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Leukemia & Lymphoma Jul 2024
High remission rates and transition to allogeneic transplant in older patients with newly diagnosed FLT-3 mutated acute myelogenous leukemia with midostaurin plus intensive chemotherapy.
Topics: Humans; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3; Aged; Hematopoietic Stem Cell Transplantation; Mutation; Staurosporine; Antineoplastic Combined Chemotherapy Protocols; Remission Induction; Male; Transplantation, Homologous; Female; Middle Aged; Treatment Outcome
PubMed: 38635368
DOI: 10.1080/10428194.2024.2332506 -
Cancer Chemotherapy and Pharmacology Mar 2024
Correction to: Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.
PubMed: 38438807
DOI: 10.1007/s00280-024-04657-5 -
Scientific Reports May 2024Chronic Heart Failure (CHF) is a significant global public health issue, with high mortality and morbidity rates and associated costs. Disease modules, which are...
Chronic Heart Failure (CHF) is a significant global public health issue, with high mortality and morbidity rates and associated costs. Disease modules, which are collections of disease-related genes, offer an effective approach to understanding diseases from a biological network perspective. We employed the multi-Steiner tree algorithm within the NeDRex platform to extract CHF disease modules, and subsequently utilized the Trustrank algorithm to rank potential drugs for repurposing. The constructed disease module was then used to investigate the mechanism by which Panax ginseng ameliorates CHF. The active constituents of Panax ginseng were identified through a comprehensive review of the TCMSP database and relevant literature. The Swiss target prediction database was utilized to determine the action targets of these components. These targets were then cross-referenced with the CHF disease module in the STRING database to establish protein-protein interaction (PPI) relationships. Potential action pathways were uncovered through Gene Ontology (GO) and KEGG pathway enrichment analyses on the DAVID platform. Molecular docking, the determination of the interaction of biological macromolecules with their ligands, and visualization were conducted using Autodock Vina, PLIP, and PyMOL, respectively. The findings suggest that drugs such as dasatinib and mitoxantrone, which have low docking scores with key disease proteins and are reported in the literature as effective against CHF, could be promising. Key components of Panax ginseng, including ginsenoside rh4 and ginsenoside rg5, may exert their effects by targeting key proteins such as AKT1, TNF, NFKB1, among others, thereby influencing the PI3K-Akt and calcium signaling pathways. In conclusion, drugs like dasatinib and midostaurin may be suitable for CHF treatment, and Panax ginseng could potentially mitigate the progression of CHF through a multi-component-multi-target-multi-pathway approach. Disease module analysis emerges as an effective strategy for exploring drug repurposing and the mechanisms of traditional Chinese medicine in disease treatment.
Topics: Panax; Heart Failure; Humans; Drug Repositioning; Molecular Docking Simulation; Protein Interaction Maps; Signal Transduction; Chronic Disease; Ginsenosides; Drugs, Chinese Herbal
PubMed: 38802411
DOI: 10.1038/s41598-024-61926-2 -
Pathology Jun 2024Early induction response assessment with day-21 bone marrow (D21-BM) is commonly performed in patients with FLT3-mutated acute myeloid leukaemia (AML), where detection...
Day-21 bone marrow findings incorrectly designate residual leukaemia in FLT3-mutated acute myeloid leukaemia treated with intensive induction plus midostaurin: a morphology-focused study.
Early induction response assessment with day-21 bone marrow (D21-BM) is commonly performed in patients with FLT3-mutated acute myeloid leukaemia (AML), where detection of residual leukaemia (RL; blasts ≥5%) typically results in the administration of a second induction course. However, whether D21-BM results predict for RL at the end of first induction has not been systematically assessed. This study evaluates the predictive role of D21-BM morphology in detecting RL following first induction. Between August 2018 and March 2022, all patients with FLT3-AML receiving 7+3 plus midostaurin, with D21-BM performed, were identified. Correlation between D21-BM morphology vs D21-BM ancillary flow/molecular results, as well as vs D28-BM end of first induction response, were retrospectively reviewed. Subsequently, D21-BMs were subjected to anonymised morphological re-assessments by independent haematopathologists (total in triplicate per patient). Of nine patients included in this study, three (33%) were designated to have RL at D21-BM, all of whom entered complete remission at D28-BM. Furthermore, only low-level measurable residual disease was detected in all three cases by flow or molecular methods at D21-BM, hence none proceeded to a second induction. Independent re-evaluations of these cases failed to correctly reassign D21-BM responses, yielding a final false positive rate of 33%. In summary, based on morphology alone, D21-BM assessment following 7+3 intensive induction plus midostaurin for FLT3-AML incorrectly designates RL in some patients; thus correlating with associated flow and molecular results is essential before concluding RL following first induction. Where remission status is unclear, repeat D28-BMs should be performed.
Topics: Humans; Staurosporine; fms-Like Tyrosine Kinase 3; Leukemia, Myeloid, Acute; Male; Female; Middle Aged; Adult; Retrospective Studies; Neoplasm, Residual; Bone Marrow; Aged; Mutation; Antineoplastic Combined Chemotherapy Protocols; Remission Induction
PubMed: 38580614
DOI: 10.1016/j.pathol.2024.01.004 -
Haematologica Oct 2023
Topics: Humans; Gemtuzumab; Czech Republic; Leukemia, Myeloid, Acute; Staurosporine; fms-Like Tyrosine Kinase 3
PubMed: 36815379
DOI: 10.3324/haematol.2022.282263 -
Cureus May 2024We present a case of an adult male who presented with pancytopenia accompanied by symptomatic anemia, necessitating chronic transfusions. He was diagnosed with systemic...
