scholarly journals Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis

2017 ◽  
Vol 8 (9) ◽  
pp. 245-261 ◽  
Author(s):  
Molly M. Gallogly ◽  
Hillard M. Lazarus ◽  
Brenda W. Cooper
Keyword(s):  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Systemic Mastocytosis ◽  
Growth Factor Receptor ◽  
Significant Activity ◽  
Resistance Mutations ◽  
Acute Myeloid

The development of FLT3-targeted inhibitors represents an important paradigm shift in the management of patients with highly aggressive fms-like tyrosine kinase 3-mutated (FLT3-mut) acute myeloid leukemia (AML). Midostaurin is an orally administered type III tyrosine kinase inhibitor which in addition to FLT3 inhibits c-kit, platelet-derived growth factor receptors, src, and vascular endothelial growth factor receptor. Midostaurin is the first FLT3 inhibitor that has been shown to significantly improve survival in younger patients with FLT3-mut AML when given in combination with standard cytotoxic chemotherapy based on the recently completed RATIFY study. Its role for maintenance therapy after allogeneic transplantation and use in combination with hypomethylating agents for older patients with FLT3-mut has not yet been defined. Midostaurin also has recently been shown to have significant activity in systemic mastocytosis and related disorders due to its inhibitory effect on c-kit bearing a D816V mutation. Activation of downstream pathways in both of these myeloid malignancies likely plays an important role in the development of resistance, and strategies to inhibit these downstream targets may be synergistic. Incorporating patient factors and tumor characteristics, such as FLT3 mutant to wild-type allele ratios and resistance mutations, likely will be important in the optimization of midostaurin and other FLT3 inhibitors in the treatment of myeloid neoplasms.

scholarly journals Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis

2018 ◽  
Vol 2 (4) ◽  
pp. 444-453 ◽  
Author(s):  
Richard M. Stone ◽  
Paul W. Manley ◽  
Richard A. Larson ◽  
Renaud Capdeville
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Systemic Mastocytosis ◽  
Angiogenesis Inhibitor ◽  
European Medicines Agency ◽  
Newly Diagnosed ◽  
Standard Chemotherapy ◽  
Acute Myeloid

Abstract Midostaurin was a prototype kinase inhibitor, originally developed as a protein kinase C inhibitor and subsequently as an angiogenesis inhibitor, based on its inhibition of vascular endothelial growth factor receptor. Despite promising preclinical data, early clinical trials in multiple diseases showed only modest efficacy. In 1996, the relatively frequent occurrence of fms-like tyrosine kinase 3 (FLT3) activating mutations in acute myeloid leukemia (AML) was first recognized. Several years later, midostaurin was discovered to be a potent inhibitor of the FLT3 tyrosine kinase and to have activity against mutant forms of KIT proto-oncogene receptor tyrosine kinase, which drive advanced systemic mastocytosis (SM). Through a series of collaborations between industry and academia, midostaurin in combination with standard chemotherapy was evaluated in the Cancer and Leukemia Group B 10603/RATIFY study, a large, phase 3, randomized, placebo-controlled trial in patients with newly diagnosed FLT3-mutated AML. This was the first study to show significant improvements in overall survival and event-free survival with the addition of a targeted therapy to standard chemotherapy in this population. Around the same time, durable responses were also observed in other trials of midostaurin in patients with advanced SM. Collectively, these clinical data led to the approval of midostaurin by the US Food and Drug Administration and the European Medicines Agency for both newly diagnosed FLT3-mutated AML and advanced SM.

Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 98 (1) ◽  
pp. 241-243 ◽  
Author(s):  
Rolf M. Mesters ◽  
Teresa Padró ◽  
Ralf Bieker ◽  
Martin Steins ◽  
Michael Kreuter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Peripheral Blood Cell ◽  
Cell Counts ◽  
Acute Myeloid

Abstract The small molecule receptor tyrosine kinase (RTK) inhibitor SU5416 targets the vascular endothelial growth factor receptor 2 and the stem cell factor receptor c-kit. Herein is described the successful treatment of a 65-year-old woman with SU5416, in second relapse of acute myeloid leukemia (AML) and refractory toward standard chemotherapy regimens. After 12 weeks of treatment with SU5416, the blast cell counts (blood and bone marrow) decreased to undetectable levels and the peripheral blood cell counts normalized with the exception of the platelet count (50-80 × 109/L [50-80 × 103/μL]). The duration of the remission is longer than 4 months during maintenance therapy with SU5416. Microvessel density in the patient's bone marrow dropped from 33.4 to 12.3 microvessels/×500-field 8 weeks after SU5416 administration and remains in the normal range. This is the first report of a stable remission achieved after administration of the RTK inhibitor SU5416 in a patient with AML relapse.

