RESUMO
BACKGROUND: Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS: In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS: Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS: In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).
Assuntos
Hepcidinas , Peptídeos , Policitemia Vera , Humanos , Hematócrito , Hepcidinas/administração & dosagem , Hepcidinas/uso terapêutico , Ferro , Policitemia/diagnóstico , Policitemia/tratamento farmacológico , Policitemia/etiologia , Policitemia Vera/tratamento farmacológico , Policitemia Vera/complicações , Policitemia Vera/diagnóstico , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Injeções , Método Duplo-Cego , Fármacos Hematológicos/administração & dosagem , Fármacos Hematológicos/uso terapêuticoRESUMO
With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate inter-study comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to i) account for gender-specific differences in determining hemoglobin levels for eligibility criteria, ii) revise definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices, and iii) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks prior to study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs. non-TDA) and graded (major vs. minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.
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Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm driven by the JAK2 V617F (or rarely exon 12) mutation. Its natural history can extend over a few decades, and therefore treatment planning is predicated on continual reassessment of traditional risk features (age, prior thrombosis) to evaluate the need for cytoreduction besides foundational therapy with low-dose aspirin and stringent phlebotomy. Shorter- and longer-term patient goals should be considered in light of several variables such as comorbid conditions (especially cardiovascular risk factors), disease symptoms, and the risk-benefit profile of available drugs. While hydroxyurea has been the pro forma choice of cytoreduction for many practitioners over the last half-century, the more recent regulatory approvals of ruxolitinib and ropeginterferon-alfa-2b, based on phase 3 randomized trials, highlight an expanding portfolio of active drugs. Obtaining high-level evidence for short-term clinical trial endpoints such as hematocrit control, symptom burden/quality of life, splenomegaly, and JAK2 V617F allele burden lies within the timeline of most studies. However, in many cases, it may not be possible to adequately power trials to capture significant differences in the typically low event rates of thrombosis as well as longer-horizon endpoints such as evolution to myelofibrosis and acute myeloid leukemia and survival. This Perspective highlights the challenges of addressing these data gaps and outstanding questions in the emerging treatment landscape of PV.
Assuntos
Policitemia Vera , Mielofibrose Primária , Trombose , Humanos , Janus Quinase 2/genética , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Policitemia Vera/terapia , Mielofibrose Primária/genética , Qualidade de Vida , Trombose/etiologiaRESUMO
Avapritinib, a highly selective inhibitor of KIT D816V, was approved by the Food and Drug Administration in 2021 for treatment of advanced systemic mastocytosis (AdvSM) and by the European Medicines Agency in 2022 for AdvSM after prior systemic therapy. The phase 1 EXPLORER and phase 2 PATHFINDER trials demonstrated that avapritinib can elicit complete and durable clinical responses and molecular remission of KIT D816V. Key management challenges relate to the complex mutational landscape of AdvSM, often found with an associated hematologic neoplasm.
Assuntos
Mastocitose Sistêmica , Mastocitose , Humanos , Mastocitose/tratamento farmacológico , Mastocitose Sistêmica/tratamento farmacológico , Mastocitose Sistêmica/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Pirazóis/uso terapêutico , Pirróis , TriazinasRESUMO
Calreticulin (CALR) mutations are frequent, disease-initiating events in myeloproliferative neoplasms (MPNs). Although the biological mechanism by which CALR mutations cause MPNs has been elucidated, there currently are no clonally selective therapies for CALR-mutant MPNs. To identify unique genetic dependencies in CALR-mutant MPNs, we performed a whole-genome clustered regularly interspaced short palindromic repeats (CRISPR) knockout depletion screen in mutant CALR-transformed hematopoietic cells. We found that genes in the N-glycosylation pathway (among others) were differentially depleted in mutant CALR-transformed cells as compared with control cells. Using a focused pharmacological in vitro screen targeting unique vulnerabilities uncovered in the CRISPR screen, we found that chemical inhibition of N-glycosylation impaired the growth of mutant CALR-transformed cells, through a reduction in MPL cell surface expression. We treated Calr-mutant knockin mice with the N-glycosylation inhibitor 2-deoxy-glucose (2-DG) and found a preferential sensitivity of Calr-mutant cells to 2-DG as compared with wild-type cells and normalization of key MPNs disease features. To validate our findings in primary human cells, we performed megakaryocyte colony-forming unit (CFU-MK) assays. We found that N-glycosylation inhibition significantly reduced CFU-MK formation in patient-derived CALR-mutant bone marrow as compared with bone marrow derived from healthy donors. In aggregate, our findings advance the development of clonally selective treatments for CALR-mutant MPNs.
