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INTRODUCTION: CXCR4/CXCL12 axis regulates cell proliferation, survival, and differentiation, as well as the homing and mobilization of hematopoietic stem cells (HSCs) from bone marrow niches to the peripheral blood. Furthermore, CXCR4 and CXCL12 are key mediators of cross-talk between hematological malignancies and their microenvironments. CXCR4 overexpression drives disease progression, boosts tumor cell survival, and promotes chemoresistance, leading to poor prognosis. AREAS COVERED: In light of these discoveries, scientific investigations, and clinical trials have underscored the therapeutic promise found in small-molecule antagonists like plerixafor, peptides/peptidomimetics, such as BKT140, monoclonal antibodies like PF-06747143 and ulocuplumab, as well as microRNAs. Their efficacy is evident in reducing tumor burden, inducing apoptosis and sensitizing malignant cells to conventional chemotherapies. This overview delves into the pathogenic role of the CXC4/CXCL12 axis in hematological neoplasms and examines the clinical application of key CXCR4 antagonists. EXPERT OPINION: The information collectively emphasizes the potential of CXCR4 antagonists as a therapeutic strategy for hematologic malignancies, showcasing advancements in preclinical and clinical studies. As these therapeutic strategies progress through clinical trials, their potential to reshape the prognosis of hematologic malignancies will become increasingly apparent.
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INTRODUCTION: Acute myeloid leukemia (AML) encompasses a heterogeneous group of aggressive myeloid malignancies, where FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent, accounting for approximately 25-30% of adult patients. The presence of this mutation is related to a dismal prognosis and high relapse rates. In the lasts years many FLT3 inhibitors have been developed. AREAS COVERED: This review provides a comprehensive overview of FLT3mut AML, summarizing the state of art of current treatment and available data about combination strategies including an FLT3 inhibitor. EXPERT OPINION: In addition, the review discusses the emergence of drug resistance and the need for a nuanced approaches in treating patients who are ineligible for or resistant to intensive chemotherapy. Specifically, it explores the historical context of FLT3 inhibitors (FLT3Is) and their impact on treatment outcomes, emphasizing the pivotal role of midostaurin, as well as gilteritinib and quizartinib, and providing detailed insights into ongoing trials exploring the safety and efficacy of novel triplet combinations involving FLT3Is in different AML settings.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Leukemia, Myeloid, Acute , Mutation , Protein Kinase Inhibitors , fms-Like Tyrosine Kinase 3 , Humans , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Drug Resistance, Neoplasm , Staurosporine/analogs & derivatives , Staurosporine/therapeutic use , Treatment Outcome , Aniline Compounds , PyrazinesABSTRACT
INTRODUCTION: Myelofibrosis (MF) is a hematologic disease characterized by bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. Recent years have seen the emergence of novel therapeutic agents, notably ruxolitinib and fedratinib, which target the Janus kinases (JAK) pathway. However, their myelosuppressive effect coupled with the persistence, and even worsening anemia remains a significant challenge, leading usually to treatment discontinuation. AREAS COVERED: This review focuses on Momelotinib (MMB), a unique JAK inhibitor that has shown promise in MF treatment, particularly in improving anemia. MMB inhibits type 1 kinase activin A receptor or activin receptor-like kinase-2 (ACVR1/ALK2), with consequent rebalancing of the SMAD pathways and reduced transcription of hepcidin. Moreover, it seems that MMB could reduce the serum levels of several inflammatory cytokines responsible for anemia. Clinical trials have demonstrated MMB's efficacy in reducing spleen size, alleviating symptoms, and improving anemia, with a favorable safety profile compared to other JAK inhibitors, both in treatment-naïve and in pre-treated patients. EXPERT OPINION: Due to its mechanism of action, MMB represents a valuable therapeutic option in MF, addressing the clinical challenge of anemia and potentially improving outcomes for patients with hematologic malignancies. Ongoing research explores MMB's potential in acute myeloid leukemia and combination therapies.
