Association of gene mutations with time‐to‐first treatment in 384 treatment‐naive chronic lymphocytic leukaemia patients
Summary This study correlated somatic mutation results and known prognostic factors with time‐to‐first treatment (TTFT) in 384 treatment‐naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease‐specific drivers of early untreated CLL. CLL DNA from either peripheral blood or...
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| Veröffentlicht in: | British journal of haematology 2019-11, Vol.187 (3), p.307-318 |
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| creator | Hu, Boyu Patel, Keyur P. Chen, Hsiang‐Chun Wang, Xuemei Luthra, Rajyalakshmi Routbort, Mark J. Kanagal‐Shamanna, Rashmi Medeiros, L. Jeffrey Yin, C. Cameron Zuo, Zhuang Ok, Chi Y. Loghavi, Sanam Tang, Guilin Tambaro, Francesco P. Thompson, Philip Burger, Jan Jain, Nitin Ferrajoli, Alessandra Bose, Prithviraj Estrov, Zeev Keating, Michael Wierda, William G. |
| description | Summary
This study correlated somatic mutation results and known prognostic factors with time‐to‐first treatment (TTFT) in 384 treatment‐naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease‐specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29‐gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P |
| doi_str_mv | 10.1111/bjh.16042 |
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This study correlated somatic mutation results and known prognostic factors with time‐to‐first treatment (TTFT) in 384 treatment‐naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease‐specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29‐gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P < 0·001), NOTCH1 (P < 0·001) and SF3B1 (P = 0·002) as well as unmutated IGHV (P < 0·001), del(11q) (P < 0·001) and trisomy 12 (P < 0·001) by hierarchal FISH and advanced Rai (P = 0·05) and Binet (P < 0·001) stages were associated with shorter TTFT. Importantly, del(17p), mutated TP53 and complex karyotype were not associated with shorter TTFT. In a reduced multivariable analysis, mutated ATM (P < 0·001) and unmutated IGHV status (P < 0·001) remained significant, showing their importance in early leukaemogenesis. High‐risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL.]]></description><identifier>ISSN: 0007-1048</identifier><identifier>ISSN: 1365-2141</identifier><identifier>EISSN: 1365-2141</identifier><identifier>DOI: 10.1111/bjh.16042</identifier><identifier>PMID: 31243771</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Bone marrow ; CD38 antigen ; Chronic lymphocytic leukemia ; CLL ; CLL FISH ; Deoxyribonucleic acid ; Disease-Free Survival ; DNA ; Female ; Fluorescence ; Fluorescence in situ hybridization ; genetics ; Hematology ; Humans ; Karyotypes ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell - mortality ; Male ; Middle Aged ; Mutation ; mutations ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; p53 Protein ; Patients ; Peripheral blood ; Point mutation ; prognostic factors ; Survival Rate ; Trisomy ; ZAP-70 protein</subject><ispartof>British journal of haematology, 2019-11, Vol.187 (3), p.307-318</ispartof><rights>2019 British Society for Haematology and John Wiley & Sons Ltd</rights><rights>2019 British Society for Haematology and John Wiley & Sons Ltd.</rights><rights>Copyright © 2019 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3882-36dde20d37aa6142f8d1504347d0bde86bc986822ff338169afd382e64cf89ef3</citedby><cites>FETCH-LOGICAL-c3882-36dde20d37aa6142f8d1504347d0bde86bc986822ff338169afd382e64cf89ef3</cites><orcidid>0000-0002-1623-3613 ; 0000-0003-0114-8384 ; 0000-0001-7829-5249 ; 0000-0002-7357-270X ; 0000-0001-9848-9497 ; 0000-0002-6822-7880 ; 0000-0002-6177-7572 ; 0000-0001-8980-3202</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbjh.16042$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbjh.16042$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31243771$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hu, Boyu</creatorcontrib><creatorcontrib>Patel, Keyur P.