Assuntos
Calreticulina , Transtornos Mieloproliferativos , Animais , Calreticulina/genética , Calreticulina/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Glucose , Glicosilação , Humanos , Janus Quinase 2/genética , Camundongos , Mutação , Transtornos Mieloproliferativos/genética , Receptores de Trombopoetina/metabolismoRESUMO
The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
Assuntos
Neoplasias Hematológicas , Leucemia , Transtornos Mieloproliferativos , Doença Aguda , Consenso , Genômica , Neoplasias Hematológicas/patologia , Humanos , Leucemia/diagnóstico , Leucemia/genética , Leucemia/patologia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Organização Mundial da SaúdeRESUMO
BACKGROUND: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry. METHODS: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years). RESULTS: Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up. CONCLUSIONS: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years.
RESUMO
Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.
Assuntos
Mastocitose Sistêmica , Humanos , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/terapia , Gerenciamento Clínico , Oncologia/normas , Oncologia/métodosRESUMO
DISEASE OVERVIEW: The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary or clonal) disorders with the potential for end-organ damage. DIAGNOSIS: Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 109/L, and may be associated with tissue damage. After the exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of various tests. They include morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ hybridization, molecular testing and flow immunophenotyping to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2022 World Health Organization and International Consensus Classification endorse a semi-molecular classification scheme of disease subtypes. This includes the major category "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-eo-TK), and the MPN subtype, "chronic eosinophilic leukemia" (CEL). Lymphocyte-variant HE is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1.5 × 109/L) without symptoms or signs of organ involvement, a watch and wait approach with close follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Pemigatinib was recently approved for patients with relapsed or refractory FGFR1-rearranged neoplasms. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. Mepolizumab, an interleukin-5 (IL-5) antagonist monoclonal antibody, is approved by the U.S Food and Drug Administration for patients with idiopathic HES. Cytotoxic chemotherapy agents, and hematopoietic stem cell transplantation have been used for aggressive forms of HES and CEL, with outcomes reported for limited numbers of patients. Targeted therapies such as the IL-5 receptor antibody benralizumab, IL-5 monoclonal antibody depemokimab, and various tyrosine kinase inhibitors for MLN-eo-TK, are under active investigation.
Assuntos
Síndrome Hipereosinofílica , Leucemia , Humanos , Hibridização in Situ Fluorescente , Consenso , Interleucina-5 , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/genética , Síndrome Hipereosinofílica/terapia , Medição de Risco , Organização Mundial da Saúde , Anticorpos MonoclonaisRESUMO
Thrombopoietin (TPO) and the TPO-receptor (TPO-R, or c-MPL) are essential for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Agents that can modulate TPO-R signaling are highly desirable for both basic research and clinical utility. We developed a series of surrogate protein ligands for TPO-R, in the form of diabodies (DBs), that homodimerize TPO-R on the cell surface in geometries that are dictated by the DB receptor binding epitope, in effect "tuning" downstream signaling responses. These surrogate ligands exhibit diverse pharmacological properties, inducing graded signaling outputs, from full to partial TPO agonism, thus decoupling the dual functions of TPO/TPO-R. Using single-cell RNA sequencing and HSC self-renewal assays we find that partial agonistic diabodies preserved the stem-like properties of cultured HSCs, but also blocked oncogenic colony formation in essential thrombocythemia (ET) through inverse agonism. Our data suggest that dampening downstream TPO signaling is a powerful approach not only for HSC preservation in culture, but also for inhibiting oncogenic signaling through the TPO-R.