Subject(s)
Primary Myelofibrosis , Pyrimidines , Humans , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/metabolism , Pyrimidines/therapeutic use , Pyrimidines/pharmacology , Animals , Benzamides/therapeutic use , Benzamides/pharmacology , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/pharmacology , Anemia/drug therapy , Bridged-Ring CompoundsABSTRACT
INTRODUCTION: Selinexor, an XPO1 inhibitor, has emerged as a promising therapeutic option in the challenging landscape of relapsed/refractory multiple myeloma (RRMM). AREAS COVERED: This article provides a review of selinexor, with a focus on available clinical studies involving MM patients and its safety profile. Clinical trials, such as STORM and BOSTON, have demonstrated its efficacy, particularly in combination regimens, showcasing notable overall response rates (ORR) and prolonged median progressionfree survival (mPFS). Selinexor's versatility is evident across various combinations, including carfilzomibdexamethasone (XKd), lenalidomidedexamethasone (XRd), and pomalidomidedexamethasone (XPd), with efficacy observed even in tripleclass refractory and highrisk patient populations. However, challenges, including resistance mechanisms and adverse events, necessitate careful management. Realworld evidence also underscores selinexor's effectiveness in RRMM, though dose adjustments and supportive measures remain crucial. Ongoing trials are exploring selinexor in diverse combinations and settings, including pomalidomidenaïve patients and postautologous stem cell transplant (ASCT) maintenance. EXPERT OPINION: The evolving landscape of selinexor's role in the sequencing of treatment for RRMM, its potential in highrisk patients, including those with extramedullary disease, as revealed in the most recent international meetings, and ongoing investigations signal a dynamic era in myeloma therapeutics. Selinexor emerges as a pivotal component in multidrug strategies and innovative combinations.
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Hydrazines , Multiple Myeloma , Triazoles , Multiple Myeloma/drug therapy , Humans , Hydrazines/therapeutic use , Hydrazines/adverse effects , Triazoles/therapeutic use , Triazoles/adverse effects , Karyopherins/antagonists & inhibitors , Exportin 1 Protein , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Progression-Free SurvivalABSTRACT
Myelodysplastic syndromes (MDS) encompass a heterogeneous set of acquired bone marrow neoplastic disorders characterized by ineffective hematopoiesis within one or more bone marrow lineages. Nearly half of MDS patients carry cytogenetic alterations, with del(5q) being the most prevalent. Since its first description, del(5q) was consistently correlated with a typical clinical phenotype marked by anemia, thrombocytosis, and a low risk of evolving into acute leukemia. Presently, the World Health Organization (WHO) classification of myeloid neoplasms recognizes a specific subtype of MDS known as "myelodysplastic neoplasm with low blast and isolated del(5q)" identified by the sole presence of 5q deletion or in combination with one other abnormality excluding -7/del(7q). Several studies have sought to unravel the biological processes triggered by del(5q) in the development of MDS, revealing the involvement of various genes localized in specific regions of chromosome 5 referred to as common deleted regions (CDR). This intricate biological landscape makes the MDS cells with del(5q) exceptionally sensitive to lenalidomide. Several studies have confirmed the efficacy of lenalidomide in this context. Regrettably, the response to lenalidomide is not conclusive, prompting ongoing research into biological mechanisms that drive patients toward leukemia and strategies to circumvent lenalidomide resistance and disease progression.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 5 , Myelodysplastic Syndromes , Humans , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/therapy , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/etiology , Chromosomes, Human, Pair 5/genetics , Lenalidomide/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacologyABSTRACT
Multiple myeloma (MM) is an incurable neoplasm characterized by significant morbidity and mortality. Despite advances in treatment, MM patients eventually experienced a relapse of the disease. Penta-drug refractory patients continue to be the hard core of relapsed/refractory (RR) settings. Teclistamab-cqyv is a humanized IgG4 antibody and a bispecific BCMA-director CD3 T-cell engager. It recruits endogenous T cells, by targeting CD3 receptors expressed on their surface, resulting in their activation against BCMA, an antigen expressed by plasma cells. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved Teclistamab-cqyv in monotherapy for the treatment of RRMM patients who have received at least three prior therapies, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (MoAbs) and have demonstrated disease progression during the last therapy. Its effectiveness was demonstrated in a pivotal clinical trial where the overall response rate (ORR) reached 60%. Other clinical studies are currently ongoing to investigate the association of the bispecific antibody with novel drugs with encouraging preliminary results, especially in the setting of heavily pretreated patients. In this review, the authors will provide a comprehensive overview of the drug, including its mechanism of action, major clinical trials, and future perspectives.
