First Report of Sorafenib in Patients With Acute Myeloid Leukemia Harboring Non-Canonical FLT3 Mutations
Naval DaverAllyson PriceChristopher B. BentonKeyur P. PatelWeiguo ZhangMarina KonoplevaNaveen PemmarajuKoichi TakahashiMichael AndreeffGautam Borthakur
6
Citation
17
Reference
10
Related Paper
Citation Trend
Abstract:
The prognostics implications of patients with acute myeloid leukemia harboring non-canonical FLT3 is unknown. The use of tyrosine kinase inhibitors in this patient population has not been previously reported. We report successful targeted therapy against non-ITD, non-D835 driver FLT3 alterations in two patient case studies with acute myeloid leukemia.Keywords:
Midostaurin
Prognostics
Targeted Therapy
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITDMUT) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors have been developed and tested clinically, but very few (midostaurin and gilteritinib) have thus far been FDA/EMA-approved for patients with newly diagnosed or relapse/refractory FLT3-ITDMUT AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITDMUT AML. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin with a potent and selective inhibitory effect on FLT3. In vitro, EC-70124 exerted a robust and specific antileukemia activity against FLT3-ITDMUT AML primary cells and cell lines with respect to cytotoxicity, CFU capacity, apoptosis and cell cycle while sparing healthy hematopoietic (stem/progenitor) cells. We also analyzed its efficacy in vivo as monotherapy using two different xenograft models: an aggressive and systemic model based on MOLM-13 cells and a patient-derived xenograft model. Orally disposable EC-70124 exerted a potent inhibitory effect on the growth of FLT3-ITDMUT AML cells, delaying disease progression and debulking the leukemia. Collectively, our findings show that EC-70124 is a promising and safe agent for the treatment of AML with FLT3-ITDMUT.
Midostaurin
CD135
Debulking
Cite
Citations (3)
FLT3 gene mutations occurred in approximately 30% of acute myeloid leukemia (AML) patients, which is closely associated with the occurrence, development and poor prognosis of AML. The therapy targeting at FLT3 mutations might be a promising treatment for AML. Midostaurin can inhibit the activities of III receptor tyrosine kinase encoded by FLT3 gene, induce cell cycle arrest and has a apoptotic effect on primitive AML cells of FLT3 -mutant, FLT3 wild-type and the expression of FLT3 mutated receptor. In view of this, the association between FLT3 mutations and AML, and research advances and clinical applications of midostaurin on the treatment of AML especially for FLT3 mutated AML, are reviewed.
Midostaurin
Cite
Citations (0)
FMS-like tyrosine kinase 3 (FLT3) is among the most common driver genes recurrently mutated in acute myeloid leukemia (AML), accounting for approximately 30% of cases. Activating mutations of the FLT3 receptor include internal tandem duplications (ITD) that map to the auto-inhibitory juxtamembrane (JM) domain or point mutations within the tyrosine kinase domain (TKD). Several FLT3 tyrosine kinase inhibitors have been developed in the last few years, but midostaurin is currently the only one approved for the treatment of newly diagnosed patients harboring FLT3 mutations. Here we describe for the first time a novel in-frame deletion in exon 14 (JM domain) of the FLT3 gene, that we identified in a young woman with CBFb-MYH11-positive AML. We demonstrated that this novel FLT3 variant is pathogenic, since it is responsible for constitutive activation of FLT3 receptor. Finally, ex-vivo studies demonstrated that this novel mutation is sensitive to midostaurin.
Midostaurin
Protein kinase domain
CD135
Cite
Citations (5)
FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase family member. Mutations in FLT3, as well known, represent the most common genomic alteration in acute myeloid leukemia (AML), identified in approximately one-third of newly diagnosed adult patients. In recent years, this has represented an important therapeutic target. Drugs such as midostaurin, gilteritinib, and sorafenib, either alone in association with conventional chemotherapy, play a pivotal role in AML therapy with the mutated FLT3 gene. A current challenge lies in treating forms of AML with extramedullary localization. Here, we describe the general features of myeloid sarcoma and the ability of a targeted drug, i.e., gilteritinib, approved for relapsed or refractory disease, to induce remission of these extramedullary leukemic localizations in AML patients with FLT3 mutation, analyzing how in the literature, there is an important development of cases describing this promising potential for care.
