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      Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study

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          Abstract

          PURPOSE

          Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML.

          PATIENTS AND METHODS

          Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m 2 per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS).

          RESULTS

          Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months).

          CONCLUSION

          Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.

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          Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study.

          Michael J Thirman, Martha Arellano, Mark Frattini … (2018)
          Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study.
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            Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome.

            Guillermo Garcia‐Manero, Elihu Estey, Stefan Faderl … (2006)
            Elderly patients (age > or = 65 years) with acute myeloid leukemia (AML) generally have a poor prognosis. AML-type therapy results are often derived from studies in younger patients and may not apply to elderly AML. Many investigators and oncologists advocate, at times, only supportive care or frontline single agents, Phase I-II studies, low-intensity regimens, or 'targeted' therapies. However, baseline expectations for outcomes of elderly AML with 'standard' AML-type therapy are not well defined. The aim was to develop prognostic models for complete response (CR), induction (8-week) mortality, and survival rates in elderly AML, which would be used to advise oncologists and patients of expectations with standard AML type therapy, and to establish baseline therapy results against which novel strategies would be evaluated. A total of 998 patients age > or = 65 years with AML or high-risk myelodysplastic syndrome (> 10% blasts) treated with intensive chemotherapy between 1980 and 2004 were analyzed. Univariate and multivariate analyses of prognostic factors associated with CR, induction (8-week) mortality, and survival used standard methods. The overall CR rate was 45% and induction mortality 29%. Multivariate analysis of prognostic factors identified consistent independent poor prognostic factors for CR, 8-week mortality, and survival. These included age > or = 75 years, unfavorable karyotypes (often complex), poor performance (3-4 ECOG [Eastern Cooperative Oncology Group]), longer duration of antecedent hematologic disorder, treatment outside the laminar airflow room, and abnormal organ functions. Patients could be divided into: 1) a favorable group (about 20% of patients) with expected CR rates above 60%, induction mortality rates of 10%, and 1-year survival rates above 50%; 2) an intermediate group (about 50-55% of patients) with expected CR rates of 50%, induction mortality rates of 30%, and 1-year survival rates of 30%; and 3) an unfavorable risk group (about 25-30% of patients) with expected CR rates of less than 20%, induction mortality rates above 50%, and 1-year survival rates of less than 10%. Prognostic models, based on standard readily available baseline characteristics, were developed for elderly patients with AML, which may assist in therapeutic and investigational decisions. These predictive models, based on a retrospective analysis, will require validation in independent study groups.
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              Survival for older patients with acute myeloid leukemia: a population-based study.

              D J Weisdorf, Betul Oran (2012)
              Acute myeloid leukemia is the second most common leukemia among United States adults with a median age of 69 years. We investigated recent clinical practices related to treatments and disease outcomes in older patients with acute myeloid leukemia in the United States. In this retrospective cohort study, we used Surveillance, Epidemiology, and End Results program data from 2000 through 2007 linked to Medicare enrollment and utilization data in the United States. Among 5,480 patients with acute myeloid leukemia (median age 78 years, range 65-93), 38.6% received leukemia therapy within three months of diagnosis (treated group). Practice changed with 16.3% of treated patients receiving hypomethylating agents after 2004 when those agents became available. Median survival was two months in the untreated group versus six months in the treated group (P<0.01) with the biggest improvements seen in those aged 65-69 years (10 months vs. 4 months; P<0.01) and 70-74 years (8 months vs. 3 months; P<0.01). In 46 patients receiving allogeneic hematopoietic cell transplantation (0.8%), the median survival from diagnosis was 22 months. Therapy for leukemia improves overall survival in older acute myeloid leukemia patients. Based on their comorbidities, most patients up to 80 years of age should be considered for treatment. New therapies including hypomethylating agents and allogeneic hematopoietic cell transplantation are promising and must be compared with other chemotherapy regimens.
              Article 0 comments Cited 124 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Clin Oncol
                Journal ID (iso-abbrev): J. Clin. Oncol
                Journal ID (hwp): jco
                Journal ID (pmc): jco
                Journal ID (publisher-id): JCO
                Title: Journal of Clinical Oncology
                Publisher: American Society of Clinical Oncology
                ISSN (Print): 0732-183X
                ISSN (Electronic): 1527-7755
                Publication date (Print): 20 May 2019
                Publication date (Electronic): 20 March 2019
                Publication date PMC-release: 20 May 2020
                Volume: 37
                Issue: 15
                Pages: 1277-1284
                Affiliations
                [ 1 ]The Alfred Hospital and Monash University, Melbourne, VIC, Australia
                [ 2 ]Vanderbilt-Ingram Cancer Center, Nashville, TN
                [ 3 ]University of Pittsburgh Medical Center Cancer Center, Pittsburgh, PA
                [ 4 ]University Medical Center Hamburg-Eppendorf, Hamburg, Germany
                [ 5 ]University of Kansas Medical Center, Kansas City, KS
                [ 6 ]University of Washington, Seattle, WA
                [ 7 ]Fred Hutchinson Cancer Research Center, Seattle, WA
                [ 8 ]Calvary Mater Hospital Newcastle, Waratah, NSW, Australia
                [ 9 ]University of Newcastle, Callaghan, NSW, Australia
                [ 10 ]Weill Cornell Medical College, New York, NY
                [ 11 ]AbbVie, North Chicago, IL
                [ 12 ]Ain Shams University, Cairo, Egypt
                [ 13 ]Genentech, South San Francisco, CA
                Author notes
                Andrew H. Wei, MBBS, PhD, Department of Haematology, The Alfred Hospital, Commercial Road, Melbourne, VIC 3004, Australia; e-mail: a.wei@ 123456alfred.org.au .
                Article
                Publisher ID: 1801600
                DOI: 10.1200/JCO.18.01600
                PMC ID: 6524989
                PubMed ID: 30892988
                SO-VID: 93d0779a-30f1-4f51-87b3-2ce3626e8529
                Copyright © © 2019 by American Society of Clinical Oncology
                License:

                Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                Date accepted : 13 February 2019
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 41, Pages: 9
                Categories
                Compound subject: , [HEMA6] Hematologic Malignancies: Leukemias: Combined Therapy
                Compound subject: , [HEMA33] Hematologic Malignancies: Leukemias: Targeted Therapy
                Subject: RAPID COMMUNICATION
                Subject: Hematologic Malignancy
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