; Lister, John

doi:10.1002/cncr.22204

Cited by 75 publications

(52 citation statements)

References 19 publications

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“…34 However, the CR/CRi rate in evaluable patients of 44% in this study (39% for total patients) exceeds the reported CR rate for azacitidine alone (20%), 12 and the CR/CRi rate for lenalidomide alone (30%). 18 Results from the phase-2 portion of this study will more accurately determine the response rate associated with the sequential combination of azacitidine and lenalidomide, allowing a more direct comparison.…”

Section: Discussioncontrasting

confidence: 61%

“…Azacitidine, an azanucleoside DNA methyltransferase inhibitor that is approved by the US Food and Drug Administration in the related myeloid malignancy myelodysplastic syndrome (MDS), 11 is associated with a low response rate (B20%) in elderly AML patients. 12 Lenalidomide is an immunomodulatory agent, Food and Drug Administration approved for use in MDS with del(5q) and in multiple myeloma. 13 In various diseases it regulates immune responses, gene expression, phosphatase activity, angiogenesis and cytokines, 13 --16 and has demonstrated single-agent activity when used as primary and salvage therapy in AML.…”

Section: Introductionmentioning

confidence: 99%

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Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia

et al. 2011

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Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

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Section: Discussioncontrasting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia

et al. 2011

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“…In a study conducted on 149 AML patients having a poor cytogenetic structure, WBC [ 15 000/ll, the ECOG performance score C2, and the response to therapy were determined to be the factors influencing overall survival [13]. When the side effects were analyzed in both treatment groups, a statistically significant difference was not detected between treatment-related neutropenia, thrombocytopenia, anemia, the amount of blood transfusion, grade of infection, diarrhea, skin reaction, hospitalizationrequiring infection, and duration of hospital stay, and this is consistent with the literature [11,21,22].…”

Section: Discussionsupporting

confidence: 78%

Low Dose Cytosine Arabinoside and Azacitidine Combination in Elderly Patients with Acute Myeloid Leukemia and Refractory Anemia with Excess Blasts (MDS-RAEB2)

Atalay

Atesoglu

2015

Indian J Hematol Blood Transfus

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Only one-third of elderly ([60 years) AML and MDS-RAEB2 patients may receive intensive chemotherapy treatment alternatives that are limited in this patient group due to the potential of severe toxicity. Previous studies have shown that azacitidine and low dose cytarabine treatments may be a beneficial treatment option for these patients. In this study, we aimed to good results with low toxicity in elderly patients. We retrospectively analyzed the AML and MDS-RAEB2 patients who received azacitidine monotherapy and azacitidine and LDL-ara-c combination therapy for a comparison of their response to therapy, survival rates, and toxicity rates and for determining the factors that could affect their overall survival. A total of 27 patients who were diagnosed with de novo AML and MDS-RAEB2 and who received at least four cycles of chemotherapy were included in the study, and the data were evaluated retrospectively. When monotherapy and combination therapy groups were compared, the pretreatment bone marrow blast count was observed to be greater in the combination therapy group. A statistically significant difference was not detected between the groups regarding the response to therapy ratios (p = 0.161) (42.9 and 57.1 %, respectively). No difference was detected between the groups regarding therapy-related toxicity. Infections were the most common complication.Progression-free survival was 30.3 % for the azacitidine monotherapy group and 66.7 % for the combination (azacitidine ? LD-ara-c) group. The factors influencing the overall survival rate were determined based on the response to the first-line therapies, more than a grade 2 infection, fever, and relapse in a multi-variance analysis. The combination therapy may be a well-tolerated treatment option for the elderly, vulnerable AML patients whose blast count is high in response to therapy rates, overall survival rates, and toxicities are not different, although the pre-treatment bone marrow blast count was greater in the combination therapy groups compared with the monotherapy group.

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“…Parenteral azacitidine has been extensively evaluated in patients with MDS, chronic myelomonocytic leukemia (CMML), and AML in large randomized clinical trials,5, 6, 7 in regional registry studies,8, 9, 10, 11, 12, 13 and in numerous smaller retrospective analyses of patients treated in community practice 14, 15. These studies show azacitidine reduces cytopenias in select lower‐risk MDS and prolongs overall survival (OS) in higher‐risk MDS and AML,5, 6, 7, 16 may be effective maintenance therapy after induction chemotherapy (IC) or allogeneic hematopoietic stem cell transplant (alloHSCT),17, 18, 19, 20 and can induce responses in patients with relapsed/refractory disease 12, 21.…”

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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Treatment of acute myelogenous leukemia with outpatient azacitidine

Cited by 75 publications

References 19 publications

Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia

Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia

Low Dose Cytosine Arabinoside and Azacitidine Combination in Elderly Patients with Acute Myeloid Leukemia and Refractory Anemia with Excess Blasts (MDS-RAEB2)

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

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