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Trials Sep 2023About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile.
METHODS
In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m bidaily day one to day three, mitoxantrone 10mg/m days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument.
CONCLUSION
Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety.
ETHICS AND DISSEMINATION
Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.
Topics: Humans; Mitoxantrone; Leukemia, Myeloid, Acute; Phenylurea Compounds; Chronic Disease; Cytarabine; fms-Like Tyrosine Kinase 3
PubMed: 37715270
DOI: 10.1186/s13063-023-07421-x -
Blood Cancer Journal Sep 2023FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive... (Review)
Review
FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course. While two large, randomized clinical trials have shown a survival benefit with the frontline use of an oral FLT3 inhibitor (midostaurin or quizartinib) in patients with FLT3-mutated AML, the role of FLT3 inhibitors in older adults with newly diagnosed FLT3-mutated AML remains unclear. A definitive improvement in survival has not been observed in intensively treated patients over 60 years of age receiving frontline FLT3 inhibitors. Furthermore, many patients with FLT3-mutated AML are unsuitable for intensive chemotherapy due to age and/or comorbidities, and this population represents a particular unmet need. For these older patients who are unfit for intensive approaches, azacitidine + venetoclax is a new standard of care and is used by many clinicians irrespective of FLT3 mutation status. However, FLT3-ITD mutations confer resistance to venetoclax and are a well-established mechanism of relapse to lower-intensity venetoclax-based regimens, leading to short durations of remission and poor survival. Preclinical and clinical data suggest synergy between FLT3 inhibitors and venetoclax, providing rationale for their combination. Novel strategies to safely incorporate FLT3 inhibitors into the standard hypomethylating agent + venetoclax backbone are now being explored in this older, less fit population with newly diagnosed FLT3-mutated AML, with encouraging early results. Herein, we discuss the frontline use of FLT3 inhibitors in older adults with FLT3-mutated AML, including the potential role of FLT3 inhibitors in combination with intensive chemotherapy and as part of novel, lower-intensity doublet and triplet regimens in this older population.
Topics: Humans; Middle Aged; Aged; Sulfonamides; Protein Kinase Inhibitors; Leukemia, Myeloid, Acute; Mutation; fms-Like Tyrosine Kinase 3
PubMed: 37696819
DOI: 10.1038/s41408-023-00911-w -
Frontiers in Endocrinology 2023Gemcitabine (GEM) is a second-line anticancer drug of choice for some colorectal cancer (CRC) patients, and GEM inability to be commonly available in the clinic due to...
BACKGROUND
Gemcitabine (GEM) is a second-line anticancer drug of choice for some colorectal cancer (CRC) patients, and GEM inability to be commonly available in the clinic due to the lack of clarity of the exact action targets.
METHODS
The half maximal inhibitory concentration (IC50) of GEM treatment for 42 CRC cell lines were accessed from the Genomics of Drug sensitivity in Cancer (GDSC) database. High-throughput sequencing data of CRC patients were captured in The Cancer Genome Atlas (TCGA) and Weighted correlation network analysis (WGCNA) was conducted. Pearson correlations were derived for GEM potency-related genes. Differential analysis was conducted in the TCGA cohort to obtain CRC development-related genes (CDRGs), and univariate COX model analysis was performed on CDRGs overlapping with GEM potency-related genes to obtain CDRGs affecting CRC prognosis. Hub genes affecting GEM potency were identified by Spearman correlation.
RESULTS
CALB2 and GPX3 were identified as potential targets for GEM treatment of CRC prognostic analysis, which we also observed to be elevated with elevated clinical stage in CRC patients. The enhanced expression of CALB2 and GPX3 genes identified in the pathway analysis might inhibit the body metabolism as well as activate immune and inflammation related pathways. In addition, we found that CALB2 and GPX3 could also be considered as prognostic biomarkers in pan-cancer. Finally, we found that CALB2 and GPX3 were remarkably associated with the drug sensitivity of MG-132, Dasatinib, Shikonin, Midostaurin, MS-275, and Z-LNle-CHO, which were expected to be the drugs of choice for GEM combination.
CONCLUSION
CALB2 and GPX3 represent prognostic biomarkers for CRC and they might be potential action targets for GEM. Our study offered innovative ideas for GEM administration strategies.
Topics: Humans; Gemcitabine; Cell Line; Dasatinib; Colorectal Neoplasms; Biomarkers
PubMed: 37664836
DOI: 10.3389/fendo.2023.1170526 -
Frontiers in Immunology 2023Mast cell leukemia is a rare and aggressive disease, predominantly with D816V mutation. With poor response to conventional poly-chemotherapy, mast cell leukemia...
