Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care
Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m 2 /day x7 days ( n = 240) or conventional care r...
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| Veröffentlicht in: | Leukemia 2018-12, Vol.32 (12), p.2546-2557 |
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| creator | Döhner, Hartmut Dolnik, Anna Tang, Lin Seymour, John F. Minden, Mark D. Stone, Richard M. del Castillo, Teresa Bernal Al-Ali, Haifa Kathrin Santini, Valeria Vyas, Paresh Beach, C. L. MacBeth, Kyle J. Skikne, Barry S. Songer, Steve Tu, Nora Bullinger, Lars Dombret, Hervé |
| description | Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m
2
/day x7 days (
n
= 240) or conventional care regimens (CCR;
n
= 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51–0.99];
P
= 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31–46% reduced risk of death vs CCR. The most frequent gene mutations were
DNMT3A
(27%),
TET2
(25%),
IDH2
(23% [R140, 15%; R172, 8%]), and
TP53
(21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with
TP53
or
NRAS
mutations and azacitidine-treated patients with
FLT3
or
TET2
mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study. |
| doi_str_mv | 10.1038/s41375-018-0257-z |
| format | Article |
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2
/day x7 days (
n
= 240) or conventional care regimens (CCR;
n
= 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51–0.99];
P
= 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31–46% reduced risk of death vs CCR. The most frequent gene mutations were
DNMT3A
(27%),
TET2
(25%),
IDH2
(23% [R140, 15%; R172, 8%]), and
TP53
(21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with
TP53
or
NRAS
mutations and azacitidine-treated patients with
FLT3
or
TET2
mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-018-0257-z</identifier><identifier>PMID: 30275526</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>45/23 ; 45/77 ; 631/67/1990/283/1897 ; 631/67/69 ; Abnormalities ; Acute myeloid leukemia ; Aged ; Aged, 80 and over ; Antimetabolites, Antineoplastic - therapeutic use ; Azacitidine - therapeutic use ; Cancer Research ; Chemotherapy ; Chromosome 5 ; Critical Care Medicine ; Cytarabine ; Cytarabine - therapeutic use ; Cytogenetics ; Cytogenetics - methods ; Female ; Hematology ; Humans ; Intensive ; Internal Medicine ; Karyotype ; Karyotypes ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; Male ; Medicine ; Medicine & Public Health ; Middle Aged ; Mutation ; Mutation - drug effects ; Mutation - genetics ; Myeloid leukemia ; Oncology ; p53 Protein ; Patients ; Risk management ; Risk reduction ; Subgroups ; Survival</subject><ispartof>Leukemia, 2018-12, Vol.32 (12), p.2546-2557</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-505b080f1b8e8ce1ca67c18a0bb903c6fb1f223924e44535638f3fc473a6c2673</citedby><cites>FETCH-LOGICAL-c470t-505b080f1b8e8ce1ca67c18a0bb903c6fb1f223924e44535638f3fc473a6c2673</cites><orcidid>0000-0003-3931-0914</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41375-018-0257-z$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41375-018-0257-z$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30275526$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Döhner, Hartmut</creatorcontrib><creatorcontrib>Dolnik, Anna</creatorcontrib><creatorcontrib>Tang, Lin</creatorcontrib><creatorcontrib>Seymour, John F.</creatorcontrib><creatorcontrib>Minden, Mark D.</creatorcontrib><creatorcontrib>Stone, Richard M.</creatorcontrib><creatorcontrib>del Castillo, Teresa Bernal</creatorcontrib><creatorcontrib>Al-Ali, Haifa Kathrin</creatorcontrib><creatorcontrib>Santini, Valeria</creatorcontrib><creatorcontrib>Vyas, Paresh</creatorcontrib><creatorcontrib>Beach, C. L.</creatorcontrib><creatorcontrib>MacBeth, Kyle J.</creatorcontrib><creatorcontrib>Skikne, Barry S.</creatorcontrib><creatorcontrib>Songer, Steve</creatorcontrib><creatorcontrib>Tu, Nora</creatorcontrib><creatorcontrib>Bullinger, Lars</creatorcontrib><creatorcontrib>Dombret, Hervé</creatorcontrib><title>Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m
