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Frontiers in Pharmacology 2024FLT3 mutations are closely associated with the occurrence of hematological and solid malignancies, especially with acute myeloid leukemia. Currently, several FLT3...
FLT3 mutations are closely associated with the occurrence of hematological and solid malignancies, especially with acute myeloid leukemia. Currently, several FLT3 inhibitors are in clinical trials, and some have been applied in clinic. However, the safety, efficacy and pharmacodynamics of these FLT3 inhibitors have not been systemically analyzed before. We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023. Our results showed the most common adverse events (AEs) were gastrointestinal adverse reactions, including diarrhea, hand-foot syndrome and nausea, while the most common hematological AEs were febrile neutropenia, anemia, and thrombocytopenia. Based on the published data, the mean overall survival (OS) and the mean progression-free survival (PFS) were 9.639 and 5.905 months, respectively. The incidence of overall response rate (ORR), complete remission (CR), partial response (PR), and stable disease (SD) for all these FLT3 inhibitors was 29.0%, 8.7%, 16.0%, and 42.3%, respectively. The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration () in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life () range was highly variable, from 6.8 to 151.8 h. FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication.
PubMed: 38828446
DOI: 10.3389/fphar.2024.1294668 -
The Lancet. Haematology May 2022On the basis of improved overall survival, treatment guidelines strongly recommend antifungal prophylaxis during remission induction chemotherapy for patients with acute... (Review)
Review
Antifungal prophylaxis in adult patients with acute myeloid leukaemia treated with novel targeted therapies: a systematic review and expert consensus recommendation from the European Hematology Association.
On the basis of improved overall survival, treatment guidelines strongly recommend antifungal prophylaxis during remission induction chemotherapy for patients with acute myeloid leukaemia. Many novel targeted agents are metabolised by cytochrome P450, but potential drug-drug interactions (DDIs) and the resulting risk-benefit ratio have not been assessed in clinical trials, leading to uncertainty in clinical management. Consequently, the European Haematology Association commissioned experts in the field of infectious diseases, haematology, oncology, clinical pharmacology, and methodology to develop up-to-date recommendations on the role of antifungal prophylaxis and management of pharmacokinetic DDIs with triazole antifungals. A systematic literature review was performed according to Cochrane methods, and recommendations were developed by use of the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework. We searched MEDLINE, Embase, and Cochrane Library, including Central Register of Controlled Trials, for randomised controlled trials and systematic reviews published from inception to March 10, 2020. We excluded studies that were not published in English. Evidence for any identified novel agent that is active against acute myeloid leukaemia was reviewed for the following outcomes: incidence of invasive fungal disease, prolongation of hospitalisation, days spent in intensive-care unit, mortality due to invasive fungal disease, quality of life, and potential DDIs. Recommendations and consensus statements were compiled for each targeted drug for patients with acute myeloid leukaemia and each specific setting. Evidence-based recommendations were developed for hypomethylating agents, midostaurin, and the venetoclax-hypomethylating agent combination. For all other agents, consensus statements were given for specific therapeutic settings, specifically for the management of patients with relapsed or refractory acute myeloid leukaemia, monotherapy, and combination with chemotherapy. Antifungal prophylaxis is recommended with moderate strength in most settings, and strongly recommended if the novel acute myeloid leukaemia agent is administered in combination with intensive induction chemotherapy. For ivosidenib, lestaurtinib, quizartinib, and venetoclax, we moderately recommend adjusting the dose of the antileukaemic agent during administration of triazoles. This is the first guidance supporting clinical decision making on antifungal prophylaxis in recipients of novel targeted drugs for acute myeloid leukaemia. Future studies including therapeutic drug monitoring will need to determine the role of dosage adjustment of novel antileukaemic drugs during concomitant administration of CYP3A4-inhibiting antifungals with respect to adverse effects and remission status.
Topics: Adult; Antifungal Agents; Hematology; Humans; Leukemia, Myeloid, Acute; Mycoses; Quality of Life; Triazoles
PubMed: 35483397
DOI: 10.1016/S2352-3026(22)00073-4 -
American Journal of Therapeutics
Meta-Analysis
Topics: Humans; Mastocytosis, Systemic; Staurosporine; Antineoplastic Agents
PubMed: 35446286
DOI: 10.1097/MJT.0000000000001508 -
Future Oncology (London, England) Apr 2022This research aimed to compare the relative efficacy of avapritinib versus midostaurin for patients with advanced systemic mastocytosis. A systematic literature review...
This research aimed to compare the relative efficacy of avapritinib versus midostaurin for patients with advanced systemic mastocytosis. A systematic literature review was performed to identify relevant evidence. Unanchored matching-adjusted indirect comparisons were conducted for overall survival (OS), overall response rate (ORR) and complete remission (CR). The systematic literature review identified the clinical trials EXPLORER and PATHFINDER (investigating avapritinib) and D2201 and A2213 (investigating midostaurin). The avapritinib versus midostaurin adjusted hazard ratio for OS was 0.44 (95% CI: 0.25-0.76), and the adjusted odds ratios for ORR and CR were 4.06 (95% CI: 3.09-5.33) and 9.56 (95% CI: 0.97-93.81), respectively. The results suggest that avapritinib improves survival and response (ORR and CR) compared with midostaurin.