We present a case of an adult male who presented with pancytopenia accompanied by symptomatic anemia, necessitating chronic transfusions. He was diagnosed with systemic mastocytosis with an associated hematologic neoplasm. Following an inadequate response to midostaurin therapy, the patient was initiated on the newly approved avapritinib. The patient showed significant improvements in all three blood cell lines; however, he developed leg edema, blepharedema, and gum bleeding on this medication. This case underscores the intricacies of managing a patient with advanced systemic mastocytosis, the emerging role of highly selective KIT inhibition in its treatment, and the practical management of adverse medication effects.
PubMed: 38868249
DOI: 10.7759/cureus.60161 -
ChemMedChem Jan 2024FLT3 is mainly expressed in immune and various cancer cells and is a drug target for acute myeloid leukemia (AML). Recently, FLT3 has also been identified as a potential...
FLT3 is mainly expressed in immune and various cancer cells and is a drug target for acute myeloid leukemia (AML). Recently, FLT3 has also been identified as a potential target for treating chronic pain. Most FLT3 inhibitors (FLT3i) identified to date, including approved drugs such as gilteritinib, midostaurin, ponatinib, quizartinib, and FLT3i in clinical trials, such as quizartinib and crenolanib, also inhibit closely-related kinases that are important for immune (c-KIT), cardiovascular (KDR/VEGFR2, FGFR, PDGFR) or kidney (RET) functions. While the aforementioned FLT3i may increase survival rates in AML, they are neither ideal for AML maintenance therapy nor for non-oncology applications, such as for the treatment of chronic pain, due to their promiscuous inhibition of many kinase anti-targets. Here, we report the identification of new FLT3i compounds that have low activities against kinases that have traditionally been difficult to differentiate from FLT3 inhibition, such as KDR/VEGFR, FGFR, PGFR, c-KIT, and RET. These selective compounds could be valuable chemical probes for studying FLT3 biology in the context of chronic pain and/or may represent good starting points to develop well-tolerated FLT3 therapeutics for non-oncology indications or for maintenance therapy for AML.
Topics: Humans; Antineoplastic Agents; Chronic Pain; Mutation; Protein Kinase Inhibitors; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3; Proto-Oncogene Proteins c-ret
PubMed: 37971283
DOI: 10.1002/cmdc.202300442 -
Case Reports in Hematology 2024Systemic mastocytosis is defined by the clonal proliferation of abnormal mast cells. The clinical course can range from indolent forms with normal life expectancy to...
Systemic mastocytosis is defined by the clonal proliferation of abnormal mast cells. The clinical course can range from indolent forms with normal life expectancy to advanced mast cell leukemia with dismal prognosis. An association with other diseases, including myeloproliferative neoplasia, has been described. We present a case of a 75-year patient with a history of cutaneous mastocytosis who was diagnosed with mast cell leukemia more than 9 years ago and did not receive treatment. The patient presented to our clinic with acute kidney failure because of renal extramedullary hematopoiesis. Bone marrow histopathology revealed extensive fibrosis and 50% infiltration by mast cells with a c D816V mutation. No mutations supporting primary myelofibrosis were identified. Treatment with midostaurin was started, and the patient was discharged after improvement of renal function. Here, we discuss diagnostic challenges between different forms of mast cell leukemia and overlaps with other hematological malignancies.
PubMed: 38213502
DOI: 10.1155/2024/3502887 -
Frontiers in Pharmacology 2024Acute myeloid leukemia (AML) is a malignancy in the myeloid lineage that is characterized by symptoms like fatigue, bleeding, infections, or anemia, and it can be fatal...
Acute myeloid leukemia (AML) is a malignancy in the myeloid lineage that is characterized by symptoms like fatigue, bleeding, infections, or anemia, and it can be fatal if untreated. In AML, mutations in tyrosine kinases (TKs) lead to enhanced tumor cell survival. The most frequent mutations in TKs are reported in -like tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), and KIT (tyrosine-protein kinase KIT), making these TKs potential targets for TK inhibitor (TKI) therapies in AML. With 30% of the mutations in TKs, mutated FLT3 is associated with poor overall survival and an increased chance of resistance to therapy. FLT3 inhibitors are used in FLT3-mutant AML, and the combination with hypomethylating agents displayed promising results. Midostaurin (MDS) is the first targeted therapy in FLT3-mutant AML, and its combination with chemotherapy showed good results. However, chemotherapies induce several side effects, and an alternative to chemotherapy might be the use of nanoparticles for better drug delivery, improved bioavailability, reduced drug resistance and induced toxicity. The herein study presents MDS-loaded gold nanoparticles and compares its efficacy with MDS alone, on both and models, using the FLT3-ITD-mutated AML cell line transfected to express luciferin. Our preclinical study suggests that MDS-loaded nanoparticles have a better tumor inhibitory effect than free drugs on models by controlling tumor growth in the first half of the treatment, while in the second part of the therapy, the tumor size was comparable to the cohort that was treatment-free.
PubMed: 38799169
DOI: 10.3389/fphar.2024.1382399 -
Annals of Hematology Mar 2024
Topics: Humans; Staurosporine; Protein Kinase Inhibitors; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3; Mutation
PubMed: 38195923
DOI: 10.1007/s00277-024-05614-1