2
/day x7 days (
n
= 240) or conventional care regimens (CCR;
n
= 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51–0.99];
P
= 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31–46% reduced risk of death vs CCR. The most frequent gene mutations were
DNMT3A
(27%),
TET2
(25%),
IDH2
(23% [R140, 15%; R172, 8%]), and
TP53
(21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with
TP53
or
NRAS
mutations and azacitidine-treated patients with
FLT3
or
TET2
mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.</description><subject>45/23</subject><subject>45/77</subject><subject>631/67/1990/283/1897</subject><subject>631/67/69</subject><subject>Abnormalities</subject><subject>Acute myeloid leukemia</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antimetabolites, Antineoplastic - therapeutic use</subject><subject>Azacitidine - therapeutic use</subject><subject>Cancer Research</subject><subject>Chemotherapy</subject><subject>Chromosome 5</subject><subject>Critical Care Medicine</subject><subject>Cytarabine</subject><subject>Cytarabine - therapeutic use</subject><subject>Cytogenetics</subject><subject>Cytogenetics - methods</subject><subject>Female</subject><subject>Hematology</subject><subject>Humans</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Karyotype</subject><subject>Karyotypes</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Mutation - drug effects</subject><subject>Mutation - genetics</subject><subject>Myeloid leukemia</subject><subject>Oncology</subject><subject>p53 Protein</subject><subject>Patients</subject><subject>Risk management</subject><subject>Risk reduction</subject><subject>Subgroups</subject><subject>Survival</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kUtvEzEUhS0EomnLD2CDLLGe4sf40Q0SinhJlbqha8vjuZO6TMbB9gQlP4LfzI0SCiy6sux7zneudQh5zdkVZ9K-Ky2XRjWM24YJZZr9M7LgrdGNUoo_JwtmrWn0tWjPyHkpD4wdhvolOZNMGKWEXpBfy11NK5igxlCon3p6uND1XH2NaSo0TsM4wxSAljlv49aP-ETT2EOmG9TAVAv9Ges99WGu6NzBmGJPR5i_wzp6WjP4Cv1Js_ch1thHzEiZhjRtEYBBiA0-wyV5MfixwKvTeUHuPn38tvzS3Nx-_rr8cNOE1rDaKKY6ZtnAOws2AA9em8CtZ113zWTQQ8cHIST-HNpWSaWlHeSAXul1ENrIC_L-yN3M3Rr6gEtkP7pNjmufdy756P6fTPHerdLWaWERZhHw9gTI6ccMpbqHNGf8RnGCK25aYwxHFT-qQk6lZBgeEzhzhwrdsUKHFbpDhW6Pnjf_rvbo-NMZCsRRUHA0rSD_jX6a-htz8qwy</recordid><startdate>20181201</startdate><enddate>20181201</enddate><creator>Döhner, Hartmut</creator><creator>Dolnik, Anna</creator><creator>Tang, Lin</creator><creator>Seymour, John F.</creator><creator>Minden, Mark D.</creator><creator>Stone, Richard M.</creator><creator>del Castillo, Teresa Bernal</creator><creator>Al-Ali, Haifa Kathrin</creator><creator>Santini, Valeria</creator><creator>Vyas, Paresh</creator><creator>Beach, C. L.</creator><creator>MacBeth, Kyle J.</creator><creator>Skikne, Barry S.</creator><creator>Songer, Steve</creator><creator>Tu, Nora</creator><creator>Bullinger, Lars</creator><creator>Dombret, Hervé</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3931-0914</orcidid></search><sort><creationdate>20181201</creationdate><title>Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care</title><author>Döhner, Hartmut ; Dolnik, Anna ; Tang, Lin ; Seymour, John F. ; Minden, Mark D. ; Stone, Richard M. ; del Castillo, Teresa Bernal ; Al-Ali, Haifa Kathrin ; Santini, Valeria ; Vyas, Paresh ; Beach, C. L. ; MacBeth, Kyle J. ; Skikne, Barry S. ; Songer, Steve ; Tu, Nora ; Bullinger, Lars ; Dombret, Hervé</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-505b080f1b8e8ce1ca67c18a0bb903c6fb1f223924e44535638f3fc473a6c2673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>45/23</topic><topic>45/77</topic><topic>631/67/1990/283/1897</topic><topic>631/67/69</topic><topic>Abnormalities</topic><topic>Acute myeloid leukemia</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antimetabolites, Antineoplastic - therapeutic use</topic><topic>Azacitidine - therapeutic use</topic><topic>Cancer Research</topic><topic>Chemotherapy</topic><topic>Chromosome 5</topic><topic>Critical Care Medicine</topic><topic>Cytarabine</topic><topic>Cytarabine - therapeutic use</topic><topic>Cytogenetics</topic><topic>Cytogenetics - methods</topic><topic>Female</topic><topic>Hematology</topic><topic>Humans</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Karyotype</topic><topic>Karyotypes</topic><topic>Leukemia</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Mutation - drug effects</topic><topic>Mutation - genetics</topic><topic>Myeloid leukemia</topic><topic>Oncology</topic><topic>p53 Protein</topic><topic>Patients</topic><topic>Risk management</topic><topic>Risk reduction</topic><topic>Subgroups</topic><topic>Survival</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Döhner, Hartmut</creatorcontrib><creatorcontrib>Dolnik, Anna</creatorcontrib><creatorcontrib>Tang, Lin</creatorcontrib><creatorcontrib>Seymour, John F.</creatorcontrib><creatorcontrib>Minden, Mark D.</creatorcontrib><creatorcontrib>Stone, Richard M.</creatorcontrib><creatorcontrib>del Castillo, Teresa Bernal</creatorcontrib><creatorcontrib>Al-Ali, Haifa Kathrin</creatorcontrib><creatorcontrib>Santini, Valeria</creatorcontrib><creatorcontrib>Vyas, Paresh</creatorcontrib><creatorcontrib>Beach, C. 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L.</au><au>MacBeth, Kyle J.</au><au>Skikne, Barry S.</au><au>Songer, Steve</au><au>Tu, Nora</au><au>Bullinger, Lars</au><au>Dombret, Hervé</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2018-12-01</date><risdate>2018</risdate><volume>32</volume><issue>12</issue><spage>2546</spage><epage>2557</epage><pages>2546-2557</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m
2
/day x7 days (
n
= 240) or conventional care regimens (CCR;
n
= 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51–0.99];
P
= 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31–46% reduced risk of death vs CCR. The most frequent gene mutations were
DNMT3A
(27%),
TET2
(25%),
IDH2
(23% [R140, 15%; R172, 8%]), and
TP53
(21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with
TP53
or
NRAS
mutations and azacitidine-treated patients with
FLT3
or
TET2
mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30275526</pmid><doi>10.1038/s41375-018-0257-z</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-3931-0914</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2018-12, Vol.32 (12), p.2546-2557 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6286388 |
| source | MEDLINE; SpringerLink Journals; Nature |
| subjects | 45/23 45/77 631/67/1990/283/1897 631/67/69 Abnormalities Acute myeloid leukemia Aged Aged, 80 and over Antimetabolites, Antineoplastic - therapeutic use Azacitidine - therapeutic use Cancer Research Chemotherapy Chromosome 5 Critical Care Medicine Cytarabine Cytarabine - therapeutic use Cytogenetics Cytogenetics - methods Female Hematology Humans Intensive Internal Medicine Karyotype Karyotypes Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Male Medicine Medicine & Public Health Middle Aged Mutation Mutation - drug effects Mutation - genetics Myeloid leukemia Oncology p53 Protein Patients Risk management Risk reduction Subgroups Survival |
| title | Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T09%3A14%3A18IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cytogenetics%20and%20gene%20mutations%20influence%20survival%20in%20older%20patients%20with%20acute%20myeloid%20leukemia%20treated%20with%20azacitidine%20or%20conventional%20care&rft.jtitle=Leukemia&rft.au=D%C3%B6hner,%20Hartmut&rft.date=2018-12-01&rft.volume=32&rft.issue=12&rft.spage=2546&rft.epage=2557&rft.pages=2546-2557&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/s41375-018-0257-z&rft_dat=%3Cproquest_pubme%3E2151747771%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2151747771&rft_id=info:pmid/30275526&rfr_iscdi=true |