Compassionate Use of Sorafenib in Relapsed and Refractory Flt3-ITD Positive Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2060-2060 ◽  
Author(s):  
Stephan Metzelder ◽  
Sebastian Scholl ◽  
Kröger Matthias ◽  
Andreas Reiter ◽  
Ralf G. Meyer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Side Effects ◽  
Myeloid Leukemia ◽  
Treatment Duration ◽  
Growth Factor Receptor ◽  
Compassionate Use ◽  
Median Treatment ◽  
Acute Myeloid

Abstract Abstract 2060 Poster Board II-37 Introduction: The Flt3-internal tandem duplication can be found in up to 30% of all acute myeloid leukemia (AML) patients and confers a poor risk status characterized by an increased relapse rate and poor overall survival. Moreover, Flt3-ITD-positive AML patients relapsing after allogenic stem cell transplantation (SCT) have very limited therapeutic options. Sorafenib is a multikinase inhibitor that is approved for the treatment of metastatic renal cell and hepatocellular carcinoma. Besides targeting Raf, the platelet derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR) it has also significant inhibitory activity against the Flt3 receptor tyrosine kinase, and, specifically the mutated variant of Flt3, Flt3-ITD. It has previously been shown that sorafenib monotherapy may have considerable activity in relapsed Flt3-ITD positive AML. Nevertheless, clinical experience is still limited. Here we report compassionate use experience on 18 relapsed or refractory Flt3-ITD positive AML patients treated with sorafenib monotherapy. Methods: A questionnaire was developed and sent to 28 centers in Germany in order to obtain more insight into the clinical efficacy and tolerablilty of sorafenib monotherapy in Flt3-ITD positive AML. Forms were returned from 13 centers, reporting 26 patients. Among them, eight had to be excluded from further analysis. Five of them were Flt3-ITD mutation negative and three received contemporary chemotherapy. Available patient information included age, FAB-classification, karyotype, type and response to prior therapy, sorafenib dosing, tolerability, treatment duration, and response. Results: Of the 18 patients (12 male, 6 female), five were primary refractory to induction chemotherapy and 13 received sorafenib in first (n=11) or second (n=2) relapse. Eight of 18 patients relapsed after SCT and were treated with sorafenib. One patient was treated for steadily increasing Flt3-ITD copy numbers, that is, in molecular relapse after SCT. Patients received between 200mg and 800mg sorafenib p.o. daily. The median treatment duration was 98 days (range, 16-425 days). All patients achieved a hematological response (HR) characterized by complete (n=17) or near complete peripheral blast clearance (n=2). Of the 18 patients the documented best response to sorafenib were: HR in 9 cases, bone marrow response (HR and blast reduction in marrow) in 4 cases, complete remission (normalization of peripheral blood counts and bone marrow blasts < 5%) in one case and complete molecular remission (molecular negativity for Flt3-ITD) in 4 patients. After a median treatment duration of 180 days (range, 82-270 days) 7 of the 18 (39%) patients developed clinical sorafenib resistance: two of eight (25%) of the SCT-group and 5 of 10 (50%) of the non-SCT group. Sorafenib was generally well tolerated. Pancytopenia or thrombocytopenia grade III and IV were the most significant side effects, observed in 13 patients. Other reported side effects such as diarrhea, exanthema were documented from the centers as being minor. Conclusion: Sorafenib monotherapy has significant clinical activity in Flt3-ITD positive relapsed and refractory AML and may be particularly effective in the context of allo-immunotherapy where 3 CMR could be seen. Disclosures: Enghofer: Bayer Schering Pharma: Employment. Off Label Use: sorafenib, used to treat Flt3-ITD positive AML patients.

