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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 -
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 -
Diagnostics (Basel, Switzerland) Dec 2023Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm characterised by the accumulation of neoplastic mast cells (MCs) in various organs, resulting in... (Review)
Review
Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm characterised by the accumulation of neoplastic mast cells (MCs) in various organs, resulting in organ dysfunction and reduced life expectancy. The subtypes include aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). The gain of function D816V mutation is present in most cases. The availability of tyrosine kinase inhibitors (TKIs) has revolutionised the treatment landscape for patients with this life-limiting disease. Patients are now able to achieve molecular remission, improved quality of life and improved overall survival. This review focuses on the targeted therapies currently available in clinical practice and within the clinical trial setting for AdvSM. This review also highlights possible future therapeutic targets and discusses therapeutic strategies for this multimutated and clinically heterogeneous disease.
PubMed: 38201389
DOI: 10.3390/diagnostics14010080 -
British Journal of Pharmacology Nov 2023Pathological cardiomyocyte hypertrophy is a response to cardiac stress that typically leads to heart failure. Despite being a primary contributor to pathological cardiac...
BACKGROUND AND PURPOSE
Pathological cardiomyocyte hypertrophy is a response to cardiac stress that typically leads to heart failure. Despite being a primary contributor to pathological cardiac remodelling, the therapeutic space that targets hypertrophy is limited. Here, we apply a network model to virtually screen for FDA-approved drugs that induce or suppress cardiomyocyte hypertrophy.
EXPERIMENTAL APPROACH
A logic-based differential equation model of cardiomyocyte signalling was used to predict drugs that modulate hypertrophy. These predictions were validated against curated experiments from the prior literature. The actions of midostaurin were validated in new experiments using TGFβ- and noradrenaline (NE)-induced hypertrophy in neonatal rat cardiomyocytes.
KEY RESULTS
Model predictions were validated in 60 out of 70 independent experiments from the literature and identify 38 inhibitors of hypertrophy. We additionally predict that the efficacy of drugs that inhibit cardiomyocyte hypertrophy is often context dependent. We predicted that midostaurin inhibits cardiomyocyte hypertrophy induced by TGFβ, but not noradrenaline, exhibiting context dependence. We further validated this prediction by cellular experiments. Network analysis predicted critical roles for the PI3K and RAS pathways in the activity of celecoxib and midostaurin, respectively. We further investigated the polypharmacology and combinatorial pharmacology of drugs. Brigatinib and irbesartan in combination were predicted to synergistically inhibit cardiomyocyte hypertrophy.
CONCLUSION AND IMPLICATIONS
This study provides a well-validated platform for investigating the efficacy of drugs on cardiomyocyte hypertrophy and identifies midostaurin for consideration as an antihypertrophic drug.
Topics: Rats; Animals; Myocytes, Cardiac; Cardiomegaly; Signal Transduction; Heart Failure; Transforming Growth Factor beta; Cells, Cultured
PubMed: 37302817
DOI: 10.1111/bph.16163 -
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 -
Molecular Cancer Nov 2023Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance...
BACKGROUND
Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML.
METHODS
We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3 CML patients.
RESULTS
We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3 BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3 BP-CML patients had significantly less favorable prognosis than FLT3 patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3 BCR::ABL1 cells and mouse xenograft models.
CONCLUSION
Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.
Topics: Animals; Mice; Humans; Blast Crisis; Fusion Proteins, bcr-abl; Drug Resistance, Neoplasm; Signal Transduction; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; fms-Like Tyrosine Kinase 3
PubMed: 37932786
DOI: 10.1186/s12943-023-01837-4 -
The Journal of Antimicrobial... Jun 2024Systemic antifungal therapy is critical for reducing the mortality from many invasive and chronic fungal infections. Triazole antifungals are the most frequently... (Review)
Review
Systemic antifungal therapy is critical for reducing the mortality from many invasive and chronic fungal infections. Triazole antifungals are the most frequently prescribed antifungals but require attention to dosing and drug interactions. Nearly 600 severe drug-drug interactions and over 1100 moderate interactions requiring dose modifications are described or anticipated with systemic antifungal agents (see https://www.aspergillus.org.uk/antifungal-drug-interactions/). In this article, we address the common and less common, but serious, drug interactions observed in clinical practice with triazole antifungals, including a group of drugs that cannot be prescribed with all or most triazole antifungals (ivabradine, ranolazine, eplerenone, fentanyl, apomorphine, quetiapine, bedaquiline, rifampicin, rifabutin, sirolimus, phenytoin and carbamazepine). We highlight interactions with drugs used in children and new agents introduced for the treatment of haematological malignancies or graft versus host disease (midostaurin, ibrutinib, ruxolitinib and venetoclax). We also summarize the multiple interactions between oral and inhaled corticosteroids and triazole antifungals, and the strategies needed to optimize the therapeutic benefits of triazole antifungal therapy while minimizing potential harm to patients.
