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BACKGROUND: Ruxolitinib (RUX) is a JAK1/2 inhibitor approved for the therapy of myelofibrosis (MF) based on clinical trials including only intermediate2-high risk (INT2/HIGH) patients. However, RUX is commonly used in intermediate-1 (INT1) patients, with scarce information on responses and outcome. METHODS: The authors investigated the benefit of RUX in 1055 MF patients, included in the "RUX-MF" retrospective study. RESULTS: At baseline (BL), 595 (56.2%) patients were at INT1-risk according to DIPSS (PMF) or MYSEC-PM (SMF). The spleen was palpable at <5 cm, between 5 and 10 cm, and >10 cm below costal margin in 5.9%, 47.4%, and 39.7% of patients, respectively; 300 (54.1%) were highly symptomatic (total symptom score ≥20). High-molecular-risk (HMR) mutations (IDH1/2, ASXL-1, SRSF2, EZH2, U2AF1Q157) were detected in 77/167 patients. A total of 101 (19.2%) patients had ≥1 cytopenia (Hb < 10 g/dL: n.36; PLT <100 x 109/L: n = 43; white blood cells <4 x 109/L: n = 40). After 6 months on RUX, IWG-MRT-defined spleen and symptoms response rates were 26.8% and 67.9%, respectively. In univariate analysis, predictors of SR at 6 months were no HMR mutations odds ratio [OR], 2.0, p = .05], no cytopenia (OR, 2.10; p = .01), and blasts <1% (OR, 1.91; p = .01). In multivariate analysis, absence of HMR maintained a significant association (OR, 2.1 [1.12-3.76]; p = .01). CONCLUSIONS: In INT1 patients, responses were more frequent and durable, whereas toxicity rates were lower compared to INT2/high-risk patients. Presence of HMR mutations, cytopenia, and peripheral blasts identified less-responsive INT1 patients, who may benefit for alternative therapeutic strategies.
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Amyloid Light Chain (AL) Amyloidosis is a rare disorder of protein misfolding and metabolism characterized by insoluble fibrils deposition in various tissues and organs, which could quickly progress and become fatal. The most frequently affected organ is heart being its involvement the most adverse prognostic feature. Kidney and liver could be other organ localizations, defining AL Amyloidosis as a multisystem disorder. Being Budd-Chiari syndrome (BCS) an uncommon congestive hepatopathy caused by blockage of hepatic veins in the absence of cardiac disorders, it could be rarely caused by a massive deposition of amyloid proteins into hepatic sinusoidal spaces, giving an uncommon clinical presentation of AL Amyloidosis.
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Médula Ósea , Síndrome de Budd-Chiari , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Humanos , Síndrome de Budd-Chiari/etiología , Síndrome de Budd-Chiari/patología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/complicaciones , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Médula Ósea/patología , Hígado/patología , Hígado/metabolismo , Hepatopatías/etiología , Hepatopatías/patología , Masculino , Persona de Mediana Edad , Femenino , Amiloidosis/patología , Amiloidosis/complicaciones , Amiloidosis/etiología , Amiloidosis/diagnóstico , Amiloidosis/metabolismoRESUMEN
VEXAS is a prototypic hemato-inflammatory disease combining rheumatologic and hematologic disorders in a molecularly defined nosological entity. In this nationwide study, we aimed at screenshotting the current diagnostic capabilities and clinical-genomic features of VEXAS, and tracked UBA1 longitudinal clonal dynamics upon different therapeutics, including allogeneic hematopoietic cell transplant. We leveraged a collaboration between the Italian Society of Experimental Hematology and of Rheumatology and disseminated a national survey to collect clinical and molecular patient information. Overall, 13/29 centers performed UBA1 genomic testing locally, including Sanger sequencing (46%), next-generation sequencing (23%), droplet digital polymerase chain reaction (8%), or combination (23%). A total of 41 male patients were identified, majority (51%) with threonine substitutions at Met41 hotspot, followed by valine and leucine (27% and 8%). Median age at VEXAS diagnosis was 67 years. All patients displayed anemia (median hemoglobin 9.1 g/dL), with macrocytosis. Bone marrow vacuoles were observed in most cases (89%). The most common rheumatologic association was polychondritis (49%). A concomitant myelodysplastic neoplasm/syndrome (MDS) was diagnosed in 71% of patients (n = 28), chiefly exhibiting lower Revised International Prognostic Scoring System risk profiles. Karyotype was normal in all patients, except three MDS cases showing -Y, t(12;16)(q13;q24), and +8. The most frequently mutated gene was DNMT3A (n = 10), followed by TET2 (n = 3). At last follow-up, five patients died and two patients progressed to acute leukemia. Longitudinal UBA1 clonal dynamics demonstrated mutational clearance following transplant. We collected a nationwide interdisciplinary VEXAS patient cohort, characterized by heterogeneous rheumatologic manifestations and treatments used. MDS was diagnosed in 71% of cases. Patients exhibited various longitudinal UBA1 clonal dynamics.