Assuntos
Receptores de Trombopoetina/metabolismo , Trombopoetina/metabolismo , Diferenciação Celular/fisiologia , Membrana Celular/metabolismo , Epitopos/imunologia , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Ligantes , Megacariócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Citocinas/metabolismo , Receptores de Trombopoetina/imunologia , Receptores de Trombopoetina/fisiologia , Transdução de Sinais/fisiologia , Trombocitemia Essencial/metabolismo , Trombopoetina/fisiologiaRESUMO
Pentraxin 2 (PTX-2; serum amyloid P component), a circulating endogenous regulator of the inflammatory response to tissue injury and fibrosis, is reduced in patients with myelofibrosis (MF). Zinpentraxin alfa (RO7490677, PRM-151) is a recombinant form of PTX-2 that has shown preclinical antifibrotic activity and no dose-limiting toxicities in phase I trials. We report results from stage 1 of a phase II trial of zinpentraxin alfa in patients with intermediate-1/2 or high-risk MF. Patients (n=27) received intravenous zinpentraxin α weekly (QW) or every 4 weeks (Q4W), as monotherapy or an additional therapy for patients on stable-dose ruxolitinib. The primary endpoint was overall response rate (ORR; investigatorassessed) adapted from International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria. Secondary endpoints included modified Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) change, bone marrow (BM) MF grade reduction, pharmacokinetics, and safety. ORR at week 24 was 33% (n=9/27) and varied across individual cohorts (QW: 38% [3/8]; Q4W: 14% [1/7]; QW+ruxolitinib: 33% [2/6]; Q4W+ruxolitinib: 50% [3/6]). Five of 18 evaluable patients (28%) experienced a ≥50% reduction in MPN-SAF TSS, and six of 17 evaluable patients (35%) had a ≥1 grade improvement from baseline in BM fibrosis at week 24. Most treatment-emergent adverse events (AE) were grade 1-2, most commonly fatigue. Among others, anemia and thrombocytopenia were infrequent (n=3 and n=1, respectively). Treatment-related serious AE occurred in four patients (15%). Overall, zinpentraxin alfa showed evidence of clinical activity and tolerable safety as monotherapy and in combination with ruxolitinib in this open-label, non-randomized trial (clinicaltrials gov. Identifier: NCT01981850).
Assuntos
Mielofibrose Primária , Proteínas Recombinantes , Humanos , Anemia , Fibrose , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Resultado do Tratamento , Proteínas Recombinantes/efeitos adversos , Quimioterapia Combinada/efeitos adversosRESUMO
Eosinophilia and eosinophil activation are recurrent features in various reactive states and certain hematologic malignancies. In patients with hypereosinophilia (HE), HE-induced organ damage is often encountered and may lead to the diagnosis of a hypereosinophilic syndrome (HES). A number of known mechanisms and etiologies contribute to the development of HE and HES. Based on these etiologies and the origin of eosinophils, HE and HES are divided into primary forms where eosinophils are clonal cells, reactive forms where an underlying reactive or neoplastic condition is detected and eosinophils are considered to be "non-clonal" cells, and idiopathic HE and HES in which neither a clonal nor a reactive underlying pathology is detected. Since 2012, this classification and the related criteria have been widely accepted and regarded as standard. However, during the past few years, new developments in the field and an increasing number of markers and targets have created a need to update these criteria and the classification of HE and HES. To address this challenge, a Working Conference on eosinophil disorders was organized in 2021. In this conference, a panel of experts representing the relevant fields, including allergy, dermatology, hematology, immunology, laboratory medicine, and pathology, met and discussed new markers and concepts as well as refinements in definitions, criteria and classifications of HE and HES. The outcomes of this conference are presented in this article and should assist in the diagnosis and management of patients with HE and HES in daily practice and in the preparation and conduct of clinical trials.
Assuntos
Eosinofilia , Síndrome Hipereosinofílica , Hipersensibilidade , Humanos , Eosinófilos/patologia , Eosinofilia/diagnóstico , Eosinofilia/etiologia , Eosinofilia/tratamento farmacológico , Síndrome , Hipersensibilidade/complicações , Síndrome Hipereosinofílica/etiologia , Síndrome Hipereosinofílica/complicaçõesRESUMO
Based on new data and increased understanding of disease molecular genetics, the international consensus classification (ICC) has made several changes in the diagnosis and classification of eosinophilic disorders and systemic mastocytosis. Myeloid/lymphoid neoplasms with eosinophilia (M/LN-eo) and gene rearrangements have been renamed as M/LN-eo with tyrosine kinase gene fusions (M/LN-eo-TK). The category has been expanded to include ETV6::ABL1 and FLT3 fusions, and to accept PCM1::JAK2 and its genetic variants as formal members. The overlaps and differences between M/LN-eo-TK and BCR::ABL1-like B-lymphoblastic leukemia (ALL)/de novo T-ALL sharing the same genetic lesions are addressed. Besides genetics, ICC for the first time has introduced bone marrow morphologic criteria in distinguishing idiopathic hypereosinophilia/hypereosinophilic syndrome from chronic eosinophilic leukemia, not otherwise specified. The major diagnostic criteria for systemic mastocytosis (SM) in the ICC remain largely based on morphology, but several minor modifications/refinements have been made in criteria related to diagnosis, subclassification, and assessment of disease burden (B- and C-findings). This review is to focus on the ICC updates related to these disease entities, illustrated through changes related to morphology, molecular genetics, clinical features, prognosis, and treatment. Two practical algorithms are provided in navigating through the diagnosis and classification systems of hypereosinophilia and SM.