Topics: Drug Interactions; Humans; Antifungal Agents; Triazoles; Mycoses; Adrenal Cortex Hormones
PubMed: 38629250
DOI: 10.1093/jac/dkae103 -
PharmacoEconomics Aug 2023The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of oral azacitidine (ONUREG), as part of the Single Technology Appraisal... (Review)
Review
The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of oral azacitidine (ONUREG), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of oral azacitidine for maintenance treatment of acute myeloid leukaemia (AML) after induction therapy compared with watch-and-wait plus best supportive care (BSC) and midostaurin. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations and describes the development of the NICE guidance by the Appraisal Committee. In the QUAZAR AML-001 trial, oral azacitidine significantly improved overall survival (OS) versus placebo: median OS gain of 9.9 months (24.7 months versus 14.8 months; hazard ratio (HR) 0.69 (95% CI 0.55-0.86), p < 0.001). The median time to relapse was also better for oral azacitidine, and the incidences of TEAEs were similar for the two arms. The company excluded two of the comparators listed in the scope, low-dose cytarabine and subcutaneous azacitidine, informed only by clinical expert opinion, leaving only best supportive care (BSC) and midostaurin for the FLT3-ITD and/or FLT3-TKD (FLT3 mutation)-positive subgroup. An ITC comparing oral azacitidine to midostaurin as maintenance therapy in the appropriate subgroup demonstrated that the OS and relapse-free survival (RFS) HRs were favourable for oral azacitidine when compared with midostaurin. However, in the only available trial of midostaurin as maintenance treatment in AML that was used for this ITC, subjects were not randomised at the maintenance phase, but at induction, which posed a substantial risk of bias. The revised and final probabilistic incremental cost-effectiveness ratio (ICER) presented by the company, including a commercial arrangement, was £32,480 per quality-adjusted life year (QALY) gained for oral azacitidine versus watch-and-wait plus BSC. Oral azacitidine was dominant versus midostaurin in the FLT-3 subgroup. The ERG's concerns included the approach of modelling haematopoietic stem cell transplantation (HSCT), the generalisability of the population and the number of cycles of consolidation therapy pre-treatment in the QUAZAR AML-001 trial to UK clinical practice, and uncertainty in the relapse utility. The revised and final ERG base case resulted in a similar probabilistic ICER of £33,830 per QALY gained versus watch-and-wait plus BSC, but with remaining uncertainty. Oral azacitidine remained dominant versus midostaurin in the FLT-3 subgroup. After the second NICE appraisal committee meeting, the NICE Appraisal Committee recommended oral azacitidine (according to the commercial arrangement), within its marketing authorisation, as an option for maintenance treatment for AML in adults who are in complete remission, or complete remission with incomplete blood count recovery, after induction therapy with or without consolidation treatment, and cannot have or do not want HSCT.
Topics: Adult; Humans; Induction Chemotherapy; Neoplasm Recurrence, Local; Azacitidine; Leukemia, Myeloid, Acute; Cost-Benefit Analysis; Technology Assessment, Biomedical; Quality-Adjusted Life Years
PubMed: 37129774
DOI: 10.1007/s40273-023-01272-9 -
British Journal of Haematology Feb 2024Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell... (Review)
Review
Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell sarcoma. SM is further partitioned into advanced (AdvSM) and non-advanced (SM-non-Adv) subcategories. AdvSM includes aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). In 2022, two separate expert committees representing the 5th edition of the World Health Organization (WHO5) and the International Consensus (ICC) classification systems submitted revised classification criteria for SM, highlighted by the ICC-proposed incorporation of mast cell cytomorphology in the diagnostic criteria for MCL and myeloid-lineage restriction for the AHN component in SM-AHN. Recent developments in SM also include the introduction of KIT-targeting tyrosine kinase inhibitors (KITi), including midostaurin and avapritinib, both drugs have shown potent activity in reducing mast cell and mutant KIT burden and alleviating mast cell-associated organopathy and mediator symptoms; however, their overall impact on survival or superiority over pre-KITi era treatment options (e.g. cladribine) has not been studied in a controlled setting. In the current review, we provide a summary of recent changes in disease classification and an analysis of recent clinical trials and their impact on our current treatment approach in AdvSM.
Topics: Humans; Mastocytosis, Systemic; Mast Cells; Leukemia, Mast-Cell; Cladribine; Mastocytosis; Proto-Oncogene Proteins c-kit
PubMed: 38054381
DOI: 10.1111/bjh.19245 -
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