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Artritis Reumatoide , Trasplante de Células Madre Hematopoyéticas , Leucemia , Síndromes Mielodisplásicos , Enfermedades Cutáneas Genéticas , Humanos , Masculino , Anciano , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , MutaciónRESUMEN
Myeloproliferative neoplasms (MPNs) are the leading causes of unusual site thrombosis, affecting nearly 40% of individuals with conditions like Budd-Chiari syndrome or portal vein thrombosis. Diagnosing MPNs in these cases is challenging because common indicators, such as spleen enlargement and elevated blood cell counts, can be obscured by portal hypertension or bleeding issues. Recent advancements in diagnostic tools have enhanced the accuracy of MPN diagnosis and classification. While bone marrow biopsies remain significant diagnostic criteria, molecular markers now play a pivotal role in both diagnosis and prognosis assessment. Hence, it is essential to initiate the diagnostic process for splanchnic vein thrombosis with a JAK2 V617F mutation screening, but a comprehensive approach is necessary. A multidisciplinary strategy is vital to accurately determine the specific subtype of MPNs, recommend additional tests, and propose the most effective treatment plan. Establishing specialized care pathways for patients with splanchnic vein thrombosis and underlying MPNs is crucial to tailor management approaches that reduce the risk of hematological outcomes and hepatic complications.
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Síndrome de Budd-Chiari , Trastornos Mieloproliferativos , Neoplasias , Trombosis , Trombosis de la Vena , Humanos , Vena Porta , Neoplasias/patología , Trombosis de la Vena/genética , Trombosis de la Vena/complicaciones , Síndrome de Budd-Chiari/complicaciones , Síndrome de Budd-Chiari/genética , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Trombosis/patología , Mutación , Janus Quinasa 2/genéticaRESUMEN
Patients with early stage cutaneous T cell lymphoma (CTCL) usually have a benign and chronic disease course, characterized by temporally response to conventional skin directed therapies and intrinsic possibility to evolve. Using the combination of psoralen plus ultraviolet A irradiation (PUVA) and low-dose interferon-α (INF), the principal treatment goal is to keep confined the disease to the skin, preventing disease progression. Among 87 patients with early stage IA to IIA MF treated with low-dose IFN-α2b and PUVA in our center, complete remission (CR) were reported in 70 patients (80.5%) and the overall response rate (ORR) was 97.8% (n = 85), with a median time to best response to therapy of 5 months (range, 1-30). Among the responders, only the 8% of patients had a relapse with major event. The median follow-up was 207 months (range, 6-295). Survival data showed a median overall survival (OS) not reached (95% CI; 235-NR months), a disease free survival (DFS) of 210 months (95% CI; 200-226 months) and a median time to next treatment (TTNT) of 38.5 months (95% CI, 33-46 months). The long follow up of this study verifies our preliminary results already published in 2006 and confirms the efficacy of INF-PUVA combination therapy in a real world setting, according conventional (OS and DFS) and emerging (TTNT) clinical endpoint of treatment efficacy.