</creatorcontrib><creatorcontrib>Chen, Hsiang‐Chun</creatorcontrib><creatorcontrib>Wang, Xuemei</creatorcontrib><creatorcontrib>Luthra, Rajyalakshmi</creatorcontrib><creatorcontrib>Routbort, Mark J.</creatorcontrib><creatorcontrib>Kanagal‐Shamanna, Rashmi</creatorcontrib><creatorcontrib>Medeiros, L. Jeffrey</creatorcontrib><creatorcontrib>Yin, C. Cameron</creatorcontrib><creatorcontrib>Zuo, Zhuang</creatorcontrib><creatorcontrib>Ok, Chi Y.</creatorcontrib><creatorcontrib>Loghavi, Sanam</creatorcontrib><creatorcontrib>Tang, Guilin</creatorcontrib><creatorcontrib>Tambaro, Francesco P.</creatorcontrib><creatorcontrib>Thompson, Philip</creatorcontrib><creatorcontrib>Burger, Jan</creatorcontrib><creatorcontrib>Jain, Nitin</creatorcontrib><creatorcontrib>Ferrajoli, Alessandra</creatorcontrib><creatorcontrib>Bose, Prithviraj</creatorcontrib><creatorcontrib>Estrov, Zeev</creatorcontrib><creatorcontrib>Keating, Michael</creatorcontrib><creatorcontrib>Wierda, William G.</creatorcontrib><title>Association of gene mutations with time‐to‐first treatment in 384 treatment‐naive chronic lymphocytic leukaemia patients</title><title>British journal of haematology</title><addtitle>Br J Haematol</addtitle><description><![CDATA[Summary
This study correlated somatic mutation results and known prognostic factors with time‐to‐first treatment (TTFT) in 384 treatment‐naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease‐specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29‐gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P < 0·001), NOTCH1 (P < 0·001) and SF3B1 (P = 0·002) as well as unmutated IGHV (P < 0·001), del(11q) (P < 0·001) and trisomy 12 (P < 0·001) by hierarchal FISH and advanced Rai (P = 0·05) and Binet (P < 0·001) stages were associated with shorter TTFT. Importantly, del(17p), mutated TP53 and complex karyotype were not associated with shorter TTFT. In a reduced multivariable analysis, mutated ATM (P < 0·001) and unmutated IGHV status (P < 0·001) remained significant, showing their importance in early leukaemogenesis. High‐risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL.]]></description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Bone marrow</subject><subject>CD38 antigen</subject><subject>Chronic lymphocytic leukemia</subject><subject>CLL</subject><subject>CLL FISH</subject><subject>Deoxyribonucleic acid</subject><subject>Disease-Free Survival</subject><subject>DNA</subject><subject>Female</subject><subject>Fluorescence</subject><subject>Fluorescence in situ hybridization</subject><subject>genetics</subject><subject>Hematology</subject><subject>Humans</subject><subject>Karyotypes</subject><subject>Leukemia</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - mortality</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>mutations</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>p53 Protein</subject><subject>Patients</subject><subject>Peripheral blood</subject><subject>Point mutation</subject><subject>prognostic factors</subject><subject>Survival Rate</subject><subject>Trisomy</subject><subject>ZAP-70 protein</subject><issn>0007-1048</issn><issn>1365-2141</issn><issn>1365-2141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc9OGzEQh60KVALtoS-ALHEphw3-l13vERCQokhc6NlyvOPGYXcdbG-jXBCPwDPyJBhCWwmpc5gZjT59GumH0DdKxjTXyXy5GNOSCPYJjSgvJwWjgu6gESGkKigRcg_tx7gkhHIyoZ_RHqdM8KqiI_RwGqM3Tifne-wt_gU94G5Ib4eI1y4tcHIdPD8-JZ-bdSEmnALo1EGfsOsxl-LfISO9dr8Bm0XwvTO43XSrhTeb9LrDcKehcxqvsj_T8QvatbqN8PV9HqCflxe359NidnP14_x0VhguJSt42TTASMMrrUsqmJUNnRDBRdWQeQOynJtalpIxazmXtKy1bbhkUApjZQ2WH6DvW-8q-PsBYlKdiwbaVvfgh6gYE5JXdc1kRo8-oEs_hD5_pxgn9STrRZ2p4y1lgo8xgFWr4DodNooS9RqKyqGot1Aye_huHOYdNH_JPylk4GQLrF0Lm_-b1Nn1dKt8AcEKmiQ</recordid><startdate>201911</startdate><enddate>201911</enddate><creator>Hu, Boyu</creator><creator>Patel, Keyur P.