A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations
Summary Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinos...
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| Veröffentlicht in: | British journal of haematology 2015-06, Vol.169 (5), p.694-700 |
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| creator | Fiedler, Walter Kayser, Sabine Kebenko, Maxim Janning, Melanie Krauter, Jürgen Schittenhelm, Marcus Götze, Katharina Weber, Daniela Göhring, Gudrun Teleanu, Veronica Thol, Felicitas Heuser, Michael Döhner, Konstanze Ganser, Arnold Döhner, Hartmut Schlenk, Richard F. |
| description | Summary
Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara‐C)/daunorubicin induction (7+3) followed by three cycles of intermediate‐dose Ara‐C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose‐limiting toxicity (DLT), prolonged haemotoxicity and hand‐foot syndrome. At dose level −1, sunitinib 25 mg was restricted to days 1–7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3–internal tandem duplication and 5/8 with FLT3‐tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse‐free and event‐free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild‐type subclones. |
| doi_str_mv | 10.1111/bjh.13353 |
| format | Article |
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Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara‐C)/daunorubicin induction (7+3) followed by three cycles of intermediate‐dose Ara‐C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose‐limiting toxicity (DLT), prolonged haemotoxicity and hand‐foot syndrome. At dose level −1, sunitinib 25 mg was restricted to days 1–7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3–internal tandem duplication and 5/8 with FLT3‐tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse‐free and event‐free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild‐type subclones.</description><identifier>ISSN: 0007-1048</identifier><identifier>EISSN: 1365-2141</identifier><identifier>DOI: 10.1111/bjh.13353</identifier><identifier>PMID: 25818407</identifier><language>eng</language><publisher>England</publisher><subject>acute myeloid leukaemia ; Age Factors ; Aged ; Antineoplastic Agents - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; elderly patients ; Female ; FLT3 mutation ; fms-Like Tyrosine Kinase 3 - genetics ; Humans ; Indoles - administration & dosage ; Leukemia, Myeloid, Acute - diagnosis ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - mortality ; Male ; Middle Aged ; Mutation ; phase I/II study ; Pyrroles - administration & dosage ; Remission Induction ; sunitinib ; Treatment Outcome</subject><ispartof>British journal of haematology, 2015-06, Vol.169 (5), p.694-700</ispartof><rights>2015 John Wiley & Sons Ltd</rights><rights>2015 John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4003-eb4edd834b3e420e51a98cbb18ec61949e1b93cd404a21bcd416598b75c5847a3</citedby><cites>FETCH-LOGICAL-c4003-eb4edd834b3e420e51a98cbb18ec61949e1b93cd404a21bcd416598b75c5847a3</cites></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.13353$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbjh.13353$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25818407$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fiedler, Walter</creatorcontrib><creatorcontrib>Kayser, Sabine</creatorcontrib><creatorcontrib>Kebenko, Maxim</creatorcontrib><creatorcontrib>Janning, Melanie</creatorcontrib><creatorcontrib>Krauter, Jürgen</creatorcontrib><creatorcontrib>Schittenhelm, Marcus</creatorcontrib><creatorcontrib>Götze, Katharina</creatorcontrib><creatorcontrib>Weber, Daniela</creatorcontrib><creatorcontrib>Göhring, Gudrun</creatorcontrib><creatorcontrib>Teleanu, Veronica</creatorcontrib><creatorcontrib>Thol, Felicitas</creatorcontrib><creatorcontrib>Heuser, Michael</creatorcontrib><creatorcontrib>Döhner, Konstanze</creatorcontrib><creatorcontrib>Ganser, Arnold</creatorcontrib><creatorcontrib>Döhner, Hartmut</creatorcontrib><creatorcontrib>Schlenk, Richard F.</creatorcontrib><title>A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations</title><title>British journal of haematology</title><addtitle>Br J Haematol</addtitle><description>Summary
Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara‐C)/daunorubicin induction (7+3) followed by three cycles of intermediate‐dose Ara‐C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose‐limiting toxicity (DLT), prolonged haemotoxicity and hand‐foot syndrome. At dose level −1, sunitinib 25 mg was restricted to days 1–7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3–internal tandem duplication and 5/8 with FLT3‐tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse‐free and event‐free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild‐type subclones.