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Linfoma Cutáneo de Células T , Micosis Fungoide , Neoplasias Cutáneas , Ficusina/uso terapéutico , Humanos , Interferón-alfa/uso terapéutico , Linfoma Cutáneo de Células T/patología , Micosis Fungoide/tratamiento farmacológico , Micosis Fungoide/patología , Micosis Fungoide/radioterapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia PUVA/métodos , Pronóstico , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Despite distinct clinical entities, the myeloproliferative neoplasms (MPN) share morphological similarities, propensity to thrombotic events and leukemic evolution, and a complex molecular pathogenesis. Well-known driver mutations, JAK2, MPL and CALR, determining constitutive activation of JAK-STAT signaling pathway are the hallmark of MPN pathogenesis. Recent data in MPN patients identified the presence of co-occurrence somatic mutations associated with epigenetic regulation, messenger RNA splicing, transcriptional mechanism, signal transduction, and DNA repair mechanism. The integration of genetic information within clinical setting is already improving patient management in terms of disease monitoring and prognostic information on disease progression. Even the current therapeutic approaches are limited in disease-modifying activity, the expanding insight into the genetic basis of MPN poses novel candidates for targeted therapeutic approaches. This review aims to explore the molecular landscape of MPN, providing a comprehensive overview of the role of drive mutations and additional mutations, their impact on pathogenesis as well as their prognostic value, and how they may have future implications in therapeutic management.
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Trastornos Mieloproliferativos , Transducción de Señal , Calreticulina/genética , Calreticulina/metabolismo , Epigénesis Genética , Humanos , Janus Quinasa 2/metabolismo , Mutación , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Neoplasias/genética , Receptores de Trombopoyetina , Factores de Transcripción STAT , Transducción de Señal/genéticaRESUMEN
Venetoclax and hypomethylating agent (HMA) combination therapy is FDA-approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment- naïve and relapsed/refractory AML patients. A total of 44 treatment-naïve AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n = 27) were studied. The CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (P = .005). Response rates were similar with TP53, FLT3, NPM1 and IDH mutations (P = .31). Moreover, CEPBA mutations (P = .03) and neutropenia (P = .05) emerged as predictors of complete response. Survivalwas prolonged in patients achieving CR/CRi (17 vs 3 months without CR/CRi, P < .001; conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received ≥2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. A group of 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia, JAK2, DNMT3A, and BCOR mutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 vs 3 months with/without CR/CRi; P < .001), and TP53 mutation status (P = .04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment -naïve and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mieloide Aguda , Mutación , Proteínas de Neoplasias/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Nucleofosmina , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Tasa de SupervivenciaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Crisis Blástica , Neoplasias Hematológicas , Trastornos Mieloproliferativos , Anciano , Anciano de 80 o más Años , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/mortalidad , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/mortalidad , Estudios Retrospectivos , Sulfonamidas/administración & dosificación , Tasa de SupervivenciaAsunto(s)
Síndrome Hipereosinofílico , Leucemia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Síndrome Hipereosinofílico/sangre , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/genética , Síndrome Hipereosinofílico/patología , Leucemia/sangre , Leucemia/diagnóstico , Leucemia/genética , Leucemia/patología , Masculino , Persona de Mediana EdadRESUMEN
Bone marrow (BM) acts as a dynamic organ within the bone cavity, responsible for hematopoiesis, skeletal remodeling, and immune system control. Bone marrow adipose tissue (BMAT) was long simply considered a filler of space, but now it is known that it instead constitutes an essential element of the BM microenvironment that participates in homeostasis, influences bone health and bone remodeling, alters hematopoietic stem cell functions, contributes to the commitment of mesenchymal stem cells, provides effects to immune homeostasis and defense against infections, and participates in energy metabolism and inflammation. BMAT has emerged as a significant contributor to the development and progression of various diseases, shedding light on its complex relationship with health. Notably, BMAT has been implicated in metabolic disorders, hematological malignancies, and skeletal conditions. BMAT has been shown to support the proliferation of tumor cells in acute myeloid leukemia and niche adipocytes have been found to protect cancer cells against chemotherapy, contributing to treatment resistance. Moreover, BMAT's impact on bone density and remodeling can lead to conditions like osteoporosis, where high levels of BMAT are inversely correlated with bone mineral density, increasing the risk of fractures. BMAT has also been associated with diabetes, obesity, and anorexia nervosa, with varying effects on individuals depending on their weight and health status. Understanding the interaction between adipocytes and different diseases may lead to new therapeutic strategies.
