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      Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results

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          Abstract

          Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open‐label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high‐risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28‐day cycles from day −3, with intravenous cytarabine 100 mg/m 2 on days 1‐7 and daunorubicin 60 mg/m 2 on days 1‐3. Patients in remission then received consolidation therapy (2‐4 cycles of cytarabine 1 g/m 2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27‐75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7‐54.1) achieved investigator‐reported CR. Among patients ≥55 years old ( n = 60), 40.0% (80% CI 31.9‐48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4‐19.3) months, with 12‐month survival probability 66.6% (80% CI 58.5‐73.4). The most common treatment‐related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high‐risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.

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          International scoring system for evaluating prognosis in myelodysplastic syndromes.

          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.

            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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              Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study.

              Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters. A total of 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenously over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks, or best supportive care. Response was assessed using the International Working Group criteria and required that response criteria be met for at least 8 weeks. Patients who were treated with decitabine achieved a significantly higher overall response rate (17%), including 9% complete responses, compared with supportive care (0%) (P < .001). An additional 12 patients who were treated with decitabine (13%) achieved hematologic improvement. Responses were durable (median, 10.3 mos) and were associated with transfusion independence. Patients treated with decitabine had a trend toward a longer median time to acute myelogenous leukemia (AML) progression or death compared with patients who received supportive care alone (all patients, 12.1 mos vs. 7.8 mos [P = 0.16]; those with International Prognostic Scoring System intermediate-2/high-risk disease, 12.0 mos vs. 6.8 mos [P = 0.03]; those with de novo disease, 12.6 mos vs. 9.4 mos [P = 0.04]; and treatment-naive patients, 12.3 mos vs. 7.3 mos [P = 0.08]). Decitabine was found to be clinically effective in the treatment of patients with MDS, provided durable responses, and improved time to AML transformation or death. The duration of decitabine therapy may improve these results further. 2006 American Cancer Society
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                Author and article information

                Contributors
                jcortes@mdanderson.org
                Journal
                Am J Hematol
                Am. J. Hematol
                10.1002/(ISSN)1096-8652
                AJH
                American Journal of Hematology
                John Wiley & Sons, Inc. (Hoboken, USA )
                0361-8609
                1096-8652
                09 September 2018
                November 2018
                : 93
                : 11 ( doiID: 10.1002/ajh.v93.11 )
                : 1301-1310
                Affiliations
                [ 1 ] Department of Leukemia University of Texas, MD Anderson Cancer Center Houston Texas
                [ 2 ] Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore Maryland
                [ 3 ] Leukemia Service, Department of Medicine Roswell Park Comprehensive Cancer Center Buffalo New York
                [ 4 ] Department of Medicine, Keck School of Medicine University of Southern California Los Angeles California
                [ 5 ] Fred Hutchinson Cancer Research Center Seattle Washington
                [ 6 ] Department of Hematology and Medical Oncology Emory University School of Medicine Atlanta Georgia
                [ 7 ] Dana‐Farber Cancer Institute and Harvard Medical School Boston Massachusetts
                [ 8 ] Division of Hematology University of Colorado School of Medicine Aurora Colorado
                [ 9 ] Leukemia Program Cleveland Clinic Cleveland Ohio
                [ 10 ] Department of Hematology Medical University of Lodz Lodz Poland
                [ 11 ] Pfizer Oncology New York New York
                [ 12 ] Division of Oncology Washington University School of Medicine St Louis Missouri
                Author notes
                [*] [* ] Correspondence

                Jorge E. Cortes, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.

                Email: jcortes@ 123456mdanderson.org

                Author information
                http://orcid.org/0000-0002-3411-6357
                Article
                AJH25238
                10.1002/ajh.25238
                6221102
                30074259
                fd01459d-a0cb-44cd-bec9-8a4b7f474df2
                © 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 17 July 2018
                : 25 July 2018
                : 27 July 2018
                Page count
                Figures: 1, Tables: 3, Pages: 10, Words: 7801
                Funding
                Funded by: Pfizer Inc.
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                ajh25238
                November 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.1 mode:remove_FC converted:07.11.2018

                Hematology
                Hematology

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