Mast cell leukemia is a rare and aggressive disease, predominantly with D816V mutation. With poor response to conventional poly-chemotherapy, mast cell leukemia responded to the midostaurin treatment with a 50% overall response rate (ORR), but complete remission rate is approximately 0%. Therefore, the potential mechanisms of midostaurin resistance and the exact impacts of midostaurin on both gene expression profile and mast cell leukemia microenvironment are essential for design tailored combination therapy targeting both the tumor cells and the tumor microenvironment. Here we report a 59-year-old male mast cell leukemia patient with F522C mutation treated with midostaurin. Single-cell sequencing of peripheral blood and whole exome sequencing (WES) of bone marrow were performed before and 10 months after midostaurin treatment. In accordance with the clinical response, compared to the pretreatment aberration, the decline of mast cells and increase of T-, NK, B-cells in peripheral blood, and the decrease of the F522C mutation burden in bone marrow were observed. Meanwhile, the emergence of mutation, upregulations of genes expression (, , , ) on tumor cells, and increased frequencies of T and NK cells with , and expression were observed after midostaurin treatment, predicting the disease progression of this patient. As far as we know, this is the first case reporting the clinical, immunological, and molecular changes in mast cell leukemia patients before and after midostaurin treatment, illustrating the mechanisms of midostaurin resistance in mast cell leukemia, providing important clues to develop a sequential option to circumvent tumor progression after targeting oncogene addiction and prolong patients' survival.
Topics: Male; Humans; Middle Aged; Leukemia, Mast-Cell; Staurosporine; Combined Modality Therapy; Mast Cells; Tumor Microenvironment
PubMed: 37638009
DOI: 10.3389/fimmu.2023.1210909 -
Journal of Functional Biomaterials Jul 2023Tyrosine kinase inhibitor (TKI) therapy is gaining attraction in advanced cancer therapeutics due to the ubiquity of kinases in cell survival and differentiation. Great...
Tyrosine kinase inhibitor (TKI) therapy is gaining attraction in advanced cancer therapeutics due to the ubiquity of kinases in cell survival and differentiation. Great progress was made in the past years in identifying tyrosine kinases that can function as valuable molecular targets and for the entrapment of their corresponding inhibitors in delivery compounds for triggered release. Herein we present a class of drug-delivery nanocompounds based on TKI Midostaurin-loaded gold nanoparticles that have the potential to be used as theranostic agents for the targeting of the FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia. We optimized the nanocompounds' formulation with loading efficiency in the 84-94% range and studied the drug release behavior in the presence of stimuli-responsive polymers. The therapeutic activity of MDS-loaded particles, superior to that of the free drug, was confirmed with toxicities depending on specific dosage ranges. No effect was observed on FLT3-negative cells or for the unloaded particles. Beyond druggability, we can track this type of nanocarrier inside biological structures as demonstrated via dark field microscopy. These properties might contribute to the facilitation of personalized drug dosage administration, critical for attaining a maximal therapeutic effect.
PubMed: 37623644
DOI: 10.3390/jfb14080399 -
Blood Advances Nov 2023The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (<60 years) with...
The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (<60 years) with newly diagnosed (ND) FLT3mut acute myeloid leukemia (AML). Considering that AML often present in older patients who show poor response to chemotherapy, this open-label, multicenter phase 3b trial was designed to further assess safety and efficacy of midostaurin plus chemotherapy in induction, consolidation, and maintenance monotherapy in young (≤60 years) and older (>60 years) patients with FLT3mut ND-AML. Compared with RATIFY, this study extended midostaurin treatment from 14 days to 21 days, substituted anthracyclines (idarubicin or daunorubicin), and introduced variation in standard combination chemotherapy dosing ("7+3" or "5+2" in more fragile patients). Total 301 patients (47.2% >60 years and 82.7% with FLT3-ITDmut) of median age 59 years entered induction phase. Overall, 295 patients (98.0%) had at least 1 adverse event (AE), including 254 patients (84.4%) with grade ≥3 AE. The grade ≥3 serious AEs occurred in 134 patients. No difference was seen in AE frequency between age groups, but grade ≥3AE frequency was higher in older patients. Overall, complete remission (CR) rate including incomplete hematologic recovery (CR + CRi) (80.7% [95% confidence interval, 75.74-84.98]) was comparable between age groups (≤60 years [83.5%]; >60 to ≤70 years [82.5%]; in patients >70 years [64.1%]) and the type of anthracycline used in induction. CR + CRi rate was lower in males (76.4%) than females (84.4%). Overall, the safety and efficacy of midostaurin remains consistent with previous findings, regardless of age, sex, or induction regimen. The trial is registered at www.clinicaltrials.gov as #NCT03379727.