Assuntos
Síndrome Hipereosinofílica , Leucemia , Mastocitose Sistêmica , Transtornos Mieloproliferativos , Humanos , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/genética , Consenso , Leucemia/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/genética , Síndrome Hipereosinofílica/patologiaRESUMO
Mast cell (MC) activation is a key event in allergic reactions, other inflammatory states, and MC activation syndromes. MC-stabilizing agents, mediator-targeting drugs, and drugs interfering with mediator effects are often prescribed for these patients. However, the clinical efficacy of these drugs varies depending on the numbers of involved MCs and the underlying pathology. One straightforward approach would be to eradicate the primary target cell. To date however, no MC-eradicating treatment approach has been developed for patients with MC activation disorders. Nevertheless, recent data suggest that long-term treatment with agents effectively inhibiting KIT function results in the virtual eradication of tissue MCs and a sustained decrease in serum tryptase levels. In many of these patients, MC depletion is associated with a substantial improvement in mediator-induced symptoms. In patients with an underlying KIT D816V-positive mastocytosis, such MC eradication requires an effective inhibitor of KIT D816V, such as avapritinib. However, the use of KIT inhibitors must be balanced against their potential side effects. Here we discuss MC-eradicating strategies in various disease models, the feasibility of this approach, available clinical data, and future prospects for the use of KIT-targeting drugs in MC activation disorders.
Assuntos
Transtornos da Ativação de Mastócitos , Mastocitose Sistêmica , Mastocitose , Humanos , Mastócitos/patologia , Mastocitose/tratamento farmacológico , Mastocitose/patologia , Mastocitose Sistêmica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-kit/genética , Estaurosporina/uso terapêuticoRESUMO
Mast cell neoplasms are an emerging challenge in the fields of internal medicine, allergy, immunology, dermatology, laboratory medicine, and pathology. In this review, we discuss the current standards for the diagnosis and prognostication of mast cell neoplasms with special reference to clinically relevant germline and somatic gene variants. In patients with cutaneous mastocytosis or with indolent systemic mastocytosis (SM), various KIT-activating mutations act as key molecular drivers of the disease. In adults, KIT p.D816V is by far the most prevalent driver, whereas other KIT mutants are detected in nearly 40% of children. In advanced SM, including aggressive SM, SM with an associated hematological neoplasm, and mast cell leukemia, additional somatic mutations in other genes, such as SRSF2, JAK2, RUNX1, ASXL1, or RAS, may be detected. These drivers are more frequently detected in SM with an associated hematological neoplasm, particularly in male patients. Recently, hereditary alpha-tryptasemia has been identified as a genetic trait more prevalent in SM compared with healthy controls. Moreover, hereditary alpha-tryptasemia is more frequent in patients with SM with Hymenoptera venom allergy and severe mediator-related symptoms than in patients with SM without symptoms. On the basis of this knowledge, we propose a diagnostic algorithm in which genetic markers are applied together with clinical and histopathologic criteria to establish the diagnosis and prognosis in SM.