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Tejido Adiposo , Médula Ósea , Humanos , Tejido Adiposo/metabolismo , Médula Ósea/patología , Médula Ósea/metabolismo , AnimalesRESUMEN
Sarcoidosis, a multi-organ system disease, often presents insidiously. Thrombocytopenia in sarcoidosis is frequent because of hypersplenism, granulomas infiltrating the bone marrow, or immune thrombocytopenia (ITP). The diagnosis of ITP relies on exclusionary criteria, given the absence of a definitive laboratory diagnostic feature. In the era prior to modern ITP management, sarcoidosis-associated ITP was known to manifest severely, often showing resistance to treatment and an increased risk of mortality. In this case, we present a young male who was admitted to a district hospital's emergency room, displaying symptoms of hematuria, gingival bleeding, and a petechial rash. Blood tests revealed severe thrombocytopenia with a platelet count of 0, while all other metabolic and serological exams returned normal results. Infectious and autoimmune causes were ruled out, and a bone marrow examination excluded any hematological disorder. Initial management, including platelet transfusion and presumptive treatment for ITP with dexamethasone and Human Immunoglobulin IV (IVIG), failed to improve the patient's platelet count or alleviate the hemorrhagic diathesis. Second-line therapy with Rituximab and Methylprednisolone was initiated with no benefit. Considering the hemorrhagic signs and the delayed response of Rituximab, we shifted to third-line therapy with Romiplostim at the maximal dose and continued Methylprednisolone. The platelet count recovered completely after the second Romiplostim administration (over 350 × 109 platelets/L) and Methylprednisolone was rapidly tapered. To further study the causes of thrombocytopenia a total body CT scan was performed and it identified non-homogeneously hypodense tissue in the bilateral hilar area extending medially to the subcarinal area, suggesting possible lymphatic origin and raising suspicion of sarcoidosis. Further investigations, including Angiotensin Converting Enzyme (ACE) titration, bronchoscopy, bronchoalveolar lavage, and EndoBronchial UltraSound-guided TransBronchial Needle Aspiration (EBUS-TBNA), confirmed the diagnosis of sarcoidosis. Despite a mild restrictive insufficiency noted in spirometry, the patient remained asymptomatic with only a mild respiratory insufficiency, and hence, was enlisted for follow-up. As for the ITP, the platelet count remained normal over a year. Notably, while sarcoidosis onset often predates ITP onset by an average of 48 months, in our case the onset of the two diseases was simultaneously. Our case adds valuable information to the limited body of knowledge regarding the treatment of sarcoidosis-associated ITP.
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The outcome of multiple myeloma (MM) has significantly improved in the last few decades due to several factors such as new biological discoveries allowing to better stratify disease risk, development of more effective therapies and better management of side effects related to them. However, handling all these aspects requires an interdisciplinary approach involving multiple knowledge and collaboration of different specialists. The hematologist, faced with a patient with MM, must not only choose a treatment according to patient and disease characteristics but must also know when therapy needs to be started and how to monitor it during and after treatment. Moreover, he must deal not only with organ issues related to MM such as bone disease, renal failure or neurological disease but also with adverse events, often very serious, related to novel therapies, particularly new generation immunotherapies such as CAR T cell therapy and bispecific antibodies. In this review, we provide an overview on the newer MM diagnostic and monitoring strategies and on the main side effects of MM therapies, focusing on adverse events occurring during treatment with CAR T cells and bispecific antibodies.