Topics: Male; Female; Humans; Aged; Middle Aged; Daunorubicin; Idarubicin; Leukemia, Myeloid, Acute; Staurosporine; Antibiotics, Antineoplastic; Anthracyclines; fms-Like Tyrosine Kinase 3
PubMed: 37581981
DOI: 10.1182/bloodadvances.2023009847 -
International Journal of Molecular... Jul 2023Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to...
Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 10 single-nucleotide polymorphisms performed on Alzheimer's disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a humanized model over-expressing the Aβ peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin's effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.
Topics: Animals; Mice; Alzheimer Disease; Genome-Wide Association Study; Caenorhabditis elegans; Staurosporine; Drug Repositioning
PubMed: 37569459
DOI: 10.3390/ijms241512079 -
Leukemia Oct 2023Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by...
Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure. This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated. We identified 56 patients treated with FLT3i at molecular failure. The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69-93) and molecular event-free survival 56% (95%CI 44-72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.
Topics: Humans; fms-Like Tyrosine Kinase 3; Leukemia, Myeloid, Acute; Mutation; Neoplasm Recurrence, Local; Prospective Studies; Protein Kinase Inhibitors; Salvage Therapy
PubMed: 37558736
DOI: 10.1038/s41375-023-01994-x -
PloS One 2023Drug repurposing has emerged as an important strategy and it has a great potential in identifying therapeutic applications for COVID-19. An extensive virtual screening...
Drug repurposing has emerged as an important strategy and it has a great potential in identifying therapeutic applications for COVID-19. An extensive virtual screening of 4193 FDA approved drugs has been carried out against 24 proteins of SARS-CoV2 (NSP1-10 and NSP12-16, envelope, membrane, nucleoprotein, spike, ORF3a, ORF6, ORF7a, ORF8, and ORF9b). The drugs were classified into top 10 and bottom 10 drugs based on the docking scores followed by the distribution of their therapeutic indications. As a result, the top 10 drugs were found to have therapeutic indications for cancer, pain, neurological disorders, and viral and bacterial diseases. As drug resistance is one of the major challenges in antiviral drug discovery, polypharmacology and network pharmacology approaches were employed in the study to identify drugs interacting with multiple targets and drugs such as dihydroergotamine, ergotamine, bisdequalinium chloride, midostaurin, temoporfin, tirilazad, and venetoclax were identified among the multi-targeting drugs. Further, a pathway analysis of the genes related to the multi-targeting drugs was carried which provides insight into the mechanism of drugs and identifying targetable genes and biological pathways involved in SARS-CoV2.
Topics: Humans; COVID-19; Drug Repositioning; RNA, Viral; Protease Inhibitors; SARS-CoV-2; Polypharmacology; Molecular Docking Simulation; Antiviral Agents
PubMed: 37556478
DOI: 10.1371/journal.pone.0289890 -
Annals of Hematology Oct 2023The addition of midostaurin to standard chemotherapy has improved survival in patients with FLT3-mutated AML. However, the impact of midostaurin and other FLT3... (Review)
Review
Treatment with midostaurin and other FLT3 targeting inhibitors is associated with an increased risk of cardiovascular adverse events in patients who underwent allogeneic hematopoietic stem cell transplantation with FLT3-mutated AML.
The addition of midostaurin to standard chemotherapy has improved survival in patients with FLT3-mutated AML. However, the impact of midostaurin and other FLT3 inhibitors (FLT3i) on cardiovascular adverse events (CAEs) has not been studied in patients who underwent allogeneic hematopoietic stem cell transplantation in a real-world setting. We reviewed 132 patients with AML who were treated with intensive induction therapy and consecutive allogeneic stem cell transplantation at our institution (42 FLT3-mutated AML and 90 with FLT3 wildtype). We identified treatment with midostaurin and/or FLT3i as an independent risk factor for CAEs not resulting in higher non-relapse mortality (NRM) or impaired overall survival (OS). Hence, close monitoring for CAEs is warranted for these patients.
Topics: Humans; Leukemia, Myeloid, Acute; Mutation; Staurosporine; Protein Kinase Inhibitors; Hematopoietic Stem Cell Transplantation; fms-Like Tyrosine Kinase 3
PubMed: 37552323
DOI: 10.1007/s00277-023-05396-y