Cargando…

Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid

5-azacytidine (AZA) has become standard treatment for patients with higher-risk myelodysplastic syndrome (MDS). Response rate is about 50% and response duration is limited. Histone deactylase (HDAC) inhibitors are attractive partners for epigenetic combination therapy. We treated 24 patients with AZ...

Descripción completa

Detalles Bibliográficos
Autores principales: Kuendgen, Andrea, Bug, Gesine, Ottmann, Oliver G., Haase, Detlef, Schanz, Julie, Hildebrandt, Barbara, Nachtkamp, Kathrin, Neukirchen, Judith, Dienst, Ariane, Haas, Rainer, Germing, Ulrich, Gattermann, Norbert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer-Verlag 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365387/
https://www.ncbi.nlm.nih.gov/pubmed/22704349
http://dx.doi.org/10.1007/s13148-011-0031-9
_version_ 1782234670064205824
author Kuendgen, Andrea
Bug, Gesine
Ottmann, Oliver G.
Haase, Detlef
Schanz, Julie
Hildebrandt, Barbara
Nachtkamp, Kathrin
Neukirchen, Judith
Dienst, Ariane
Haas, Rainer
Germing, Ulrich
Gattermann, Norbert
author_facet Kuendgen, Andrea
Bug, Gesine
Ottmann, Oliver G.
Haase, Detlef
Schanz, Julie
Hildebrandt, Barbara
Nachtkamp, Kathrin
Neukirchen, Judith
Dienst, Ariane
Haas, Rainer
Germing, Ulrich
Gattermann, Norbert
author_sort Kuendgen, Andrea
collection PubMed
description 5-azacytidine (AZA) has become standard treatment for patients with higher-risk myelodysplastic syndrome (MDS). Response rate is about 50% and response duration is limited. Histone deactylase (HDAC) inhibitors are attractive partners for epigenetic combination therapy. We treated 24 patients with AZA (100 mg/m(2), 5 days) plus valproate (VPA; continuous dosing, trough serum level 80–110 μg/ml). According to WHO classification, 5 patients had MDS, 2 had MDS/MPD, and 17 had acute myeloid leukemia (AML). Seven patients (29%) had previously received intensive chemotherapy, and five had previous HDAC inhibitor treatment. The overall response rate was 37% in the entire cohort but significantly higher (57%) in previously untreated patients, especially those with MDS (64%). Seven (29%) patients achieved CR (29%) and two PR (8%), respectively. Hematological CR was accompanied by complete cytogenetic remission according to conventional cytogenetics in all evaluable cases. Some patients also showed complete remission according to FISH on bone marrow mononuclear cells and CD34(+) peripheral blood cells, as well as by follow-up of somatic mitochondrial DNA mutations. Four additional patients achieved at least marrow remissions. Factors influencing response were AML (vs. MDS), marrow blast count, pretreatment, transfusion dependency, concomitant medication with hydroxyurea, and valproic acid (VPA) serum level. This trial is the first to assess the combination of AZA plus VPA without additional ATRA. A comparatively good CR rate, relatively short time to response, and the influence of VPA serum levels on response suggest that VPA provided substantial additional benefit. However, the importance of HDAC inhibitors in epigenetic combination therapy can only be proven by randomized trials.
format Online
Article
Text
id pubmed-3365387
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Springer-Verlag
record_format MEDLINE/PubMed
spelling pubmed-33653872012-06-02 Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid Kuendgen, Andrea Bug, Gesine Ottmann, Oliver G. Haase, Detlef Schanz, Julie Hildebrandt, Barbara Nachtkamp, Kathrin Neukirchen, Judith Dienst, Ariane Haas, Rainer Germing, Ulrich Gattermann, Norbert Clin Epigenetics Original Article 5-azacytidine (AZA) has become standard treatment for patients with higher-risk myelodysplastic syndrome (MDS). Response rate is about 50% and response duration is limited. Histone deactylase (HDAC) inhibitors are attractive partners for epigenetic combination therapy. We treated 24 patients with AZA (100 mg/m(2), 5 days) plus valproate (VPA; continuous dosing, trough serum level 80–110 μg/ml). According to WHO classification, 5 patients had MDS, 2 had MDS/MPD, and 17 had acute myeloid leukemia (AML). Seven patients (29%) had previously received intensive chemotherapy, and five had previous HDAC inhibitor treatment. The overall response rate was 37% in the entire cohort but significantly higher (57%) in previously untreated patients, especially those with MDS (64%). Seven (29%) patients achieved CR (29%) and two PR (8%), respectively. Hematological CR was accompanied by complete cytogenetic remission according to conventional cytogenetics in all evaluable cases. Some patients also showed complete remission according to FISH on bone marrow mononuclear cells and CD34(+) peripheral blood cells, as well as by follow-up of somatic mitochondrial DNA mutations. Four additional patients achieved at least marrow remissions. Factors influencing response were AML (vs. MDS), marrow blast count, pretreatment, transfusion dependency, concomitant medication with hydroxyurea, and valproic acid (VPA) serum level. This trial is the first to assess the combination of AZA plus VPA without additional ATRA. A comparatively good CR rate, relatively short time to response, and the influence of VPA serum levels on response suggest that VPA provided substantial additional benefit. However, the importance of HDAC inhibitors in epigenetic combination therapy can only be proven by randomized trials. Springer-Verlag 2011-04-08 /pmc/articles/PMC3365387/ /pubmed/22704349 http://dx.doi.org/10.1007/s13148-011-0031-9 Text en © Springer-Verlag 2011
spellingShingle Original Article
Kuendgen, Andrea
Bug, Gesine
Ottmann, Oliver G.
Haase, Detlef
Schanz, Julie
Hildebrandt, Barbara
Nachtkamp, Kathrin
Neukirchen, Judith
Dienst, Ariane
Haas, Rainer
Germing, Ulrich
Gattermann, Norbert
Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid
title Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid
title_full Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid
title_fullStr Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid
title_full_unstemmed Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid
title_short Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid
title_sort treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365387/
https://www.ncbi.nlm.nih.gov/pubmed/22704349
http://dx.doi.org/10.1007/s13148-011-0031-9
work_keys_str_mv AT kuendgenandrea treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT buggesine treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT ottmannoliverg treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT haasedetlef treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT schanzjulie treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT hildebrandtbarbara treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT nachtkampkathrin treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT neukirchenjudith treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT dienstariane treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT haasrainer treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT germingulrich treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid
AT gattermannnorbert treatmentofpoorriskmyelodysplasticsyndromesandacutemyeloidleukemiawithacombinationof5azacytidineandvalproicacid