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1.
N Engl J Med ; 390(8): 723-735, 2024 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-38381675

RESUMEN

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.).


Asunto(s)
Hepcidinas , Péptidos , Policitemia Vera , Humanos , Hematócrito , Hepcidinas/administración & dosificación , Hepcidinas/uso terapéutico , Hierro , Policitemia/diagnóstico , Policitemia/tratamiento farmacológico , Policitemia/etiología , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/complicaciones , Policitemia Vera/diagnóstico , Péptidos/administración & dosificación , Péptidos/uso terapéutico , Inyecciones , Método Doble Ciego , Fármacos Hematológicos/administración & dosificación , Fármacos Hematológicos/uso terapéutico
2.
Blood ; 144(17): 1813-1820, 2024 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-39116296

RESUMEN

ABSTRACT: 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 interstudy 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 (1) account for gender-specific differences in determining hemoglobin levels for eligibility criteria; (2) revise the definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices; and (3) 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 before 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.


Asunto(s)
Anemia , Mielofibrosis Primaria , Humanos , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/terapia , Mielofibrosis Primaria/sangre , Anemia/diagnóstico , Anemia/terapia , Anemia/etiología , Anemia/sangre , Femenino , Masculino , Hemoglobinas/análisis , Europa (Continente) , Transfusión Sanguínea
3.
Blood ; 139(19): 2871-2881, 2022 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-35271702

RESUMEN

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.


Asunto(s)
Policitemia Vera , Mielofibrosis Primaria , Trombosis , Humanos , Janus Quinasa 2/genética , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Policitemia Vera/terapia , Mielofibrosis Primaria/genética , Calidad de Vida , Trombosis/etiología
4.
Blood ; 140(15): 1667-1673, 2022 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-35877999

RESUMEN

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.


Asunto(s)
Mastocitosis Sistémica , Mastocitosis , Humanos , Mastocitosis/tratamiento farmacológico , Mastocitosis Sistémica/tratamiento farmacológico , Mastocitosis Sistémica/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Pirazoles/uso terapéutico , Pirroles , Triazinas
5.
Blood ; 140(11): 1291-1304, 2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-35763665

RESUMEN

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.


Asunto(s)
Calreticulina , Trastornos Mieloproliferativos , Animales , Calreticulina/genética , Calreticulina/metabolismo , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Glucosa , Glicosilación , Humanos , Janus Quinasa 2/genética , Ratones , Mutación , Trastornos Mieloproliferativos/genética , Receptores de Trombopoyetina/metabolismo
6.
Blood ; 140(11): 1200-1228, 2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-35767897

RESUMEN

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.


Asunto(s)
Neoplasias Hematológicas , Leucemia , Trastornos Mieloproliferativos , Enfermedad Aguda , Consenso , Genómica , Neoplasias Hematológicas/patología , Humanos , Leucemia/diagnóstico , Leucemia/genética , Leucemia/patología , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Organización Mundial de la Salud
7.
Haematologica ; 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-39385741

RESUMEN

Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event - free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of >70-year patients who completed intensive therapy (induction + >3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 - 15.2) and OS was 40.0% (95%CI, 36.4 - 44.1) at 5yr. In univariate analysis, age >70 (hazard ratio (HR) 1.78, [95%CI, 1.15 - 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 - 13.8], p=<.0001), no consolidation therapy (HR, 0.75 [95%CI, 0.47 - 1.84], p=.04) and less than 3 cycles of consolidation (HR, 1.48 [95%CI, 0.75 - 3.2], p=.0004), predicted poorer EFS. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a CR seems to be the most important first step and at least 3 cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.

8.
Allergy ; 79(9): 2470-2481, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38651829

RESUMEN

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.


Asunto(s)
Mastocitosis , Sistema de Registros , Humanos , Adulto , Persona de Mediana Edad , Masculino , Femenino , Anciano , Mastocitosis/epidemiología , Mastocitosis/diagnóstico , Mastocitosis/complicaciones , Prevalencia , Adulto Joven , Adolescente , Anciano de 80 o más Años , Proyectos Piloto , Factores de Riesgo , Hipersensibilidad/epidemiología , Hipersensibilidad/diagnóstico
9.
J Natl Compr Canc Netw ; 22(2D)2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38862005

RESUMEN

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.


Asunto(s)
Mastocitosis Sistémica , Humanos , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/terapia , Manejo de la Enfermedad , Oncología Médica/normas , Oncología Médica/métodos
10.
Am J Hematol ; 99(5): 946-968, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38551368

RESUMEN

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.