Assuntos
Neoplasias Hematológicas , Mastocitose Sistêmica , Adulto , Criança , Análise Citogenética , Marcadores Genéticos , Humanos , Masculino , Mastócitos/patologia , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Mutação , Proteínas Proto-Oncogênicas c-kit/genéticaRESUMO
An enhanced understanding of the importance of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signalling in multiple disease states has led to an increasing applicability of therapeutic intervention with JAK inhibitors. These agents have revolutionised treatments for a heterogeneous group of disorders, such as myeloproliferative neoplasms, rheumatoid arthritis, inflammatory bowel disease, and multiple immune-driven dermatological diseases, exemplifying rapid bench-to-bedside translation. In this Therapeutics paper, we summarise the currently available data concerning the successes and safety of an array of JAK inhibitors and hypothesise on how these fields could develop.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Nitrilas/uso terapêutico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Pirrolidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacosRESUMO
Systemic mastocytosis (SM) has greatly benefited from the broad application of precision medicine techniques to hematolymphoid neoplasms. Sensitive detection of the recurrent KIT D816V mutation and use of next-generation sequencing (NGS) panels to profile the genetic landscape of SM variants have been critical adjuncts to the diagnosis and subclassification of SM, and development of clinical-molecular prognostic scoring systems. Multilineage KIT involvement and multimutated clones are characteristic of advanced SM (advSM), especially SM with an associated hematologic neoplasm (AHN). A major challenge is how to integrate conventional markers of mast cell disease burden (percentage of bone marrow mast cell infiltration and serum tryptase levels) with molecular data (serial monitoring of both KIT D816V variant allele frequency and NGS panels) to lend more diagnostic and prognostic clarity to the heterogeneous clinical presentations and natural histories of advSM. The approval of the multikinase/KIT inhibitor midostaurin has validated the paradigm of KIT inhibition in advSM, and the efficacy and safety of second-generation agents, such as the switch-control inhibitor ripretinib (DCC-2618) and the D816V-selective inhibitor avapritinib (BLU-285) are being further defined in ongoing clinical trials. Looking forward, perhaps the most fruitful marriage of the advances in molecular genetics and treatment will be the design of adaptive basket trials that combine histopathology and genetic profiling to individualize treatment approaches for patients with diverse AHNs and relapsed/refractory SM.
Assuntos
Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/terapia , Animais , Aberrações Cromossômicas , Transplante de Células-Tronco Hematopoéticas , Humanos , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Mutação , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/genética , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico , Triazinas/uso terapêuticoRESUMO
There are unresolved questions regarding the association between persistent leukocytosis and risk of thrombosis and disease evolution in polycythemia vera (PV), as much of the published literature on the topic does not appropriately use repeated-measures data or time-dependent modeling to answer these questions. To address this knowledge gap, we analyzed a retrospective database of 520 PV patients seen at 10 academic institutions across the United States. Taking hematologic laboratory data at â¼3-month intervals (or as available) for all patients for duration of follow-up, we used group-based trajectory modeling to identify latent clusters of patients who follow distinct trajectories with regard to their leukocyte, hematocrit, and platelet counts over time. We then tested the association between trajectory membership and hazard of 2 major outcomes: thrombosis and disease evolution to myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia. Controlling for relevant covariates, we found that persistently elevated leukocyte trajectories were not associated with the hazard of a thrombotic event (P = .4163), but were significantly associated with increased hazard of disease evolution in an ascending stepwise manner (overall P = .0002). In addition, we found that neither hematocrit nor platelet count was significantly associated with the hazard of thrombosis or disease evolution.
Assuntos
Leucemia Mieloide Aguda/patologia , Leucocitose/fisiopatologia , Síndromes Mielodisplásicas/patologia , Policitemia Vera/complicações , Mielofibrose Primária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/etiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/etiologia , Policitemia Vera/patologia , Mielofibrose Primária/etiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Trombose , Adulto JovemRESUMO
The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.
Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Mielofibrose Primária , Trombocitemia Essencial , Adulto , Humanos , Oncologia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/terapia , Policitemia Vera/diagnóstico , Mielofibrose Primária/diagnóstico , Trombocitemia Essencial/diagnósticoRESUMO
DISEASE OVERVIEW: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary or clonal) disorders with potential for end-organ damage. DIAGNOSIS: Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 109 /L. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ hybridization, next generation sequencing gene assays, and flow immunophenotyping to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes. This includes the major category "myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2", and the myeloproliferative neoplasm subtype, "chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant HE is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (eg, < 1.5 × 109 /L) without symptoms or signs of organ involvement, a watch and wait approach with close follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. Mepolizumab, an interleukin-5 (IL-5) antagonist monoclonal antibody, was recently approved by the US Food and Drug Administration for patients with idiopathic HES. The use of the IL-5 receptor antibody benralizumab, as well as other targeted therapies such as JAK2 and FGFR1 inhibitors, is under active investigation.