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Clinical and Translational Science Oct 2023Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes...
Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real-life study to evaluate (i) how often concerns around PCZ-midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ-midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ-midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (C ) was greater than three times higher than reported; moreover, midostaurin C , maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient.
Topics: Humans; Antifungal Agents; Micafungin; Prospective Studies; Leukemia, Myeloid, Acute; Neutropenia; fms-Like Tyrosine Kinase 3
PubMed: 37515369
DOI: 10.1111/cts.13595 -
Leukemia & Lymphoma 2023Real-world US healthcare resource utilization (HRU) and costs during first salvage therapy for relapsed/refractory (R/R) acute myeloid leukemia (AML) are described using...
Real-world US healthcare resource utilization (HRU) and costs during first salvage therapy for relapsed/refractory (R/R) acute myeloid leukemia (AML) are described using IBM MarketScan® data (1/1/2007-6/30/2020). Treatments included high- (HIC) and low-intensity chemotherapy (LIC) alone, and gilteritinib, other FLT3 tyrosine kinase inhibitors (TKIs), and venetoclax with or without chemotherapy. Patients were diagnosed with R/R AML at ≥18 years of age between 1/1/2017-12/31/2019. Patient monthly all-cause HRU and costs were analyzed using a fixed-effects model. Data from 399 patients were analyzed (HIC, = 104; LIC, = 133; gilteritinib, = 14; other FLT3 TKIs, = 68; venetoclax, = 80). Inpatient HRU was generally highest with HIC, whereas outpatient HRU was generally highest with LIC and venetoclax. Total all-cause incremental monthly costs appeared to be highest with HIC ($171,982) and similar for LIC ($60,512), gilteritinib ($47,218), other FLT3 TKIs ($43,218), and venetoclax ($77,566). Results highlight HRU and cost differences for R/R AML during first salvage therapy.
Topics: Humans; United States; Salvage Therapy; Patient Acceptance of Health Care; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3; Mutation
PubMed: 37486091
DOI: 10.1080/10428194.2023.2235044 -
Journal of Cancer 2023Acute myeloid leukemia (AML) is a devastating blood cancer with high heterogeneity and ill-fated outcome. Despite numerous advances in AML treatment, the prognosis...
Acute myeloid leukemia (AML) is a devastating blood cancer with high heterogeneity and ill-fated outcome. Despite numerous advances in AML treatment, the prognosis remains poor for a significant proportion of patients. Consequently, it is necessary to accurately and comprehensively identify biomarkers as soon as possible to enhance the efficacy of diagnosis, prognosis and treatment of AML. In this study, we aimed to identify prognostic markers of AML by analyzing the cohorts from TCGA-LAML database and GEO microarray datasets. Interestingly, the transcriptional level of microtubule-associated protein TBCB in AML patients was noticeably increased when compared with normal individuals, and this was verified in two independent cohorts (GSE9476 and GSE13159) and with our AML patients. Furthermore, univariate and multivariate regression analysis revealed that high expression was an independent poor prognostic factor for AML. GO and GSEA enrichment analysis hinted that immune-related signaling pathways were enriched in up-regulated DEGs between two populations separated by the median expression level of . By constructing a protein-protein interaction network, we obtained six hub genes, all of which are immune-related molecules, and their expression levels were positively linked to that of . In addition, the high expression of three hub genes was significantly associated with a poor prognosis in AML. Moreover, we found that the tumor microenvironment in AML with high expression tended to be infiltrated by NK cells, especially CD56 NK cells. The transcriptional levels of NK cell inhibitory receptors and their ligands were positively related to that of , and their high expression levels also predicted poor prognosis in AML. Notably, we found that the down-regulation of TBCB suppressed cell proliferation in AML cell lines by enhancing the apoptosis and cell cycle arrest. Finally, drug sensitivity prediction illustrated that cells with high expression were more responsive to ATRA and midostaurin but resistant to cytarabine, dasatinib, and imatinib. In conclusion, our findings shed light on the feasibility of as a potential predictor of poor outcome and to be an alternative target of treatment in AML.
