The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin

Marcus M. Schittenhelm, Kerstin M. Kampa, Kevin Yee, Michael Heinrich

    Research output: Contribution to journalArticle

    23 Citations (Scopus)

    Abstract

    AML remains a difficult disease to treat. Despite response to induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20-30% of AML patients and predict poor outcome. First clinical data with the FLT3 inhibitor tandutinib demonstrated antileukemic activity in approximately half of the patients - predominantly with FLT3 ITD positive AML. But the data also show that optimal use of tandutinib will require combination therapy with cytotoxic agents. Notably, single agent tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity - the dose limiting toxicities of AML chemotherapy. We determined the feasibility of combining tandutinib with the standard "3 + 7" induction regimen in AML and show that, in contrast to other structurally unrelated FLT3 inhibitors recently evaluated in clinical trials, the use of tandutinib displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin. Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on FLT3 ITD positive blasts. Further we demonstrate, that addition of tandutinib may allow dose reduction of chemotherapy without loss of overall antileukemic activity -resulting in a potential decrease of side effects. This approach might be an interesting novel strategy especially in the treatment of elderly/comorbid patients. Our data provide a rationale for combining tandutinib with induction chemotherapy in intensified as well as in dose reduction protocols for FLT3 ITD positive AML.

    Original languageEnglish (US)
    Pages (from-to)2621-2630
    Number of pages10
    JournalCell Cycle
    Volume8
    Issue number16
    StatePublished - Aug 15 2009

    Fingerprint

    Daunorubicin
    Cytarabine
    Induction Chemotherapy
    Drug Therapy
    Mucositis
    Cytotoxins
    tandutinib
    Therapeutics
    Clinical Trials
    Recurrence

    Keywords

    • AML
    • Chemotherapy
    • FLT3 ITD
    • Synergy
    • Tandutinib

    ASJC Scopus subject areas

    • Cell Biology
    • Molecular Biology
    • Developmental Biology

    Cite this

    The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin. / Schittenhelm, Marcus M.; Kampa, Kerstin M.; Yee, Kevin; Heinrich, Michael.

    In: Cell Cycle, Vol. 8, No. 16, 15.08.2009, p. 2621-2630.

    Research output: Contribution to journalArticle

    @article{d548ed645eb344cb9e8d14ba7411979b,
    title = "The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin",
    abstract = "AML remains a difficult disease to treat. Despite response to induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20-30{\%} of AML patients and predict poor outcome. First clinical data with the FLT3 inhibitor tandutinib demonstrated antileukemic activity in approximately half of the patients - predominantly with FLT3 ITD positive AML. But the data also show that optimal use of tandutinib will require combination therapy with cytotoxic agents. Notably, single agent tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity - the dose limiting toxicities of AML chemotherapy. We determined the feasibility of combining tandutinib with the standard {"}3 + 7{"} induction regimen in AML and show that, in contrast to other structurally unrelated FLT3 inhibitors recently evaluated in clinical trials, the use of tandutinib displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin. Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on FLT3 ITD positive blasts. Further we demonstrate, that addition of tandutinib may allow dose reduction of chemotherapy without loss of overall antileukemic activity -resulting in a potential decrease of side effects. This approach might be an interesting novel strategy especially in the treatment of elderly/comorbid patients. Our data provide a rationale for combining tandutinib with induction chemotherapy in intensified as well as in dose reduction protocols for FLT3 ITD positive AML.",
    keywords = "AML, Chemotherapy, FLT3 ITD, Synergy, Tandutinib",
    author = "Schittenhelm, {Marcus M.} and Kampa, {Kerstin M.} and Kevin Yee and Michael Heinrich",
    year = "2009",
    month = "8",
    day = "15",
    language = "English (US)",
    volume = "8",
    pages = "2621--2630",
    journal = "Cell Cycle",
    issn = "1538-4101",
    publisher = "Landes Bioscience",
    number = "16",

    }

    TY - JOUR

    T1 - The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin

    AU - Schittenhelm, Marcus M.

    AU - Kampa, Kerstin M.

    AU - Yee, Kevin

    AU - Heinrich, Michael

    PY - 2009/8/15

    Y1 - 2009/8/15

    N2 - AML remains a difficult disease to treat. Despite response to induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20-30% of AML patients and predict poor outcome. First clinical data with the FLT3 inhibitor tandutinib demonstrated antileukemic activity in approximately half of the patients - predominantly with FLT3 ITD positive AML. But the data also show that optimal use of tandutinib will require combination therapy with cytotoxic agents. Notably, single agent tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity - the dose limiting toxicities of AML chemotherapy. We determined the feasibility of combining tandutinib with the standard "3 + 7" induction regimen in AML and show that, in contrast to other structurally unrelated FLT3 inhibitors recently evaluated in clinical trials, the use of tandutinib displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin. Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on FLT3 ITD positive blasts. Further we demonstrate, that addition of tandutinib may allow dose reduction of chemotherapy without loss of overall antileukemic activity -resulting in a potential decrease of side effects. This approach might be an interesting novel strategy especially in the treatment of elderly/comorbid patients. Our data provide a rationale for combining tandutinib with induction chemotherapy in intensified as well as in dose reduction protocols for FLT3 ITD positive AML.

    AB - AML remains a difficult disease to treat. Despite response to induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20-30% of AML patients and predict poor outcome. First clinical data with the FLT3 inhibitor tandutinib demonstrated antileukemic activity in approximately half of the patients - predominantly with FLT3 ITD positive AML. But the data also show that optimal use of tandutinib will require combination therapy with cytotoxic agents. Notably, single agent tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity - the dose limiting toxicities of AML chemotherapy. We determined the feasibility of combining tandutinib with the standard "3 + 7" induction regimen in AML and show that, in contrast to other structurally unrelated FLT3 inhibitors recently evaluated in clinical trials, the use of tandutinib displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin. Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on FLT3 ITD positive blasts. Further we demonstrate, that addition of tandutinib may allow dose reduction of chemotherapy without loss of overall antileukemic activity -resulting in a potential decrease of side effects. This approach might be an interesting novel strategy especially in the treatment of elderly/comorbid patients. Our data provide a rationale for combining tandutinib with induction chemotherapy in intensified as well as in dose reduction protocols for FLT3 ITD positive AML.

    KW - AML

    KW - Chemotherapy

    KW - FLT3 ITD

    KW - Synergy

    KW - Tandutinib

    UR - http://www.scopus.com/inward/record.url?scp=69249212433&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=69249212433&partnerID=8YFLogxK

    M3 - Article

    C2 - 19625780

    AN - SCOPUS:69249212433

    VL - 8

    SP - 2621

    EP - 2630

    JO - Cell Cycle

    JF - Cell Cycle

    SN - 1538-4101

    IS - 16

    ER -