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The presence of neutrophilic leukocytosis may underlie a wide variety of diseases. Some rare causes of neutrophilia might be chronic neutrophilic leukemia (CNL) and myelodysplastic/myeloproliferative neoplasm with neutrophilia (MDS with neutrophilia). Here we report a case of a 78-year-old woman who came to our ER due to severe leukocytosis and anemia on a routine check-up. The patient was asymptomatic and the last exams available showed a mild leukopenia and thrombocytopenia. The abdominal echography showed mild splenomegaly The patient underwent bone marrow (BM) examinations. One week later, the patient presented mental deterioration. The patient underwent a cranial CT and RMN that showed multiple lesions of 11 mm in the brain parenchyma, cerebellum and encephalic trunk. Another week later, the clinical presentations worsened: she was in a comatous state and feverish 40 °C unresponsive to steroid therapy. Autopsy showed a leukemic and hemorrhage infiltration in multiple organs and in the BM a cellularity of 100% represented by myeloid elements with a slowdown maturation with blasts 5%. According to WHO 2016 this case can be reported as an aCML, an MDS/MPN overlap syndrome that is difficult to differentiate from a CNL.
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In multiple myeloma impressive outcomes have improved with the introduction of new therapeutic approaches, mainly those including naked monoclonal antibodies such as daratumumab and isatuximab. However, moving to earlier lines of therapy with effective anti-myeloma drugs led to an increase in the number of patients who developed multi-refractoriness to them early on. Currently, triple- or multi-refractory MM represents an unmet medical need, and their management remains a complicated challenge. The recent approval of new immunotherapeutic approaches such as conjugated monoclonal antibodies, bispecific antibodies, and CAR T cells could be a turning point for these heavily pretreated patients. Nevertheless, several issues regarding their use are unsolved, such as how to select patients for each strategy or how to sequence these therapies within the MM therapeutic landscape. Here we provide an overview of the most recent data about approved conjugated monoclonal antibody belantamab, mafodotin, bispecific antibody teclistamab, and other promising compounds under development, mainly focusing on the ongoing clinical trials with monoclonal antibody combination approaches in advanced and earlier phases of MM treatment.
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Among primary cutaneous T-cell lymphomas (CTCL), mycosis fungoides (MF) is the most frequent and, along with Sézary syndrome (SS), the best-studied subtype. Most available studies on epidemiology of MF and SS are based on small cohorts or different inclusion criteria. Moreover, although this has become a hot topic, most studies show limitations, such as selection bias and lack of clinical information or follow-up data. Therefore, no reliable conclusions can be drawn. This paper reviews the current data underpinning our understanding of the epidemiology of MF and SS, and presents some original findings based on data retrieved from the cutaneous lymphoma registry of the Italian Marche region. The Marche Regional Cutaneous Lymphoma Registry is a multidisciplinary team founded 27 years ago to share the management of these rare disorders. All patients with a clinical and histologically confirmed diagnosis of primary cutaneous lymphoma are centralized in Ancona (Italy) at the Haematology Clinic, Polytechnic University of Marche, for clinical evaluation, staging, treatment, and follow-up. This paper emphasizes the need for a national registry of pCLs in Italy, as no detailed epidemiological information is available in the country except for the Marche Regional Cutaneous Lymphoma Registry. A national registry would allow for more comprehensive data collection from all over Italy and could provide more accurate information on incidence and epidemiology. This would be beneficial for understanding the pathogenesis and diagnostic procedures of these diseases and could improve patient outcomes. Therefore, we advise the creation of a national registry of pCLs in Italy.