Subject(s)
Antineoplastic Agents , Multiple Myeloma , Humans , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , B-Cell Maturation Antigen , Neoplasm Recurrence, Local/drug therapy , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Proteasome Inhibitors/therapeutic useABSTRACT
Tagraxofusp (or SL-401) is a recombinant molecule composed of human interleukin-3 that binds CD123 on neoplastic cells fused to a truncated diphtheria toxin (DT). Tagraxofusp's most significant success has come from studies involving patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive disease that is usually refractory to conventional chemotherapy. Tagraxofusp had an acceptable safety profile and high efficacy in early phase I/II studies on patients with BPDCN. Another phase II study confirmed the good response rates, resulting in Food and Drugs Administration and European Medicine Agency approval of tagraxofusp for the treatment of BPDCN. Considering its high efficacy and its manageable safety profile, tagraxofusp has been suddenly explored in other myeloid malignancies with high expression of cell surface CD123, both in monotherapy or combination strategies. The triplet tagraxofusp-azacytidine-venetoclax appears to be of particular interest among these combinations. Furthermore, combination strategies may be used to overcome tagraxofusp resistance. The downregulation of DPH1 (diphthamide biosynthesis 1), the enzyme responsible for the conversion of histidine 715 on eEF2 to diphthamide, which is then the direct target of ADP ribosylation DT, is typically associated with this resistance phenomenon. It has been discovered that azacitidine can reverse DHP1 expression and restore sensitivity to tagraxofusp. In conclusion, the success of tagraxofusp in BPDCN paved the way for its application even in other CD123-positive malignancies. Nowadays, several ongoing trials are exploring the use of tagraxofusp in different myeloid neoplasms. This review aims to summarize the actual role of tagraxofusp in BPDCN and other CD123-positive myeloid malignancies.
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Hematologic Neoplasms , Myeloproliferative Disorders , Recombinant Fusion Proteins , Skin Neoplasms , Humans , Interleukin-3 Receptor alpha Subunit/metabolism , Interleukin-3 Receptor alpha Subunit/therapeutic use , Dendritic Cells/pathology , Azacitidine/therapeutic use , Myeloproliferative Disorders/pathology , Acute Disease , Skin Neoplasms/pathology , Hematologic Neoplasms/pathology , Clinical Trials, Phase II as TopicABSTRACT
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 in vitro 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.
Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Humans , Hedgehog Proteins , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Pyridines/adverse effects , Antineoplastic Agents/adverse effects , MutationABSTRACT
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.
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Antineoplastic Agents , Leukemia, Myeloid, Acute , Humans , Hedgehog Proteins , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Benzimidazoles/therapeutic use , Phenylurea Compounds/adverse effects , Antineoplastic Agents/adverse effectsABSTRACT
In polycythemia vera (PV), the prognostic relevance of an ELN-defined complete response (CR) to hydroxyurea (HU), the predictors of response, and patients' triggers for switching to ruxolitinib are uncertain. In a real-world analysis, we evaluated the predictors of response, their impact on the clinical outcomes of CR to HU, and the correlations between partial or no response (PR/NR) and a patient switching to ruxolitinib. Among 563 PV patients receiving HU for ≥12 months, 166 (29.5%) achieved CR, 264 achieved PR, and 133 achieved NR. In a multivariate analysis, the absence of splenomegaly (p = 0.03), pruritus (p = 0.002), and a median HU dose of ≥1 g/day (p < 0.001) remained associated with CR. Adverse events were more frequent with a median HU dose of ≥1 g/day. Overall, 283 PR/NR patients (71.3%) continued HU, and 114 switched to ruxolitinib. In the 449 patients receiving only HU, rates of thrombosis, hemorrhages, progression, and overall survival were comparable among the CR, PR, and NR groups. Many PV patients received underdosed HU, leading to lower CR and toxicity rates. In addition, many patients continued HU despite a PR/NR; however, splenomegaly and other symptoms were the main drivers of an early switch. Better HU management, standardization of the criteria for and timing of responses to HU, and adequate intervention in poor responders should be advised.