</creator><creator>Chen, Hsiang‐Chun</creator><creator>Wang, Xuemei</creator><creator>Luthra, Rajyalakshmi</creator><creator>Routbort, Mark J.</creator><creator>Kanagal‐Shamanna, Rashmi</creator><creator>Medeiros, L. Jeffrey</creator><creator>Yin, C. Cameron</creator><creator>Zuo, Zhuang</creator><creator>Ok, Chi Y.</creator><creator>Loghavi, Sanam</creator><creator>Tang, Guilin</creator><creator>Tambaro, Francesco P.</creator><creator>Thompson, Philip</creator><creator>Burger, Jan</creator><creator>Jain, Nitin</creator><creator>Ferrajoli, Alessandra</creator><creator>Bose, Prithviraj</creator><creator>Estrov, Zeev</creator><creator>Keating, Michael</creator><creator>Wierda, William G.</creator><general>Blackwell Publishing Ltd</general><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>7T5</scope><scope>H94</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-1623-3613</orcidid><orcidid>https://orcid.org/0000-0003-0114-8384</orcidid><orcidid>https://orcid.org/0000-0001-7829-5249</orcidid><orcidid>https://orcid.org/0000-0002-7357-270X</orcidid><orcidid>https://orcid.org/0000-0001-9848-9497</orcidid><orcidid>https://orcid.org/0000-0002-6822-7880</orcidid><orcidid>https://orcid.org/0000-0002-6177-7572</orcidid><orcidid>https://orcid.org/0000-0001-8980-3202</orcidid></search><sort><creationdate>201911</creationdate><title>Association of gene mutations with time‐to‐first treatment in 384 treatment‐naive chronic lymphocytic leukaemia patients</title><author>Hu, Boyu ; Patel, Keyur P. ; Chen, Hsiang‐Chun ; Wang, Xuemei ; Luthra, Rajyalakshmi ; Routbort, Mark J. ; Kanagal‐Shamanna, Rashmi ; Medeiros, L. Jeffrey ; Yin, C. Cameron ; Zuo, Zhuang ; Ok, Chi Y. ; Loghavi, Sanam ; Tang, Guilin ; Tambaro, Francesco P. ; Thompson, Philip ; Burger, Jan ; Jain, Nitin ; Ferrajoli, Alessandra ; Bose, Prithviraj ; Estrov, Zeev ; Keating, Michael ; Wierda, William G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3882-36dde20d37aa6142f8d1504347d0bde86bc986822ff338169afd382e64cf89ef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Bone marrow</topic><topic>CD38 antigen</topic><topic>Chronic lymphocytic leukemia</topic><topic>CLL</topic><topic>CLL FISH</topic><topic>Deoxyribonucleic acid</topic><topic>Disease-Free Survival</topic><topic>DNA</topic><topic>Female</topic><topic>Fluorescence</topic><topic>Fluorescence in situ hybridization</topic><topic>genetics</topic><topic>Hematology</topic><topic>Humans</topic><topic>Karyotypes</topic><topic>Leukemia</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - mortality</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>mutations</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - metabolism</topic><topic>p53 Protein</topic><topic>Patients</topic><topic>Peripheral blood</topic><topic>Point mutation</topic><topic>prognostic factors</topic><topic>Survival Rate</topic><topic>Trisomy</topic><topic>ZAP-70 protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hu, Boyu</creatorcontrib><creatorcontrib>Patel, Keyur P.</creatorcontrib><creatorcontrib>Chen, Hsiang‐Chun</creatorcontrib><creatorcontrib>Wang, Xuemei</creatorcontrib><creatorcontrib>Luthra, Rajyalakshmi</creatorcontrib><creatorcontrib>Routbort, Mark J.</creatorcontrib><creatorcontrib>Kanagal‐Shamanna, Rashmi</creatorcontrib><creatorcontrib>Medeiros, L. 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Cameron</creatorcontrib><creatorcontrib>Zuo, Zhuang</creatorcontrib><creatorcontrib>Ok, Chi Y.</creatorcontrib><creatorcontrib>Loghavi, Sanam</creatorcontrib><creatorcontrib>Tang, Guilin</creatorcontrib><creatorcontrib>Tambaro, Francesco P.