Asunto(s)
Síndrome Hipereosinofílico , Leucemia , Humanos , Hibridación Fluorescente in Situ , Consenso , Interleucina-5 , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/genética , Síndrome Hipereosinofílico/terapia , Medición de Riesgo , Organización Mundial de la Salud , Anticuerpos Monoclonales
11.
Proc Natl Acad Sci U S A ; 118(2)2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33384332

RESUMEN

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.


Asunto(s)
Receptores de Trombopoyetina/metabolismo , Trombopoyetina/metabolismo , Diferenciación Celular/fisiología , Membrana Celular/metabolismo , Epítopos/inmunología , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Ligandos , Megacariocitos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Receptores de Citocinas/metabolismo , Receptores de Trombopoyetina/inmunología , Receptores de Trombopoyetina/fisiología , Transducción de Señal/fisiología , Trombocitemia Esencial/metabolismo , Trombopoyetina/fisiología
12.
Haematologica ; 108(10): 2730-2742, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37165840

RESUMEN

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).


Asunto(s)
Mielofibrosis Primaria , Proteínas Recombinantes , Humanos , Anemia , Fibrosis , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/tratamiento farmacológico , Resultado del Tratamiento , Proteínas Recombinantes/efectos adversos , Quimioterapia Combinada/efectos adversos
13.
Allergy ; 78(1): 47-59, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36207764

RESUMEN

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.


Asunto(s)
Eosinofilia , Síndrome Hipereosinofílico , Hipersensibilidad , Humanos , Eosinófilos/patología , Eosinofilia/diagnóstico , Eosinofilia/etiología , Eosinofilia/tratamiento farmacológico , Síndrome , Hipersensibilidad/complicaciones , Síndrome Hipereosinofílico/etiología , Síndrome Hipereosinofílico/complicaciones
14.
Am J Hematol ; 98(8): 1286-1306, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37283522

RESUMEN

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.


Asunto(s)
Síndrome Hipereosinofílico , Leucemia , Mastocitosis Sistémica , Trastornos Mieloproliferativos , Humanos , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/genética , Consenso , Leucemia/genética , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/tratamiento farmacológico , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/genética , Síndrome Hipereosinofílico/patología
15.
J Allergy Clin Immunol ; 149(6): 1866-1874, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35421448

RESUMEN

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.


Asunto(s)
Trastornos de la Activación de los Mastocitos , Mastocitosis Sistémica , Mastocitosis , Humanos , Mastocitos/patología , Mastocitosis/tratamiento farmacológico , Mastocitosis/patología , Mastocitosis Sistémica/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-kit/genética , Estaurosporina/uso terapéutico
16.
J Allergy Clin Immunol ; 149(6): 1855-1865, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35430191

RESUMEN

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.


Asunto(s)
Neoplasias Hematológicas , Mastocitosis Sistémica , Adulto , Niño , Análisis Citogenético , Marcadores Genéticos , Humanos , Masculino , Mastocitos/patología , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/patología , Mutación , Proteínas Proto-Oncogénicas c-kit/genética
17.
Lancet ; 398(10302): 803-816, 2021 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-34454676

RESUMEN

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.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Nitrilos/uso terapéutico , Piperidinas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Pirrolidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Humanos , Trastornos Mieloproliferativos/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos
18.
Blood ; 135(16): 1365-1376, 2020 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-32106312

RESUMEN

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.


Asunto(s)
Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/terapia , Animales , Aberraciones Cromosómicas , Trasplante de Células Madre Hematopoyéticas , Humanos , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/patología , Mutación , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/genética , Pirazoles/uso terapéutico , Pirroles/uso terapéutico , Estaurosporina/análogos & derivados , Estaurosporina/uso terapéutico , Triazinas/uso terapéutico
19.
Blood ; 135(19): 1696-1703, 2020 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-32107559

RESUMEN

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 ∼3-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.


Asunto(s)
Leucemia Mieloide Aguda/patología , Leucocitosis/fisiopatología , Síndromes Mielodisplásicos/patología , Policitemia Vera/complicaciones , Mielofibrosis Primaria/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/etiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/etiología , Policitemia Vera/patología , Mielofibrosis Primaria/etiología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Trombosis , Adulto Joven
20.
J Natl Compr Canc Netw ; 20(9): 1033-1062, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36075392

RESUMEN

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.


Asunto(s)
Trastornos Mieloproliferativos , Policitemia Vera , Mielofibrosis Primaria , Trombocitemia Esencial , Adulto , Humanos , Oncología Médica , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/terapia , Policitemia Vera/diagnóstico , Mielofibrosis Primaria/diagnóstico , Trombocitemia Esencial/diagnóstico
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