Midostaurin
Targeted Therapy
Cite
Citations (11)
Midostaurin
Hematologic Neoplasms
Cite
Citations (252)
Abstract: Acute myeloid leukemia (AML) is a highly heterogeneous disease. Mutation with internal tandem duplication of fms-like tyrosine kinase-3 ( FLT3 -ITD) is one of the two most common driver mutations and the presence of FLT3 -ITD delivers poor prognosis. A number of ongoing clinical efforts are focused on FLT3 inhibitor use to improve the outcomes of this otherwise difficult leukemia. Midostaurin has been shown to improve outcomes in FLT3 -mutated AML in the frontline setting. Several FLT3 inhibitors, especially second-generation agents, have shown clinically meaningful activity in relapsed or refractory AML and in patients not amenable to intensive therapy. In this article, we briefly review the biology of FLT3 in the physiological state and its role in leukemogenesis. We present a detailed review of current clinical evidence of FLT3 inhibitors and their use in the induction, treatment of relapsed or refractory disease, and maintenance setting. Keywords: fms-like tyrosine kinase 3, FLT3 inhibitor, FLT3-ITD mutation, leukemia, myeloid, acute, protein kinase inhibitors
Midostaurin
Cite
Citations (37)
Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. The management of SM is highly individualized and was largely palliative for patients without a targeted form of therapy in past decades. Targeted therapy with midostaurin, a multiple kinase inhibitor that inhibits KIT, has demonstrated efficacy in patients with advanced SM. This led to the recent approval of midostaurin by the United States Food and Drug Administration and European Medicines Agency. However, the overall survival of patients treated with midostaurin remains unsatisfactory. The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies. This review briefly summarizes recent developments in the understanding of SM pathogenesis and potential treatment strategies for patients with SM.
Midostaurin
Targeted Therapy
Pathogenesis
GNAQ
Cite
Citations (16)
FLT3, a membrane-bound receptor tyrosine kinase (TK) expressed by immature hematopoietic cells, plays an important role in an early stage of hematopoiesis.1 FLT3 is among the most commonly mutated genes in acute myeloid leukemia (AML). Approximately 30% of AML patients have mutations of FLT3 that result in constitutive phosphorylation and activation of FLT3, and subsequent activation of downstream signal molecules important for cellular proliferation, differentiation, and survival.2 These mutations typically result in either an internal tandem duplication (ITD) of between 3 and 33 or more amino acids in the juxtamembrane region of the FLT3 protein (25% of patients), or a less common (5-10%) point mutation in the activation loop of the thyrosine kinase domaine (TKD).
Midostaurin
Cite
Citations (1)
The FMS-like tyrosine kinase 3 (FLT3-ITD) acute myeloid leukemia (AML) often present with more aggressive disease and have a significantly higher marrow blast percentage, higher likelihood of relapse, and shorter survival. Activating mutations of the kinase occur in about one third of patients with AML. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). A number of small-molecule kinase inhibitors such as lestaurtinib (CEP-701), midostaurin (PKC412), and tandutinib (MLN518) block the autophosphorylation of FLT3 and lead to inhibition of cell proliferation and induction of apoptosis; they have demonstrated clinical activity in patients with AML, in particular those with mutations. This review summarizes what is known regarding the FLT3-ITD targeting therapy.
Midostaurin
Induction chemotherapy
Cite
Citations (0)
Abstract: The Fms-like tyrosine kinase-3 (FLT3; fetal liver kinase-2; human stem cell tyrosine kinase-1; CD135) is a class III receptor tyrosine kinase that is normally involved in regulating the proliferation, differentiation, and survival of both hematopoietic cells and dendritic cells. Mutations leading it to be constitutively activated make it an oncogenic driver in ~30% of acute myeloid leukemia (AML) patients where it is associated with poor prognosis. The prevalence of oncogenic FLT3 and the dependency on its constitutively activated kinase activity for leukemia growth make this protein an attractive target for therapeutic intervention. Of the numerous small molecule inhibitors under clinical investigation for the treatment of oncogenic FLT3-positive AML, the N-benzoyl-staurosporine, midostaurin (CGP41251; PKC412; Rydapt ® ; Novartis Pharma AG, Basel, Switzerland), is the first to be approved by the US Food and Drug Administration for the treatment, in combination with standard chemotherapy, of newly diagnosed adult AML patients who harbor mutations in FLT3. Here, we describe the early design of midostaurin, the preclinical discovery of its activity against oncogenic FLT3, and its subsequent clinical development as a therapeutic agent for FLT3 mutant-positive AML. Keywords: AML, acute myeloid leukemia, PKC412, midostaurin, FLT3-ITD, oncogenic FLT3, targeted therapy
Midostaurin
CD135
Targeted Therapy
Staurosporine
Cite
Citations (14)