Condensed versus standard schedule of high-dose cytarabine consolidation therapy with pegfilgrastim growth factor support in acute myeloid leukemia

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Abstract

The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule given on days 1, 3 and 5 (HDAC-135) as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in younger patients with acute myeloid leukemia in first complete remission. One hundred and seventy-six patients were treated with HDAC-135 and 392 patients with HDAC-123 with prophylactic pegfilgrastim at days 10 and 8, respectively, in the AMLSG 07-04 and the German AML Intergroup protocol. Time from start to chemotherapy until hematologic recovery with white blood cells >1.0 G/l and neutrophils >0.5 G/l was in median 4 days shorter in patients receiving HDAC-123 compared with HDAC-135 ( P<0.0001, each), and further reduced by 2 days ( P<0.0001) by pegfilgrastim. Rates of infections were reduced by HDAC-123 ( P<0.0001) and pegfilgrastim ( P=0.002). Days in hospital and platelet transfusions were significantly reduced by HDAC-123 compared with HDAC-135. Survival was neither affected by HDAC-123 versus HDAC-135 nor by pegfilgrastim. In conclusion, consolidation therapy with HDAC-123 leads to faster hematologic recovery and less infections, platelet transfusions as well as days in hospital without affecting survival.

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Most cited references 17

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Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.

Richard F Schlenk, Konstanze Döhner, Jürgen Krauter … (2008)

Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein alpha gene (CEPBA), the myeloid-lymphoid or mixed-lineage leukemia gene (MLL), and the neuroblastoma RAS viral oncogene homolog (NRAS). We evaluated the associations of these mutations with clinical outcomes in patients. We compared the mutational status of the NPM1, FLT3, CEBPA, MLL, and NRAS genes in leukemia cells with the clinical outcome in 872 adults younger than 60 years of age with cytogenetically normal AML. Patients had been entered into one of four trials of therapy for AML. In each study, patients with an HLA-matched related donor were assigned to undergo stem-cell transplantation. A total of 53% of patients had NPM1 mutations, 31% had FLT3 internal tandem duplications (ITDs), 11% had FLT3 tyrosine kinase-domain mutations, 13% had CEBPA mutations, 7% had MLL partial tandem duplications (PTDs), and 13% had NRAS mutations. The overall complete-remission rate was 77%. The genotype of mutant NPM1 without FLT3-ITD, the mutant CEBPA genotype, and younger age were each significantly associated with complete remission. Of the 663 patients who received postremission therapy, 150 underwent hematopoietic stem-cell transplantation from an HLA-matched related donor. Significant associations were found between the risk of relapse or the risk of death during complete remission and the leukemia genotype of mutant NPM1 without FLT3-ITD (hazard ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61), the mutant CEBPA genotype (hazard ratio, 0.48; 95% CI, 0.30 to 0.75), and the MLL-PTD genotype (hazard ratio, 1.56; 95% CI, 1.00 to 2.43), as well as receipt of a transplant from an HLA-matched related donor (hazard ratio, 0.60; 95% CI, 0.44 to 0.82). The benefit of the transplant was limited to the subgroup of patients with the prognostically adverse genotype FLT3-ITD or the genotype consisting of wild-type NPM1 and CEBPA without FLT3-ITD. Genotypes defined by the mutational status of NPM1, FLT3, CEBPA, and MLL are associated with the outcome of treatment for patients with cytogenetically normal AML. Copyright 2008 Massachusetts Medical Society.

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2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline.

Thomas Smith, James Khatcheressian, Gary H Lyman … (2006)

To update the 2000 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSF). The Update Committee completed a review and analysis of pertinent data published from 1999 through September 2005. Guided by the 1996 ASCO clinical outcomes criteria, the Update Committee formulated recommendations based on improvements in survival, quality of life, toxicity reduction and cost-effectiveness. The 2005 Update Committee agreed unanimously that reduction in febrile neutropenia (FN) is an important clinical outcome that justifies the use of CSFs, regardless of impact on other factors, when the risk of FN is approximately 20% and no other equally effective regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. CSF use allows a modest to moderate increase in dose-density and/or dose-intensity of chemotherapy regimens. Dose-dense regimens should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Prophylactic CSF for patients with diffuse aggressive lymphoma aged 65 years and older treated with curative chemotherapy (CHOP or more aggressive regimens) should be given to reduce the incidence of FN and infections. Current recommendations for the management of patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs, includes the prompt administration of CSF or pegylated G-CSF.

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An update of current treatments for adult acute myeloid leukemia.

