Identification of a secondary FLT3/A848P mutation in a patient with FLT3-ITD-positive blast phase CMML and response to sunitinib and sorafenib

Bubnoff, Nikolas von; Rummelt, Christoph; Menzel, Helge; Sigl, M; Peschel, Christian; Duyster, Justus

doi:10.1038/leu.2010.122

Cited by 18 publications

(15 citation statements)

References 9 publications

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“…Treatment with midostaurin led to a secondary FLT3 mutation at codon 676 in one AML patient . Furthermore, an A848 mutation of FLT3 caused secondary resistance in a patient with chronic myelomonocytic leukaemia (CMML) receiving treatment with sunitinib and sorafenib (von Bubnoff et al, 2010). This is similar to the mechanism of resistance to imatinib in chronic myeloid leukaemia (CML) that is potently overcome by the second line BCR/ABL1 inhibitors nilotinib or dasatinib (Gorre et al, 2001;Weisberg et al, 2007).…”

Section: Discussionmentioning

confidence: 96%

Ponatinib may overcome resistance of FLT3‐ITD harbouring additional point mutations, notably the previously refractory F691I mutation

et al. 2012

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SummaryFms‐like tyrosine kinase (FLT3) mutations are the most frequent mutations in patients with acute myeloid leukaemia (AML) that confer a poor prognosis. Constitutively active FLT3‐ITD (internal tandem duplications) mutations define a promising target for therapeutic approaches using small molecule inhibitors. However, several point mutations of the FLT3 tyrosine kinase domain (FLT3‐TKD) have been identified to mediate resistance towards FLT3 tyrosine kinase inhibitors (FLT3‐TKI), including secondary mutations of FLT3. We investigated the cellular effects of the recently characterised FLT3‐TKI ponatinib (AP24534) on murine myeloid cells transfected with FLT3‐ITD with or without additional point mutations of the FLT3‐TKD including the (so far) multi‐resistant F691I mutation. Ponatinib effectively induced apoptosis not only in the parental FLT3‐ITD cell line but also in all stably transfected subclones harbouring additional FLT3‐TKD point mutations (N676D, F691I or G697R). These observations correlated with a strong inhibition of FLT3‐ITD and its downstream targets STAT5, AKT and ERK1/2 upon ponatinib incubation, as determined by Western blotting. We conclude that ponatinib represents a promising FLT3‐TKI that should be further investigated in clinical trials. The targeted therapy of FLT3‐ITD‐positive AML with ponatinib might be associated with a lower frequency of secondary resistance caused by acquired FLT3‐TKD mutations.

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Section: Discussionmentioning

confidence: 96%

Ponatinib may overcome resistance of FLT3‐ITD harbouring additional point mutations, notably the previously refractory F691I mutation

et al. 2012

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“…The appearance of an A848 TKD mutation was also demonstrated in a patient with chronic myelomonocytic leukaemia treated with alternating courses of sunitinib and sorafenib. 60 In a heavily pretreated cohort of 13 patients with FLT3-ITD, sorafenib monotherapy resulted in significant clearance of marrow blasts in 12 of them. 61 Comparison of FLT3 genotype before and after sorafenib treatment in six patients demonstrated, in addition to ITD, the presence of TKD D835H mutation in one and D835Y mutation in three patients at leukaemia progression.…”

Section: Loss Of Response To Flt3 Inhibitors: Clinical Evidence Of Emmentioning

confidence: 99%

FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia

2012

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Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene is a gain-of-function mutation common in acute myeloid leukaemia (AML). It is associated with inferior prognosis and response to chemotherapy. Single base mutations at the FLT3 tyrosine kinase domain (TKD) also leads to a gain of function, although its prognostic significance is less well defined because of its rarity. The clinical benefits of FLT3 inhibition are generally limited to AML with FLT3-ITD. However, responses are transient and leukaemia progression invariably occurs. There is compelling evidence that leukaemia clones carrying both ITD and TKD mutations appear when resistance to FLT3 inhibitors occurs. Interestingly, the emergence of double ITD and TKD mutants can be recapitulated in vitro when FLT3-ITD+ leukaemia cell lines are treated with mutagens and FLT3 inhibitors. Furthermore, murine xenotransplantation models also suggest that, in some cases, the FTL3-ITD and TKD double mutants actually exist in minute amounts before treatment with FLT3 inhibitors, expand under the selection pressure of FLT3 inhibition and become the predominant resistant clone(s) during the drug-refractory phase. On the basis of this model of clonal evolution, a multipronged strategy using more potent FLT3 inhibitors, and a combinatorial approach targeting both FLT3-dependent and FLT3-independent pathways, will be needed to improve outcome.

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“…von Bubnoff and colleagues reported a hematological response in a similar case exposed to alternating sunitinib and sorafenib but without CR. 4 This patient developed an FLT3-ITD/A848P mutation in the kinase domain that conferred resistance to both inhibitors. 4 Sorafenib has been tested alone and in combination with other chemotherapeutics in FLT3-ITD AML with promising results.…”

Section: Sorafenib and Cmml Transformationmentioning

confidence: 97%

“…4 This patient developed an FLT3-ITD/A848P mutation in the kinase domain that conferred resistance to both inhibitors. 4 Sorafenib has been tested alone and in combination with other chemotherapeutics in FLT3-ITD AML with promising results. [5][6][7] However, when used alone, a recent study showed that response is lost in most patients in a range of 54 to 287 days, with selection of sorafenib-resistant clones expressing both FLT3-ITD and D835 mutation.…”

Section: Sorafenib and Cmml Transformationmentioning

confidence: 97%

Sustained Leukemia-Free State and Molecular Response to Sorafenib in a Patient With Chronic Myelomonocytic Leukemia in Transformation Driven by Homozygous FLT3-ITD Malignant Hematopoiesis

Kosmider

Chapuis

Kaltenbach

et al. 2013

Clinical Lymphoma Myeloma and Leukemia

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Identification of a secondary FLT3/A848P mutation in a patient with FLT3-ITD-positive blast phase CMML and response to sunitinib and sorafenib

Cited by 18 publications

References 9 publications

Ponatinib may overcome resistance of FLT3‐ITD harbouring additional point mutations, notably the previously refractory F691I mutation

Ponatinib may overcome resistance of FLT3‐ITD harbouring additional point mutations, notably the previously refractory F691I mutation

FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia

Sustained Leukemia-Free State and Molecular Response to Sorafenib in a Patient With Chronic Myelomonocytic Leukemia in Transformation Driven by Homozygous FLT3-ITD Malignant Hematopoiesis

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