Topics: Humans; Mastocytosis, Systemic; Pyrazoles; Pyrroles; Staurosporine; Triazines
PubMed: 35114819
DOI: 10.2217/fon-2021-1509 -
Expert Opinion on Emerging Drugs Mar 2022The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with Acute Myeloid Leukemia (AML). Midostaurin, quizartinib, and gilteritinib have been...
INTRODUCTION
The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with Acute Myeloid Leukemia (AML). Midostaurin, quizartinib, and gilteritinib have been approved in the last years for the treatment of AML, and more Tyrosine Kinase Inhibitors (TKIs) targeting FLT3 are being developed such as crenolanib.
AREAS COVERED
In this systematic review, we will analyze the available clinical data on FLT3 inhibitors in development and describe the potential role that these FLT3-TKIs may play in the future management of FLT3-mutated (FLT3mut) AML.
EXPERT OPINION
Although several aspects may challenge the use of FLT3 inhibitors in AML (resistance mechanisms, on- and off-target toxicities or drug-drug interactions), these drugs are generally well tolerated, particularly if we compare their safety profile with classical chemotherapy agents or even with newer immunotherapies, thus enabling their use in fit and unfit AML patients, alone or combined. As AML is a polyclonal disease and FLT3 mutations are a late leukemogenic event, combinations of these FLT3 inhibitors with other antileukemic agents (like venetoclax or hypomethylating agents) seem a necessary research pathway.
Topics: Antineoplastic Agents; Humans; Leukemia, Myeloid, Acute; Mutation; Protein Kinase Inhibitors; fms-Like Tyrosine Kinase 3
PubMed: 35076348
DOI: 10.1080/14728214.2021.2009800 -
Acta Oncologica (Stockholm, Sweden) Oct 2021For patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) for acute myeloid leukemia (AML), disease relapse remains the most common reason for... (Meta-Analysis)
Meta-Analysis
BACKGROUND
For patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) for acute myeloid leukemia (AML), disease relapse remains the most common reason for transplant failure and patient death. Recent randomized controlled trials (RCTs) have aimed to reduce the risk of relapse by means of post-transplant maintenance therapy.
METHODS
We performed a systematic review and meta-analysis of RCTs comparing the efficacy and safety of maintenance with observation or placebo in patients with AML after allogeneic HSCT. We searched Cochrane Library, PubMed and conference proceedings up to Febuary 2021.
RESULTS
Our search yielded five trials including 736 patients. Maintenance therapy consisted of tyrosine kinase inhibitors (TKIs) in 3 studies (sorafenib 2 studies; midostaurin 1 study) and hypomethylating agents (HMAs) in 2 studies (decitabine and azacytidine 1 study each). Maintenance therapy was associated with an improved overall survival (OS), HR = 0.61 (95% CI 0.47-0.80). Subgroup analysis revealed advantage in OS with either TKI or HMA maintenance. Relapse free survival (RFS) was also improved in the maintenance arm compared with the control arm HR = 0.51(95% CI 0.40 - 0.66). There was no difference between the two arms in overall grade 3/4 adverse events or overall infections, in grade 3/4 infections, or in acute and chronic graft versus host disease.
CONCLUSIONS
Our meta-analysis shows that post-transplant maintenance therapy in AML patients is effective in improving RFS and OS, with a satisfactory safety profile.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Recurrence; Sorafenib
PubMed: 34325602
DOI: 10.1080/0284186X.2021.1955969 -
Frontiers in Immunology 2021This analysis aimed to systematically review and synthesize the existing evidence regarding the outcome of tyrosine kinase inhibitor (TKI) maintenance therapy after... (Meta-Analysis)
Meta-Analysis
This analysis aimed to systematically review and synthesize the existing evidence regarding the outcome of tyrosine kinase inhibitor (TKI) maintenance therapy after allogeneic stem-cell transplantation for patients with -ITD-mutated acute myeloid leukemia (AML). We searched publicly available databases, references lists of relevant reviews, registered trials, and relevant conference proceedings. A total of 7 studies comprising 680 patients were included. Five studies evaluated sorafenib and 2 studies evaluated midostaurin, compared with control. The incidence of relapse was significantly reduced after TKI therapy, showing an overall pooled risk ratio (RR) of 0.35 (95% confidence interval [CI], 0.23-0.51; < 0.001), with a marked 65% reduced risk for relapse. The overall pooled RR for relapse-free survival and overall survival showed significantly improved outcome after TKI maintenance therapy, being 0.48 (95% CI, 0.37-0.61; < 0.001) and 0.48 (95% CI, 0.36-0.64; < 0.001). The risk for relapse or death from any cause was reduced by 52% using TKI. No difference in outcome was seen for non-relapse mortality, and the risk for chronic or acute graft-vs. -host disease appeared to be increased, at least for sorafenib. In conclusion, post-transplant maintenance therapy with TKI was associated with significantly improved outcome in relapse and survival in patients with -ITD positive AML.
