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      Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome

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          Abstract

          Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m 2 subcutaneously (days 1–5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration.

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          Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.

          Pierre Fenaux, Ghulam J Mufti, Eva Hellstrom-Lindberg … (2009)
          Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments. Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.
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            International scoring system for evaluating prognosis in myelodysplastic syndromes.

            P. Greenberg, C. Cox, M M LeBeau … (1997)
            Despite multiple disparate prognostic risk analysis systems for evaluating clinical outcome for patients with myelodysplastic syndrome (MDS), imprecision persists with such analyses. To attempt to improve on these systems, an International MDS Risk Analysis Workshop combined cytogenetic, morphological, and clinical data from seven large previously reported risk-based studies that had generated prognostic systems. A global analysis was performed on these patients, and critical prognostic variables were re-evaluated to generate a consensus prognostic system, particularly using a more refined bone marrow (BM) cytogenetic classification. Univariate analysis indicated that the major variables having an impact on disease outcome for evolution to acute myeloid leukemia were cytogenetic abnormalities, percentage of BM myeloblasts, and number of cytopenias; for survival, in addition to the above, variables also included age and gender. Cytogenetic subgroups of outcome were as follows: "good" outcomes were normal, -Y alone, del(5q) alone, del(20q) alone; "poor" outcomes were complex (ie, > or = 3 abnormalities) or chromosome 7 anomalies; and "intermediate" outcomes were other abnormalities. Multivariate analysis combined these cytogenetic subgroups with percentage of BM blasts and number of cytopenias to generate a prognostic model. Weighting these variables by their statistical power separated patients into distinctive subgroups of risk for 25% of patients to undergo evolution to acute myeloid leukemia, with: low (31% of patients), 9.4 years; intermediate-1 (INT-1; 39%), 3.3 years; INT-2 (22%), 1.1 years; and high (8%), 0.2 year. These features also separated patients into similar distinctive risk groups for median survival: low, 5.7 years; INT-1, 3.5 years; INT-2, 1.2 years; and high, 0.4 year. Stratification for age further improved analysis of survival. Compared with prior risk-based classifications, this International Prognostic Scoring System provides an improved method for evaluating prognosis in MDS. This classification system should prove useful for more precise design and analysis of therapeutic trials in this disease.
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              Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia.

              Bruce D Cheson, Peter Greenberg, John Bennett … (2006)
              The myelodysplastic syndromes (MDSs) are heterogeneous with respect to clinical characteristics, pathologic features, and cytogenetic abnormalities. This heterogeneity is a challenge for evaluating response to treatment. Therapeutic trials in MDS have used various criteria to assess results, making cross-study comparisons problematic. In 2000, an International Working Group (IWG) proposed standardized response criteria for evaluating clinically significant responses in MDS. These criteria included measures of alteration in the natural history of disease, hematologic improvement, cytogenetic response, and improvement in health-related quality of life. The relevance of the response criteria has now been validated prospectively in MDS clinical trials, and they have gained acceptance in research studies and in clinical practice. Because limitations of the IWG criteria have surfaced, based on practical and reported experience, some modifications were warranted. In this report, we present recommendations for revisions of some of the initial criteria.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Blood Cancer J
                Journal ID (iso-abbrev): Blood Cancer J
                Title: Blood Cancer Journal
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2044-5385
                Publication date (Print): January 2014
                Publication date (Electronic): 10 January 2014
                Publication date PMC-release: 1 January 2014
                Volume: 4
                Issue: 1
                Page: e170
                Affiliations
                [1 ]Department of Clinical Haematology, Alfred Hospital, Australian Centre for Blood Diseases, Monash University , Melbourne, Victoria, Australia
                [2 ]Australian Centre for Blood Diseases, Biotechnology Division, Eastern Clinical Research Unit, Monash University , Melbourne, Victoria, Australia
                [3 ]Institute of Medical and Veterinary Science, Department of Haematology and Centre for Cancer Biology , Adelaide, South Australia, Australia
                [4 ]Division of Cancer Services, Princess Alexandra Hospital , Brisbane, Queensland, Australia
                [5 ]Department of Haematology, Austin Hospital , Melbourne, Victoria, Australia
                Author notes
                [* ]Department of Clinical Haematology, Alfred Hospital, Australian Centre for Blood Diseases, Monash University, Commercial Road , Melbourne, Victoria 3004, Australia. E-mail: a.wei@ 123456alfred.org.au or aspencer@ 123456netspace.net.au
                [6]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: bcj201368
                DOI: 10.1038/bcj.2013.68
                PMC ID: 3913937
                PubMed ID: 24413064
                SO-VID: 67d2ba81-7df8-4e9c-9373-576c0486db0b
                Copyright © Copyright © 2014 Macmillan Publishers Limited
                License:

                This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/

                History
                Date received : 04 September 2013
                Date revision received : 12 November 2013
                Date accepted : 22 November 2013
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: azacitidine,epigenetic therapy,acute myeloid leukemia,histone deacetylase inhibitor,myelodysplastic syndrome
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: azacitidine, epigenetic therapy, acute myeloid leukemia, histone deacetylase inhibitor, myelodysplastic syndrome

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