Sorafenib Monotherapy Is Effective In Relapsed and RefractoryFlt3-ITD Positive Acute Myeloid Leukemia, Particularly After Allogenic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3314-3314 ◽  
Author(s):  
Stephan Metzelder ◽  
Anemone Finck ◽  
Martin Fey ◽  
Sebastian Scholl ◽  
Matthias Kröger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Growth Factor ◽  
Side Effects ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Growth Factor Receptor ◽  
Allogenic Stem Cell Transplantation ◽  
Acute Myeloid

Abstract Abstract 3314 Introduction: The FLT3-internal tandem duplication is the most frequent genetic aberration in normal karyotype acute myeloid leukemia (NK-AML) and associated with a poor prognosis. Patients with FLT3-ITD positive AML relapsing after allogenic stem cell transplantation (allo-SCT) have very limited therapeutic options. Sorafenib is a multikinase inhibitor, which is approved in Europe for the treatment of metastatic renal cell and hepatocellular carcinoma. It inhibits the FLT3 receptor tyrosine kinase, and, at low nanomolar concentrations also the mutated variant of FLT3, FLT3-ITD. Sorafenib also inhibits Raf, the platelet derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR). We have previously reported that sorafenib monotherapy is effective in relapsed FLT3-ITD positive AML (Metzelder et al., Blood 2009; Metzelder et al., ASH 2009, poster #2060). Here we significantly extend these compassionate use experiences by reporting on clinical response details from 39 relapsed or refractory FLT3-ITD positive AML patients treated with sorafenib monotherapy. Methods: A questionnaire was developed and sent to 60 centers in Germany, Singapore and the United States, where FLT3-ITD-positive patients had been treated with sorafenib monotherapy. 26 centers returned information on therapy details of 55 patients. These included data on age, FAB-classification, karyotype, FLT3-ITD molecular testing, type and duration of response to prior therapy and to sorafenib, sorafenib dosing and tolerability. 16 patients were excluded from further analysis because of FLT3-ITD negativity or application of chemotherapy concomitant to sorafenib. Results: There were 39 evaluable patients (20 male, 19 female), grouped into i) primary refractory patients (PR-P) (n=11), receiving one (n=5) or two cycles (n=6) of chemotherapy before commencing sorafenib, ii) relapsing patients (REL-P) (n=12) with hematological recurrence after between one and four cycles of prior chemotherapy, syngenic, or autologous SCT, and iii) patients relapsing after allogenic SCT (SCT-P) (n=16). One patient was treated first line with sorafenib. One patient was treated before and after allo-SCT. Patients received between 200mg and 800mg sorafenib p.o. daily. The median treatment duration was 71 days (range, 13 to 270) for PR-P, 76 days (range, 9 to 160 days) for REL-P, and 76 days (range, 20 to 489 days) for SCT-P. All reported patients in this cohort responded to sorafenib. In the PR-P group, there were 6 hematological remissions (HR), characterized by complete (n=4) or near complete peripheral blast clearance (n=2), 4 complete remissions (bone marrow blasts < 5% with (CR) or without (CRp) normalization of peripheral blood counts) and one complete molecular remission (CMR, molecular negativity for FLT3-ITD). Six of these 11 PR-P underwent allo-SCT after responding to sorafenib induction. In the REL-P group there was one patient with a partial blast clearance (PR), 8 HR, 2 bone marrow responses (which includes a HR) and 1 CRp. In the SCT-P group there were 3PR, 2HR, 7 BMR and 4 CMR. Notably, the median time to treatment failure due to frank clinical sorafenib resistance was 119 days for PR-P and REL-P, but was not reached in the SCT-P group. This difference was statistically significant (p-value 0.0217). Sorafenib was generally well tolerated. Pancytopenia or thrombocytopenia grade III and IV were the most significant but manageable side effects. Other reported side effects such as diarrhea, exanthema were documented from the centers as being minor. Conclusion: This analysis on a large cohort of 39 FLT3-ITD positive patients confirms our previous reports on the remarkable clinical activity of sorafenib monotherapy in FLT3-ITD positive AML. Evidence is accumulating that sorafenib may be particularly effective in the context of allo-SCT, where long-term responses were seen. Disclosures: No relevant conflicts of interest to declare.