Topics: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Mutation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Recurrence; fms-Like Tyrosine Kinase 3
PubMed: 33790903
DOI: 10.3389/fimmu.2021.630429 -
Systematic Reviews Dec 2020FMS-like tyrosine kinase 3 (FLT3) is the most frequent mutation in AML. With two FLT3 inhibitors recently approved by the FDA (midostaurin and gilteritinib), there is a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
FMS-like tyrosine kinase 3 (FLT3) is the most frequent mutation in AML. With two FLT3 inhibitors recently approved by the FDA (midostaurin and gilteritinib), there is a need to evaluate these targeted agents.
PURPOSE
To assess the clinical effectiveness of FLT3 inhibitors in AML patients.
METHODS
Standard systematic review methods were utilised. Searches were conducted to July 2020 for completed and in-progress randomised controlled trials of FLT3 inhibitors in AML. A fixed-effect meta-analysis was undertaken.
RESULTS
Eight completed trials involving 2656 patients and assessing five different FLT3 inhibitors (sorafenib, lestaurtinib, midostaurin, gilteritinib and quizartinib) were included. The pooled results were as follows (FLT3 inhibitor/control): overall survival hazard ratio (HR) = 0.83 (95% confidence interval [CI] 0.75 to 0.92, p = 0.0005), event-free survival HR = 0.85 (95% CI 0.77 to 0.94, p = 0.002), relapse-free survival HR = 0.76 (95% CI 0.64 to 0.90, p = 0.001), complete remission relative risk (RR) = 1.11 (95% CI 1.00 to 1.22. p = 0.05) and 60-day mortality RR = 1.04 (95% CI 0.77 to 1.40, p = 0.79). Relative risk of grade 3 and above vascular, dermatological, respiratory and hepatobiliary adverse events were found to be statistically significantly higher in the FLT3 inhibitor group compared to control, but the actual numbers of events were relatively small. Nineteen ongoing trials are still in progress, only one of which specifically targets older patients with AML.
CONCLUSIONS
There is evidence to support the use of FLT3 inhibitors in patients with AML, but more data is needed to verify the optimum use of the drugs regarding type of inhibitor, disease stage and patient characteristics, not only in relation to disease control, but adverse events and quality of life. There are a large number of ongoing trials; therefore, the results of this review are not a fait accompli; thus, is it recommended that the review be updated in a couple of years' time. Given the challenges in extracting the complete data set required to assess clinical effectiveness, it is highly recommended that ongoing and future trials improve transparency and consistency of reporting of all trial outcomes, particularly disease control and adverse events, to enable a global clinical effectiveness assessment.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42017055581.
Topics: Humans; Leukemia, Myeloid, Acute; Neoplasm Recurrence, Local; Quality of Life; Treatment Outcome; fms-Like Tyrosine Kinase 3
PubMed: 33287892
DOI: 10.1186/s13643-020-01540-1 -
Hematology (Amsterdam, Netherlands) Oct 2018E26 transformation-specific variant 6 gene (ETV6) is one of the most consistently rearranged genes in acute leukaemia. It encodes a principal hematopoietic transcription... (Review)
Review
OBJECTIVES
E26 transformation-specific variant 6 gene (ETV6) is one of the most consistently rearranged genes in acute leukaemia. It encodes a principal hematopoietic transcription factor.
METHODS
We performed a systematic review focusing on the mechanisms responsible for etv6 acquisition, and its effect on the development of AML. We also review the Characteristics of ETV6 mutations and its fusion genes. Finally, for using ETV6 as a molecular target, we discuss future therapeutic approaches available to mitigate the associated disease.
RESULTS
ETV6 rearrangements often accompany other molecular mutations. Thirty-three distinct partner bands of ETV6 that contain various fusion genes were detected which plays a vital role in obtaining information about leukaemia genesis. RXDX-101 and PKC412 were reported to be inhibitors of ETV6-NTRK3.
DISCUSSION
Future researches are needed to explain how ETV6 mutations act within the microenvironment of leukemic cells and how it affects the progression of leukaemia.
Topics: Benzamides; Gene Rearrangement; Humans; Indazoles; Leukemia, Myeloid, Acute; Mutation; Oncogene Proteins, Fusion; Proto-Oncogene Proteins c-ets; Repressor Proteins; Staurosporine; Tumor Microenvironment; ETS Translocation Variant 6 Protein
PubMed: 29894279
DOI: 10.1080/10245332.2018.1482051