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Linfoma Cutáneo de Células T , Linfoma , Micosis Fungoide , Síndrome de Sézary , Neoplasias Cutáneas , Humanos , Micosis Fungoide/patología , Síndrome de Sézary/patología , Neoplasias Cutáneas/patología , Italia/epidemiología , Linfoma Cutáneo de Células T/epidemiología , Linfoma Cutáneo de Células T/terapia , Linfoma Cutáneo de Células T/patologíaRESUMEN
We analyzed the clinicopathological, cytogenetic, and molecular features of 18 primary cutaneous diffuse large B-cell lymphomas (PCDLBCLs) and 15 DLBCLs secondarily localized to the skin (SCDLBCLs), highlighting biological similarities and differences between the 2 groups. PCDLBCLs were subclassified after histopathological review as PCDLBCL-leg type (PCDLBCL-LT, 10 cases) and the PCDLBCL-not otherwise specified (PCDLBCL-NOS, 8 cases). Immunohistochemistry for Hans' algorithm markers, BCL2, and MYC was performed. The molecular study included the determination of the cell of origin (COO) by Lymph2Cx assay on NanoString platform, FISH analysis of IgH, BCL2, BCL6, and MYC genes, as well as the mutation analysis of MYD88 gene. In immunohistochemistry analysis, BCL2 and MYC hyperexpression was more frequent in LT than in NOS cases and, according to Hans' algorithm, PCDLBCL-LTs were mostly of the non-GC type (8/10), whereas in PCDLBCL-NOS, the GC type prevailed (6/8). The determination of COO using Lymph2Cx supported and further confirmed these results. In FISH analysis, all but one LT cases versus 5 of 8 PCDLBCL-NOS showed at least one gene rearrangement among IgH, BCL2, MYC, or BCL6. In addition, MYD88 mutations were more frequently present in LT than in NOS subtypes. Interestingly, MYD88-mutated patients were older, with a non-GC phenotype and had worse OS, compared to MYD88 WT cases. Overall, SCDLBCL did not show, at the genetic and expression level, different profiles than PCDLBCL, even if they bear a significantly worse prognosis. At survival analysis, the most important prognostic factors in patients with PCDLBCL were age and MYD88 mutation, whereas relapse and high Ki-67 expression were relevant in patients with SCDLBCL. Our study comprehensively analyzed the clinicopathological and molecular features of PCDLBCL-LT, PCDLBCL-NOS, and SCDLBCL, underlining the differences among them and the importance of properly identifying these entities at the time of diagnosis.
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Linfoma de Células B Grandes Difuso , Neoplasias Cutáneas , Humanos , Linfoma de Células B Grandes Difuso/patología , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Biomarcadores de Tumor/análisis , Neoplasias Cutáneas/patología , Recurrencia Local de Neoplasia , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Análisis CitogenéticoRESUMEN
PURPOSE OF REVIEW: Myeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic stem cell neoplasms comprising of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) that share driver mutations (JAK2/CALR/MPL) resulting in constitutive activation of JAK/STAT and other signaling pathways. Patients with MPN have shortened survival and an inherent risk for leukemic evolution. Prognostically relevant clinical and genetic parameters have been incorporated into mutation-enhanced scoring systems (MIPSS70-plus version 2.0, MIPSS-ET/PV). In the current review, we describe clinical and pathological features along with prognostic significance of MPN with monocytosis. RECENT FINDINGS: Monocytosis, defined by an absolute monocyte count (AMC) ≥ 1 × 10 9/L, is a typical manifestation of chronic myelomonocytic leukemia (CMML) but is also associated with 21% and 17% of PV and PMF patients, respectively. Recent studies on the subject have reported that MPN patients with monocytosis are older and present with concomitant leukocytosis. In regard to PV, patients with monocytosis harbor unfavorable cytogenetic abnormalities including +8, 7/7q, i(17q), 5/5q-,12p-, inv(3), or 11q23 rearrangement and SRSF2 mutations, whereas PMF patients with monocytosis had significant thrombocytopenia, higher circulating blasts, higher symptom burden, and ASXL1 mutations. Moreover, presence of monocytosis predicted inferior survival in both PV and PMF. Monocytosis in MPN is associated with a distinct clinical and genetic profile and may serve as a marker of aggressive disease biology.
