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Expert Opinion on Emerging Drugs Dec 2023Systemic mastocytosis (SM) is a complex and heterogeneous disease, characterized by the clonal accumulation of mast cells in one or more organs. In 2022 both the World... (Review)
Review
INTRODUCTION
Systemic mastocytosis (SM) is a complex and heterogeneous disease, characterized by the clonal accumulation of mast cells in one or more organs. In 2022 both the World Health Organization (WHO) and the International Consensus Classification (ICC) modified the diagnostic and classification criteria of SM. Moreover, the identification of new clinical and molecular variables has improved prognostic tools and led to increasingly individualized therapeutic strategies.
AREAS COVERED
The aim of this review is to present the updates introduced by the International Consensus Classification in diagnostic criteria of SM. In addition, we report the latest data available from the most important clinical trials in patients both with non-advanced and advanced disease, including elenestinib and bezuclastinib.
EXPERT OPINION
Diagnosis and classification of SM has evolved over years. The most recent WHO and ICC classification improved SM diagnostic work-up, providing clinicians with a clear and simplified diagnostic scheme. New approved targeted therapies such as midostaurin and avapritinib modified the treatment paradigm in patients in advanced stage, and next-generation inhibitors actually investigated in clinical trials are expected in the next future.
Topics: Humans; Adult; Mastocytosis, Systemic; Mast Cells; Prognosis
PubMed: 37256917
DOI: 10.1080/14728214.2023.2221028 -
Journal of Clinical Medicine Oct 2023Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral... (Review)
Review
Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood. The prevalence of FLT3 gene mutations is high and escalates the probability of relapse and mortality. The survival rates for AML patients, particularly those over 65, are low. FLT3 mutation screening at diagnosis is mandatory, and FLT3 inhibitors are crucial in treating AML patients with mutations. There are two categories of FLT3 mutations: FLT3-ITD located in the juxtamembrane domain and FLT3-TKD in the tyrosine kinase domain. FLT3-ITD is the most common type, affecting nearly a quarter of patients, whereas FLT3-TKD only affects 6-8% of patients. FLT3 inhibitors are now crucial in treating AML patients with FLT3 mutations. When dealing with FLT3-mutated AML, the recommended course of treatment typically involves chemotherapy and midostaurin, followed by allogeneic hematopoietic cell transplantation (HCT) to maximize the likelihood of success. Maintenance therapy can lower the risk of relapse, and gilteritinib is a better option than salvage chemotherapy for relapsed or refractory cases. Clinical trials for new or combined therapies are the most effective approach. This review discusses treatment options for patients with FLT3-mutated AML, including induction chemotherapy and options for relapsed or refractory disease. Additional treatment options may become available as more studies are conducted based on the patient's condition and susceptibility.
PubMed: 37892567
DOI: 10.3390/jcm12206429 -
American Journal of Hematology Jul 2023Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extracutaneous organs.
OVERVIEW
Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extracutaneous organs.
DIAGNOSIS
The major criterion is presence of multifocal MC clusters in the bone marrow and/or extracutaneous organs. Minor diagnostic criteria include elevated serum tryptase level, MC CD25/CD2/CD30 expression, and presence of activating KIT mutations.
RISK STRATIFICATION
Establishing SM subtype as per the International Consensus Classification/World Health Organization classification systems is an important first step. Patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM-AMN), and mast cell leukemia. Identification of poor-risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Several risk models are available to help assign prognosis in SM patients.
MANAGEMENT
Treatment goals for ISM patients are primarily directed toward anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to reverse disease-related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM-AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era. Treatment of SM-AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.
Topics: Humans; Adult; Mastocytosis, Systemic; Imatinib Mesylate; Mast Cells; Leukemia, Mast-Cell; Risk Assessment
PubMed: 37309222
DOI: 10.1002/ajh.26962 -
Expert Opinion on Pharmacotherapy 2023Traditional treatment strategies for acute myeloid leukemia (AML) have primarily relied on standard chemotherapy regimens for four decades. Indeed, the landscape of AML... (Review)
Review
INTRODUCTION
Traditional treatment strategies for acute myeloid leukemia (AML) have primarily relied on standard chemotherapy regimens for four decades. Indeed, the landscape of AML therapy has evolved substantially in recent years, mainly due to the introduction of hypomethylating agents and small molecules.Bcl2 inhibitor venetoclax, Fms-like tyrosine kinase 3 (FLT3) inhibitors such as midostaurin and gilteritinib, and isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) inhibitors ivosidenib and enasidenib, as well as hedgehog (HH) pathway inhibitor glasdegib represented a significant step forward in AML therapeutic armamentarium. Smoothened (SMO) inhibitor in combination with low-dose cytarabine marks a recent milestone.