</description><subject>acute myeloid leukaemia</subject><subject>Age Factors</subject><subject>Aged</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>elderly patients</subject><subject>Female</subject><subject>FLT3 mutation</subject><subject>fms-Like Tyrosine Kinase 3 - genetics</subject><subject>Humans</subject><subject>Indoles - administration & dosage</subject><subject>Leukemia, Myeloid, Acute - diagnosis</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - mortality</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>phase I/II study</subject><subject>Pyrroles - administration & dosage</subject><subject>Remission Induction</subject><subject>sunitinib</subject><subject>Treatment Outcome</subject><issn>0007-1048</issn><issn>1365-2141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kD1PwzAQQC0EglIY-APoVoZQX-ykyQiIQlElFpgj27kSQ_Oh2GmVP8LvJSXAxi2-s57e8Bi7QH6Nw8z0e3GNQkTigE1QxFEQosRDNuGczwPkMjlhp869c46CR3jMTsIowUTy-YR93kBTKEewnC2X4HyX91CvwXWV9bayGlSVg608Vc5uCUxBZe0LalXTD9_QKG-p8g7qLbUQc-hJtW5vUG8EO-sLUKbzBGVPm9rmsKHuQ1Fp1bdYGW-3g6J6g8XqRUDZ-eGqK3fGjtZq4-j8552y18X9y91jsHp-WN7drAIjORcBaUl5ngipBcmQU4QqTYzWmJCJMZUpoU6FySWXKkQ9LBhHaaLnkYkSOVdiyq5Gr2lr51paZ01rS9X2GfJs3zYb2mbfbQf2cmSbTpeU_5G_MQdgNgI7u6H-f1N2-_Q4Kr8AmWWEvQ</recordid><startdate>201506</startdate><enddate>201506</enddate><creator>Fiedler, Walter</creator><creator>Kayser, Sabine</creator><creator>Kebenko, Maxim</creator><creator>Janning, Melanie</creator><creator>Krauter, Jürgen</creator><creator>Schittenhelm, Marcus</creator><creator>Götze, Katharina</creator><creator>Weber, Daniela</creator><creator>Göhring, Gudrun</creator><creator>Teleanu, Veronica</creator><creator>Thol, Felicitas</creator><creator>Heuser, Michael</creator><creator>Döhner, Konstanze</creator><creator>Ganser, Arnold</creator><creator>Döhner, Hartmut</creator><creator>Schlenk, Richard F.</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>201506</creationdate><title>A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations</title><author>Fiedler, Walter ; Kayser, Sabine ; Kebenko, Maxim ; Janning, Melanie ; Krauter, Jürgen ; Schittenhelm, Marcus ; Götze, Katharina ; Weber, Daniela ; Göhring, Gudrun ; Teleanu, Veronica ; Thol, Felicitas ; Heuser, Michael ; Döhner, Konstanze ; Ganser, Arnold ; Döhner, Hartmut ; Schlenk, Richard F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4003-eb4edd834b3e420e51a98cbb18ec61949e1b93cd404a21bcd416598b75c5847a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>acute myeloid leukaemia</topic><topic>Age Factors</topic><topic>Aged</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>elderly patients</topic><topic>Female</topic><topic>FLT3 mutation</topic><topic>fms-Like Tyrosine Kinase 3 - genetics</topic><topic>Humans</topic><topic>Indoles - administration & dosage</topic><topic>Leukemia, Myeloid, Acute - diagnosis</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - mortality</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>phase I/II study</topic><topic>Pyrroles - administration & dosage</topic><topic>Remission Induction</topic><topic>sunitinib</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fiedler, Walter</creatorcontrib><creatorcontrib>Kayser, Sabine</creatorcontrib><creatorcontrib>Kebenko, Maxim</creatorcontrib><creatorcontrib>Janning, Melanie</creatorcontrib><creatorcontrib>Krauter, Jürgen</creatorcontrib><creatorcontrib>Schittenhelm, Marcus</creatorcontrib><creatorcontrib>Götze, Katharina</creatorcontrib><creatorcontrib>Weber, Daniela</creatorcontrib><creatorcontrib>Göhring, Gudrun</creatorcontrib><creatorcontrib>Teleanu, Veronica</creatorcontrib><creatorcontrib>Thol, Felicitas</creatorcontrib><creatorcontrib>Heuser, Michael</creatorcontrib><creatorcontrib>Döhner, Konstanze</creatorcontrib><creatorcontrib>Ganser, Arnold</creatorcontrib><creatorcontrib>Döhner, Hartmut</creatorcontrib><creatorcontrib>Schlenk, Richard F.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>British journal of haematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fiedler, Walter</au><au>Kayser, Sabine</au><au>Kebenko, Maxim</au><au>Janning, Melanie</au><au>Krauter, Jürgen</au><au>Schittenhelm, Marcus</au><au>Götze, Katharina</au><au>Weber, Daniela</au><au>Göhring, Gudrun</au><au>Teleanu, Veronica</au><au>Thol, Felicitas</au><au>Heuser, Michael</au><au>Döhner, Konstanze</au><au>Ganser, Arnold</au><au>Döhner, Hartmut</au><au>Schlenk, Richard F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations</atitle><jtitle>British journal of haematology</jtitle><addtitle>Br J Haematol</addtitle><date>2015-06</date><risdate>2015</risdate><volume>169</volume><issue>5</issue><spage>694</spage><epage>700</epage><pages>694-700</pages><issn>0007-1048</issn><eissn>1365-2141</eissn><abstract>Summary
Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara‐C)/daunorubicin induction (7+3) followed by three cycles of intermediate‐dose Ara‐C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose‐limiting toxicity (DLT), prolonged haemotoxicity and hand‐foot syndrome. At dose level −1, sunitinib 25 mg was restricted to days 1–7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3–internal tandem duplication and 5/8 with FLT3‐tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse‐free and event‐free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild‐type subclones.</abstract><cop>England</cop><pmid>25818407</pmid><doi>10.1111/bjh.13353</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | acute myeloid leukaemia Age Factors Aged Antineoplastic Agents - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use elderly patients Female FLT3 mutation fms-Like Tyrosine Kinase 3 - genetics Humans Indoles - administration & dosage Leukemia, Myeloid, Acute - diagnosis Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - mortality Male Middle Aged Mutation phase I/II study Pyrroles - administration & dosage Remission Induction sunitinib Treatment Outcome |
| title | A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations |
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