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Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening, rare acute thrombotic microangiopathy (TMA), caused by a severe ADAMTS13 deficiency. As the COVID-19 pandemic rapidly spread around the globe, much data about the pathogenicity of this virus were published. Soon after the detection of the first cases of COVID-19, it was clear that there was a wide range of COVID coagulopathy manifestations, such as deep venous thrombosis, pulmonary thromboembolism, and thrombotic microangiopathies. In the literature, little data have been reported about the association between TTP and COVID-19, and the treatment of COVID-19-associated TTP is still under debate. Here we present the case of a 46-year-old woman who developed a COVID-associated TTP, successfully treated with plasma exchange (PEX), steroids, and caplacizumab.
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COVID-19 , Myeloproliferative Disorders , Humans , Nitriles , Pyrimidines , Pyrazoles/therapeutic useABSTRACT
The paper discusses the role that sociology and digital social research methods could play in developing E-health and Telemedicine, specifically after the COVID-19 pandemic, and the possibility of dealing with new pandemics. In this article, we will reflect on an interdisciplinary research pilot project carried out by a team of sociologists, medical doctors, and software engineers at The University of Calabria (Italy), to give a proof of concept of the importance to develop Telemedicine through the contribution of digital social research. We apply a web and app survey to administrate a structured questionnaire to a self-selected sample of the University Community. Digital social research has highlighted socioeconomic and cultural gaps that affect the perception of Telemedicine in the University Community. In particular, gender, age, educational, and professional levels influence medical choices and behaviors during Covid-19. There is often an unconscious involvement in Telemedicine (people use it but don't know it is Telemedicine), and an optimistic perception grows with age, education, professional, and income levels; equally important are the comprehension of digital texts and the effective use of Telemedicine. Limited penetration of technological advances must be addressed primarily by overcoming sociocultural and economic barriers and developing knowledge and understanding of digital environments. The key findings of this study could help direct public and educational policies to reduce existing gaps and promote Telemedicine in Calabria.
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Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/drug therapy , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Antineoplastic Combined Chemotherapy ProtocolsABSTRACT
Myelodysplastic syndromes (MDS) are acquired bone marrow malignant disorders characterized by ineffective hematopoiesis, resulting from a complex interaction between genetic and epigenetic mutations, alterations of the marrow microenvironment, and the immune system. In 2001, the World Health Organization (WHO) proposed a classification that integrates morphologic and genetic information, considering the MDS with ring sideroblasts (MDS-RS) as a distinct entity. Considering the strong association between MDS-RS and SF3B1 mutation and its importance in the development of MDS, the last WHO classification replaced the prior entity of MDS-RS with MDS with SF3B1 mutation. Several studies were performed to explore this genotype-phenotype correlation. Mutant SF3B1 protein deregulates the expression of genes implicated in developing hematopoietic stem and progenitor cells. Of paramount importance are PPOX and ABCB7 involved in iron metabolism. Another essential role in hemopoiesis is played by the transforming growth factor-beta (TGF-ß) receptor. This gene exerts its effects on SMAD pathways, regulating hematopoiesis through effects on balancing proliferation and apoptosis cell inactivity, differentiation, and migration. Luspatercept (ACE-536) is a soluble fusion protein that inhibits molecules in the TGF-ß superfamily. Since its structure resembles the TGF-ß family receptor, it catches TGF-ß superfamily ligands before binding to the receptor, resulting in reduced activation of SMAD signaling, thus enabling erythroid maturation. Luspatercept was investigated in the phase III trial MEDALIST, showing promising efficacy in treating anemia compared to placebo. Nowadays, further studies are needed to explore the real potential of luspatercept, investigating the biological features likely associated with treatment response, the potential use in combination treatments, and its role in the treatment of naïve MDS.