</creatorcontrib><creatorcontrib>Thompson, Philip</creatorcontrib><creatorcontrib>Burger, Jan</creatorcontrib><creatorcontrib>Jain, Nitin</creatorcontrib><creatorcontrib>Ferrajoli, Alessandra</creatorcontrib><creatorcontrib>Bose, Prithviraj</creatorcontrib><creatorcontrib>Estrov, Zeev</creatorcontrib><creatorcontrib>Keating, Michael</creatorcontrib><creatorcontrib>Wierda, William G.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>British journal of haematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hu, Boyu</au><au>Patel, Keyur P.</au><au>Chen, Hsiang‐Chun</au><au>Wang, Xuemei</au><au>Luthra, Rajyalakshmi</au><au>Routbort, Mark J.</au><au>Kanagal‐Shamanna, Rashmi</au><au>Medeiros, L. Jeffrey</au><au>Yin, C. Cameron</au><au>Zuo, Zhuang</au><au>Ok, Chi Y.</au><au>Loghavi, Sanam</au><au>Tang, Guilin</au><au>Tambaro, Francesco P.</au><au>Thompson, Philip</au><au>Burger, Jan</au><au>Jain, Nitin</au><au>Ferrajoli, Alessandra</au><au>Bose, Prithviraj</au><au>Estrov, Zeev</au><au>Keating, Michael</au><au>Wierda, William G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Association of gene mutations with time‐to‐first treatment in 384 treatment‐naive chronic lymphocytic leukaemia patients</atitle><jtitle>British journal of haematology</jtitle><addtitle>Br J Haematol</addtitle><date>2019-11</date><risdate>2019</risdate><volume>187</volume><issue>3</issue><spage>307</spage><epage>318</epage><pages>307-318</pages><issn>0007-1048</issn><issn>1365-2141</issn><eissn>1365-2141</eissn><abstract><![CDATA[Summary
This study correlated somatic mutation results and known prognostic factors with time‐to‐first treatment (TTFT) in 384 treatment‐naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease‐specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29‐gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P < 0·001), NOTCH1 (P < 0·001) and SF3B1 (P = 0·002) as well as unmutated IGHV (P < 0·001), del(11q) (P < 0·001) and trisomy 12 (P < 0·001) by hierarchal FISH and advanced Rai (P = 0·05) and Binet (P < 0·001) stages were associated with shorter TTFT. Importantly, del(17p), mutated TP53 and complex karyotype were not associated with shorter TTFT. In a reduced multivariable analysis, mutated ATM (P < 0·001) and unmutated IGHV status (P < 0·001) remained significant, showing their importance in early leukaemogenesis. High‐risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL.]]></abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>31243771</pmid><doi>10.1111/bjh.16042</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-1623-3613</orcidid><orcidid>https://orcid.org/0000-0003-0114-8384</orcidid><orcidid>https://orcid.org/0000-0001-7829-5249</orcidid><orcidid>https://orcid.org/0000-0002-7357-270X</orcidid><orcidid>https://orcid.org/0000-0001-9848-9497</orcidid><orcidid>https://orcid.org/0000-0002-6822-7880</orcidid><orcidid>https://orcid.org/0000-0002-6177-7572</orcidid><orcidid>https://orcid.org/0000-0001-8980-3202</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged Aged, 80 and over Bone marrow CD38 antigen Chronic lymphocytic leukemia CLL CLL FISH Deoxyribonucleic acid Disease-Free Survival DNA Female Fluorescence Fluorescence in situ hybridization genetics Hematology Humans Karyotypes Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - genetics Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Leukemia, Lymphocytic, Chronic, B-Cell - mortality Male Middle Aged Mutation mutations Neoplasm Proteins - genetics Neoplasm Proteins - metabolism p53 Protein Patients Peripheral blood Point mutation prognostic factors Survival Rate Trisomy ZAP-70 protein |
| title | Association of gene mutations with time‐to‐first treatment in 384 treatment‐naive chronic lymphocytic leukaemia patients |
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