scholarly journals ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia

Blood ◽  
2007 ◽  
Vol 109 (8) ◽  
pp. 3400-3408 ◽  
Author(s):  
Deepa B. Shankar ◽  
Junling Li ◽  
Paul Tapang ◽  
J. Owen McCall ◽  
Lori J. Pease ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Receptor Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Tumor Formation ◽  
Parp Cleavage ◽  
Receptor Tyrosine Kinase Inhibitor ◽  
Acute Myeloid

Abstract In 15% to 30% of patients with acute myeloid leukemia (AML), aberrant proliferation is a consequence of a juxtamembrane mutation in the FLT3 gene (FMS-like tyrosine kinase 3–internal tandem duplication [FLT3-ITD]), causing constitutive kinase activity. ABT-869 (a multitargeted receptor tyrosine kinase inhibitor) inhibited the phosphorylation of FLT3, STAT5, and ERK, as well as Pim-1 expression in MV-4-11 and MOLM-13 cells (IC50 approximately 1-10 nM) harboring the FLT3-ITD. ABT-869 inhibited the proliferation of these cells (IC50 = 4 and 6 nM, respectively) through the induction of apoptosis (increased sub-G0/G1 phase, caspase activation, and PARP cleavage), whereas cells harboring wild-type (wt)–FLT3 were less sensitive. In normal human blood spiked with AML cells, ABT-869 inhibited phosphorylation of FLT3 (IC50 approximately 100 nM), STAT5, and ERK, and decreased Pim-1 expression. In methylcellulose-based colony-forming assays, ABT-869 had no significant effect up to 1000 nM on normal hematopoietic progenitor cells, whereas in AML patient samples harboring both FLT3-ITD and wt-FLT3, ABT-869 inhibited colony formation (IC50 = 100 and 1000 nM, respectively). ABT-869 dose-dependently inhibited MV-4-11 and MOLM-13 flank tumor growth, prevented tumor formation, regressed established MV-4-11 xenografts, and increased survival by 20 weeks in an MV-4-11 engraftment model. In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML.

A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 986-993 ◽  
Author(s):  
Walter Fiedler ◽  
Hubert Serve ◽  
Hartmut Döhner ◽  
Michael Schwittay ◽  
Oliver G. Ottmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Dose Level ◽  
Short Duration ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Ki 67 ◽  
Acute Myeloid

AbstractFifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67+, phospho-Kit+, phospho–kinase domain–containing receptor–positive (phospho-KDR+), phospho–signal transducer and activator of transcription 5–positive (phospho-STAT5+), and phospho-Akt+ cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.

Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 54-60 ◽  
Author(s):  
Richard M. Stone ◽  
Daniel J. DeAngelo ◽  
Virginia Klimek ◽  
Ilene Galinsky ◽  
Eli Estey ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Leukemic Cells ◽  
Median Response ◽  
Activating Mutation ◽  
Blast Count ◽  
Acute Myeloid

Abstract Leukemic cells from 30% of patients with acute myeloid leukemia (AML) have an activating mutation in the FLT3 (fms-like tyrosine kinase) gene, which represents a target for drug therapy. We treated 20 patients, each with mutant FLT3 relapsed/refractory AML or high-grade myelodysplastic syndrome and not believed to be candidates for chemotherapy, with an FLT3 tyrosine kinase inhibitor, PKC412 (N-benzoylstaurosporine), at a dose of 75 mg 3 times daily by mouth. The drug was generally well tolerated, although 2 patients developed fatal pulmonary events of unclear etiology. The peripheral blast count decreased by 50% in 14 patients (70%). Seven patients (35%) experienced a greater than 2-log reduction in peripheral blast count for at least 4 weeks (median response duration, 13 weeks; range, 9-47 weeks); PKC412 reduced bone marrow blast counts by 50% in 6 patients (2 of these to &lt; 5%). FLT3 autophosphorylation was inhibited in most of the Corresponding patients, indicating in vivo target inhibition at the dose schedule used in this study. PKC412 is an oral tyrosine kinase inhibitor with clinical activity in patients with AML whose blasts have an activating mutation of FLT3, suggesting potential use in combination with active agents, such as chemotherapy.

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