PubMed: 37476188
DOI: 10.7150/jca.84215 -
Clinical Case Reports Jul 2023Aggressive SM + AML has limited therapeutic options. Even a strong combination of decitabine-venetoclax-midostaurin has a transient effect on AML and a mitigated...
Aggressive SM + AML has limited therapeutic options. Even a strong combination of decitabine-venetoclax-midostaurin has a transient effect on AML and a mitigated effect on SM. Larger series are required to identify the best therapeutic strategy.
PubMed: 37469366
DOI: 10.1002/ccr3.7134 -
Cancer Drug Resistance (Alhambra,... 2023FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected... (Review)
Review
FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1 and 2 generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).
PubMed: 37457126
DOI: 10.20517/cdr.2022.130 -
BMC Chemistry Jul 2023Fms-like tyrosine kinase 3 (FLT3) mutation mechanisms are among the most common genetic abnormalities detected in about 30% of acute myeloid leukemia (AML) patients.... (Review)
Review
Fms-like tyrosine kinase 3 (FLT3) mutation mechanisms are among the most common genetic abnormalities detected in about 30% of acute myeloid leukemia (AML) patients. These mutations are accompanied by poor clinical response, although all these progressions in identifying and interpreting biological AML bio-targets. Several small structured FLT3 inhibitors have been ameliorated to struggle against AML. Despite all these developments regarding these inhibitors, the Overall survival rate is about five years or more in less than one-third of diagnosed AML patients. Midostaurin was the first FDA-approved FLT3 inhibitor in 2017 in the United States and Europe for AML remedy. Next, Gilteritinib was an FDA-approved FLT3 inhibitor in 2018 and in the next year, Quizartinib was approved an as FLT3 inhibitor in Japan. Interestingly, indole-based motifs had risen as advantaged scaffolds with unusual multiple kinase inhibitory activity. This review summarises indole-based FLT3 inhibitors and related scaffolds, including FDA-approved drugs, clinical candidates, and other bioactive compounds. Furthermore, their chemotypes, mechanism of action, and interaction mode over both wild and mutated FLT3 target proteins had been judgmentally discussed. Therefore, this review could offer inspiring future perspectives into the finding of new FLT3-related AML therapies.
PubMed: 37438819
DOI: 10.1186/s13065-023-00981-8 -
International Journal of Dermatology... Jun 2023Mastocytosis, a clonal proliferation of mast cells commonly involving the skin and bone marrow, has a varied clinical presentation ranging from cutaneous lesions to...
UNLABELLED
Mastocytosis, a clonal proliferation of mast cells commonly involving the skin and bone marrow, has a varied clinical presentation ranging from cutaneous lesions to systemic disease. Cutaneous mastocytosis is managed symptomatically, but systemic mastocytosis is treated with targeted therapy against the mutated receptor tyrosine kinase c-KIT, the pathogenic driver of mastocytosis. However, there are no guidelines for the treatment of cutaneous mastocytosis refractory to symptomatic management. We herein report a method to select genetically informed therapy for symptomatic and recalcitrant cutaneous mastocytosis.
CASE PRESENTATION
We performed a mutational analysis of dermal mast cells after enrichment by laser capture in a 23-year-old woman with recalcitrant cutaneous mastocytosis. The analysis revealed a aspartic acid to valine substitution at codon 816 (D816V) mutation in the protein c-KIT. Based on these results, we initiated treatment with the multi-kinase/KIT inhibitor midostaurin, a treatment effective against the D816V c-KIT mutation. After 3 months of treatment, the patient exhibited a reduction in the number and size of cutaneous lesions and reported resolution of pruritus and decreased severity of other mast cell-related symptoms.