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Trastornos Mieloproliferativos , Policitemia Vera , Trombocitemia Esencial , Humanos , Janus Quinasa 2/genética , Leucocitosis , Mutación , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Policitemia Vera/diagnósticoRESUMEN
Introduction: Myelofibrosis (MF) is characterized by anemia, splenomegaly, constitutional symptoms and bone marrow fibrosis. MF has no curative treatment to date, except for a small subset of patients that are eligible for allogeneic hematopoietic stem cell transplant. The discovery in recent years of the MF mutational landscape and the role of bone marrow microenvironment in disease pathogenesis has led to further insights into disease biology and consequentially rationally derived therapies.Areas covered: We searched PubMed/Medline/American Society of Hematology (ASH) abstracts until November 2020 using the following terms: myelofibrosis, mouse models, pre-clinical studies and clinical trials. The development of targeted therapies is aimed to modify the history of the disease. Although JAK inhibitors showed encouraging results in terms of spleen and symptoms response, long term remissions and disease modifying ability is lacking. Beyond JAK inhibitors, a range of agents targeting proliferative, metabolic, apoptotic pathways, the microenvironment, epigenetic modification and immunomodulation are in various stages of investigations. We review pre-clinical data, preliminary clinical results of these agents, and finally offer insights on the management of MF patients.Expert opinion: MF patients refractory or with suboptimal response to JAK inhibitors, may be managed by addition of agents with differing mechanisms, such as bromodomain (BET), lysine demethylase 1 (LSD1), MDM2, or Bcl-Xl inhibitors which could prevent emergence of resistance. Immunotherapies as long-acting interferons, and calreticulin directed antibodies or peptide vaccination are eagerly awaited. Historically, therapeutic challenges in MF have arisen due to the fact that rationally derived therapies that are based on murine models have limited impact on fibrosis and underlying disease biology in human studies, the latter illustrates the complex multi-faceted disease pathogenesis of MF. Together, we not only suggest individualized therapy in MF that is guided by genomic signature but also its early implementation potentially in prefibrotic MF.
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Terapia Molecular Dirigida , Mielofibrosis Primaria/terapia , Animales , Desarrollo de Medicamentos , Genómica , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Inmunoterapia/métodos , Inhibidores de las Cinasas Janus/farmacología , Ratones , Mutación , Medicina de Precisión , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/fisiopatologíaRESUMEN
BACKGROUND AND AIM: Splanchnic vein thrombosis (SVT) is a potentially life-threatening complication of liver cirrhosis. This study aimed to evaluate the impact of a multi-disciplinary approach and early anticoagulation therapy (AT) on bleeding/thrombotic events, recanalization rates and outcome of cirrhotic patients with SVT. METHODS: This is a single-center, registry-based cohort study. Over 17 years, 149 SVT patients were enrolled and prospectively evaluated. Regarding cirrhotic-SVT, a pre-specified algorithm, guiding initial posology of AT and follow-up visits schedule, was performed. Major bleeding (MB), thrombotic events, functional liver scores and all cause-mortality were investigated. Efficacy of AT was evaluated by radiological imaging. RESULTS: In cirrhotic-SVT, the incidence rate of MB was 8.4 per 100 patient-year (95% CI, 3.83-15.97), while the incidence rate of thrombosis was 5.6 per 100 patient-year (95% CI, 2.05-12.2). In incidental SVT treated with AT, MB incidence was 6.5 per 100 patient-year (95% CI: 2.8-12.82), while in symptomatic SVT was 2.2 per 100 patient-year (95% CI: 0.25-8.02). All thrombotic recurrences occurred in incidental SVT (7.7 per 100 patient-years; 95% CI, 3.71-14.26). Overall survival was significantly higher in patients who had at least a partial recanalization (p < 0.01) and partial/total recanalization was independently associated with improved MELD score at multivariate analysis (HR 2.62, 95% CI 1.1-6.47, p = 0.03). CONCLUSION: In cirrhotic SVT patients, partial or total resolution of thrombosis ameliorates liver function and is associated with higher overall survival. A multidisciplinary approach together with radiological follow-up at pre-fixed time improves patient selection and monitoring.