Hervé Dombret, Claude Gardin (2016)

Recent advances in acute myeloid leukemia (AML) biology and its genetic landscape should ultimately lead to more subset-specific AML therapies, ideally tailored to each patient's disease. Although a growing number of distinct AML subsets have been increasingly characterized, patient management has remained disappointingly uniform. If one excludes acute promyelocytic leukemia, current AML management still relies largely on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), at least in younger patients who can tolerate such intensive treatments. Nevertheless, progress has been made, notably in terms of standard drug dose intensification and safer allogeneic HSCT procedures, allowing a larger proportion of patients to achieve durable remission. In addition, improved identification of patients at relatively low risk of relapse should limit their undue exposure to the risks of HSCT in first remission. The role of new effective agents, such as purine analogs or gemtuzumab ozogamicin, is still under investigation, whereas promising new targeted agents are under clinical development. In contrast, minimal advances have been made for patients unable to tolerate intensive treatment, mostly representing older patients. The availability of hypomethylating agents likely represents an encouraging first step for this latter population, and it is hoped will allow for more efficient combinations with novel agents.

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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): May 2017

Publication date (Electronic): 26 May 2017

Publication date PMC-release: 1 May 2017

Volume: 7

Issue: 5

Page: e564

Affiliations

[1 ]Department of Internal Medicine III, University Hospital of Ulm , Ulm, Germany

[2 ]Division of Biostatistics, German Cancer Research Center , Heidelberg, Germany

[3 ]Department of Oncology and Hematology, Klinikum Braunschweig , Braunschweig, Germany

[4 ]Department of Internal Medicine II, University Hospital , Frankfurt, Germany

[5 ]Department of Medicine III, Johannes Gutenberg-University Mainz , Mainz, Germany

[6 ]Department of Internal Medicine III, Städtisches Klinikum Karlsruhe , Karlsruhe, Germany

[7 ]Department of Hematology and Oncology, Eberhard-Karls University , Tübingen, Germany

[8 ]Department of Internal Medicine I, University Hospital of Saarland , Homburg, Germany

[9 ]Department of Oncology and Hematology, Klinikum Oldenburg , Oldenburg, Germany

[10 ]Department of Internal Medicine III, Technical University of Munich , Munich, Germany

[11 ]Department of Hematology and Oncology, University Hospital of Freiburg , Freiburg, Germany

[12 ]Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University , Düsseldorf, Germany

[13 ]Department of Internal Medicine III, University Hospital of Bonn , Bonn, Germany

[14 ]Department of Hematology, Oncology and Stem Cell Transplantation, Klinikum Essen Süd , Essen, Germany

[15 ]Department of Hematology and Oncology, Asklepios Klinik Altona , Hamburg, Germany

[16 ]Department of Internal Medicine I, Klinikum Bremen Mitte , Bremen, Germany

[17 ]Department of Internal Medicine V, University Hospital Innsbruck , Innsbruck, Austria

[18 ]Department of Hematology and Oncology, University Hospital of Göttingen , Göttingen, Germany

[19 ]Department of Internal Medicine II, University Hospital Schleswig-Holstein , Kiel, Germany

[20 ]Department of Internal Medicine I, Krankenhaus der Barmherzigen Brüder , Trier, Germany

[21 ]Department of Internal Medicine II, University Medical Center Hamburg-Eppendorf , Hamburg, Germany

[22 ]Department of Internal Medicine I, Helios Universitätsklinikum Wuppertal , Wuppertal, Germany

[23 ]Department of Internal Medicine III, University of Salzburg , Salzburg, Austria

[24 ]Department of Hematology/Oncology, Caritas Krankenhaus Lebach , Lebach, Germany

[25 ]Department of Internal Medicine III, Hanuschkrankenhaus , Wien, Austria

[26 ]Department of Hematology/Oncology, Wilhelm-Anton Hospital Goch , Goch, Germany

[27 ]Department of Internal Medicine V, Klinikum Lüdenscheid , Lüdenscheid, Germany

[28 ]Institute of Human Genetics, Hannover Medical School , Hannover Germany

[29 ]Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School , Hannover, Germany

[30 ]NCT Trial Center, National Center for Tumor Diseases , Heidelberg, Germany

Author notes

[* ]NCT Trial Center, National Center for Tumor Diseases , Im Neuenheimer Feld 130.3, Heidelberg 69120, Germany. E-mail: richard.schlenk@ 123456nct-heidelberg.de

Article

Publisher Item ID: bcj201745

DOI: 10.1038/bcj.2017.45

PMC ID: 5518888

PubMed ID: 28548643

SO-VID: da68d74b-9fb8-437d-8ae9-db0217f8c88d

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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

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Date received : 17 April 2017

Date accepted : 21 April 2017

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Condensed versus standard schedule of high-dose cytarabine consolidation therapy with pegfilgrastim growth factor support in acute myeloid leukemia

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Karger: Oncology

Most cited references 17

Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.

2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline.

An update of current treatments for adult acute myeloid leukemia.

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