DISCUSSION
The treatment of mastocytosis relies heavily on whether the disease is limited to the skin or systemic. However, there are no guidelines for cutaneous mastocytosis that does not respond to symptomatic management. In the present report describing a patient with recalcitrant cutaneous mastocytosis, we describe a strategy in which skin mutational analysis is used to guide the selection of targeted therapy.
CONCLUSION
Performing mast cell mutational analyses in the skin provides a means to select targeted therapy for symptomatic and refractory cutaneous mastocytosis.
PubMed: 37396019
DOI: 10.1097/JD9.0000000000000243 -
Biomedicine & Pharmacotherapy =... Sep 2023Acute myeloid leukemia (AML) is a prevalent form of leukemia in adults. As its survival rate is low, there is an urgent need for new therapeutic options. In AML,...
Acute myeloid leukemia (AML) is a prevalent form of leukemia in adults. As its survival rate is low, there is an urgent need for new therapeutic options. In AML, FMS-like tyrosine kinase 3 (FLT3) mutations are common and have negative outcomes. However, current FLT3-targeting agents, Midostaurin and Gilteritinib, face two significant issues, specifically the emergence of acquired resistance and drug-related adverse events leading to treatment failure. Rearranged during transfection (RET), meanwhile, is a proto-oncogene linked to various types of cancer, but its role in AML has been limited. A previous study showed that activation of RET kinase enhances FLT3 protein stability, leading to the promotion of AML cell proliferation. However, no drugs are currently available that target both FLT3 and RET. This study introduces PLM-101, a new therapeutic option derived from the traditional Chinese medicine indigo naturalis with potent in vitro and in vivo anti-leukemic activities. PLM-101 potently inhibits FLT3 kinase and induces its autophagic degradation via RET inhibition, providing a superior mechanism to that of FLT3 single-targeting agents. Single- and repeated-dose toxicity tests conducted in the present study showed no significant drug-related adverse effects. This study is the first to present a new FLT3/RET dual-targeting inhibitor, PLM-101, that shows potent anti-leukemic activity and fewer adverse effects. PLM-101, therefore, should be considered for use as a potential therapeutic agent for AML.
Topics: Adult; Humans; fms-Like Tyrosine Kinase 3; Leukemia, Myeloid, Acute; Protein Kinase Inhibitors; Mutation; Proto-Oncogene Proteins c-ret
PubMed: 37392657
DOI: 10.1016/j.biopha.2023.115066 -
Expert Opinion on Pharmacotherapy 2023Over the last few years, substantial progress has been made in the management of acute myeloid leukemia (AML). The first changes in the management of AML date back to...
INTRODUCTION
Over the last few years, substantial progress has been made in the management of acute myeloid leukemia (AML). The first changes in the management of AML date back to last 2000s with the advent of hypometilant agents, later with Bcl2 inhibitor venetoclax, and Fms-like tyrosine kinase 3 (FLT3) inhibitors (midostaurin and gilteritinib), and more recently with IDH1/2 inhibitors (ivosidenib and enasidenib) and the hedgehog (HH) pathway inhibitor glasdegib.
AREAS COVERED
Glasdegid, formerly PF-04449913 or PF-913, acts as a smoothened (SMO) inhibitor and has been recently approved in combination with low-dose cytarabine (LDAC) by FDA and EMA for the treatment of naïve AML patients unfit for intensive chemotherapy.Several studies have explored the efficacy and safety of glasdegib, as a single agent or in combination with other drugs, in both the setting of relapsed/refractory and naïve AML patients, confirming its efficacy in controlling disease and safety profile.
EXPERT OPINION
All these trials suggest that glasdegib seems to be an ideal partner for both classic chemotherapy and biological treatments (such as therapy with FLT3 inhibitors). Further studies are needed to better understand which patients are more likely to respond to glasdegib.
Topics: Humans; Hedgehog Proteins; Leukemia, Myeloid, Acute; Benzimidazoles; Phenylurea Compounds; Antineoplastic Agents
PubMed: 37392098
DOI: 10.1080/14656566.2023.2232301