AREAS COVERED
Ivosidenib, the first-in-class, selective, allosteric IDH1R132 inhibitor, showed the capability to induce differentiation of primary mIDH1 AML blasts. Clinical data highlighted its exceptional safety profile, as a standalone therapy and in combination strategy. Additionally, comprehensive studies consistently demonstrated its effectiveness, both in monotherapy and in association with chemotherapy.
EXPERT OPINION
The identified ivosidenib's strengths, including its remarkable safety record and ability to yield positive therapeutic outcomes, position it as an ideal partner for both classic chemotherapy and biological treatments, i.e. hypometilant agents and/or venetoclax. Further studies are warranted to explore strategies for overcoming the occurrence of ivosidenib resistance.
Topics: Humans; Hedgehog Proteins; Leukemia, Myeloid, Acute; Pyridines; Antineoplastic Agents; Mutation
PubMed: 37874005
DOI: 10.1080/14656566.2023.2272659 -
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 -
Immunology and Allergy Clinics of North... Nov 2023Systemic mastocytosis is associated with KIT D816V mutation in more than 90% of cases. Patients with non-advanced forms of mastocytosis (indolent systemic mastocytosis,... (Review)
Review
Systemic mastocytosis is associated with KIT D816V mutation in more than 90% of cases. Patients with non-advanced forms of mastocytosis (indolent systemic mastocytosis, bone marrow mastocytosis, and smoldering systenic mastocytosis) have a low rate of progession to advanced variants and generally have a comparable life expectancy to age-matched general population. Symptomatology in non-advanced mastocytosis is variable and is related to mast cell mediator release. While some patients require no or minimal symptomatic therapy with antimediator drugs, other may suffer from refractory symptoms impacting the quality of life despite being on multiple anti-mediator drugs. KIT tyrosine kinase inhibitors have been approved for advanced SM, and avapritinib has also been recently approved as the first such inhibitor for indolent systemic mastocytosis. Other TKIs are currently in clinical trials for patients with non-advanced SM who have persistent and severe symptoms despite optimized antimediator therapy. This article will review the current state of the science and available clinical data from trials of tyrosine kinase inhibitors in non-advanced systemic mastocytosis.
PubMed: 37758410
DOI: 10.1016/j.iac.2023.05.001 -
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 -
Nature Communications Oct 2023Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial...
Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.
Topics: Humans; Lung Neoplasms; Drug Repositioning; Proto-Oncogene Proteins p21(ras); Drug Combinations; Protein Kinase Inhibitors; Mutation; Cell Line, Tumor
PubMed: 37816716
DOI: 10.1038/s41467-023-41828-z -
Current Allergy and Asthma Reports Feb 2024Provide an overview of the expanding landscape of mast cell (MC)-targeting treatments in mast cell activation syndromes (MCAS). (Review)
Review
PURPOSE OF REVIEW
Provide an overview of the expanding landscape of mast cell (MC)-targeting treatments in mast cell activation syndromes (MCAS).
RECENT FINDINGS
Tyrosine-kinase inhibitors (TKIs) targeting wild-type and mutated KIT can efficiently induce MC depletion. Avapritinib and midostaurin can also temper IgE-mediated degranulation. Avapritinib has been recently approved by the FDA for the treatment of indolent systemic mastocytosis (ISM). Targeting activation pathways and inhibitory receptors is a promising therapeutic frontier. Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM. MCAS is a heterogeneous disorder demanding a personalized therapeutic approach and, especially when presenting as anaphylaxis, has not been formally captured as outcome in prospective clinical trials with TKI. Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.
Topics: Humans; Mast Cells; Mast Cell Activation Syndrome; Prospective Studies; Mastocytosis, Systemic; Anaphylaxis; Mastocytosis
PubMed: 38217824
DOI: 10.1007/s11882-023-01123-9