RESUMEN
We sought to appraise the value of overall response and salvage chemotherapy, inclusive of allogeneic hematopoietic stem cell transplant (AHSCT), in primary refractory acute myeloid leukemia (prAML). For establishing consistency in clinical practice, the 2017 European LeukemiaNet (ELN) defines prAML as failure to attain CR after at least 2 courses of intensive induction chemotherapy. Among 60 consecutive patients (median age 63 years) correspondent with ELN-criteria for prAML, salvage was documented in 48 cases, 30/48 (63%) being administered intensive chemotherapy regimens and 2/48 consolidated with AHSCT as first line salvage. 13/48 (27%) attained response: CR, 7/13 (54%), CRi, 2/13 (15%), MLFS, 4/13 (31%). The CR/CRi rate was 9/48 (19%), with CR rate of 7/48 (15%). On univariate analysis, intermediate-risk karyotype was the only predictor of response (44% vs 17% in unfavorable karyotype; P = 0.04). Administration of any higher-dose (>1 g/m2) cytarabine intensive induction (P = 0.50), intensive salvage chemotherapy (P = 0.72), targeted salvage (FLT3 or IDH inhibitors) (P = 0.42), greater than 1 salvage regimen (P = 0.89), age < 60 years (P = 0.30), and de novo AML (P = 0.10) did not enhance response achievement, nor a survival advantage. AHSCT was performed in 12 patients with (n = 8) or without (n = 4) CR/CRi/MLFS. 1/2/5-year overall survival (OS) rates were 63%/38%/33% in patients who received AHSCT (n = 12) vs 27%/0%/0% in those who achieved CR/CRi/MLFS but were not transplanted (n = 5), vs 14%/0%/0% who were neither transplanted nor achieved CR/CRi/MLFS (n = 43; P < 0.001); the median OS was 18.6, 12.6 and 5.6 months, respectively. Although CR/CRi/MLFS bridged to AHSCT (n = 8), appeared to manifest a longer median OS (20 months), vs (13.4 months) for those with no response consolidated with AHSCT (n = 4), the difference was not significant P = 0.47. We conclude AHSCT as indispensable for securing long-term survival in prAML (p = 0.03 on multivariate analysis), irrespective of response achievement.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Quimioterapia de Inducción , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Terapia Recuperativa , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
After accounting for misdiagnosis and treatment effect, allele-specific (AS)-PCR detects the JAK2V617F mutation in >95% of polycythemia vera (PV) patients. Using database inquiry, we identified 6 of a total 220 cases with PV that were JAK2V617F-negative (prevalence=3%). Of these, five cases ( approximately 80%) were found to harbor one of the two JAK2 exon 12 mutations (F537-K539delinsL or N542-E543del) in bone marrow (BM) and/or peripheral blood cells. Similar screening of six additional cases - three each with idiopathic erythrocytosis (IE) or otherwise unexplained erythrocytosis (UE) - did not reveal either JAK2V617F or JAK2 exon 12 mutations. We found JAK2 exon 12 mutations in PV cases to be readily detected by both DNA sequencing and AS-PCR, regardless of whether BM or peripheral blood cells were used as the source for DNA. Although erythroid hyperplasia was the predominant histologic feature on BM examination, megakaryocyte abnormalities and reticulin fibrosis were noted in most PV patients harboring exon 12 mutations. However, similar BM morphologic changes can also be seen in some JAK2V617F-positive PV cases; therefore, distinct genotype-phenotype association cannot be established.
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Janus Quinasa 2/genética , Mutación Puntual , Policitemia Vera/epidemiología , Policitemia Vera/genética , Adolescente , Adulto , Anciano , Médula Ósea/patología , Bases de Datos Factuales , Células Eritroides/patología , Exones/genética , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Policitemia Vera/patología , PrevalenciaRESUMEN
By direct analysis of the polypeptide constituents of leukemic cells, we have previously detected several polypeptides that are restricted in their expression to acute lymphoblastic leukemia (ALL). In this study, we provide evidence that two polypeptides designated L2 and L4 are structurally related and represent novel markers for common ALL. Partial amino acid sequence analysis did not uncover differences between L2 and L4. The sequences obtained correspond to a previously cloned human gene designated hsp 27 that is expressed, following heat shock treatment, in a variety of cells. 32Pi incorporation studies indicate that L4 is an unphosphorylated form and L2 is a phosphorylated form of hsp27. The two forms were inducible by heat shock in leukemic and nonleukemic lymphoid cells. Thus, in acute leukemia, the common ALL subtype is uniquely characterized by the constitutive expression of a polypeptide that represents a major cellular phosphoprotein.
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Biomarcadores de Tumor/análisis , Proteínas de Choque Térmico/análisis , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Tumorales Cultivadas/análisis , Secuencia de Aminoácidos , Antígenos CD/análisis , Linfoma de Burkitt/genética , Línea Celular , Electroforesis en Gel Bidimensional , Proteínas de Choque Térmico/genética , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Datos de Secuencia Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Homología de Secuencia de Ácido Nucleico , Células Tumorales Cultivadas/inmunologíaRESUMEN
In 2012, the International Working Group for Myeloproliferative Neoplasms (MPN) Research and Treatment (IWG-MRT) reported an associations between mild bone marrow (BM) fibrosis (⩾grade 1) in polycythemia vera (PV) and a lower incidence of thrombosis during the clinical course and a higher risk of fibrotic progression. The objective in the current study of 262 patients with PV was to validate these observations and also identify other risk factors for myelofibrosis-free survival (MFFS). About 127 (48%) patients displayed ⩾grade 1 reticulin fibrosis at the time of diagnosis; presenting clinical and laboratory features were not significantly different between patients with or without BM fibrosis. In univariate analysis, BM fibrosis had no significant impact on overall, leukemia-free or thrombosis-free survival, whereas a significant association was noted for MFFS (P=0.009, hazard ratio 2.9; 95% confidence interval 1.32-6.78); other risk factors for MFFS included leukocytosis ⩾15 × 109/l, presence of palpable splenomegaly and abnormal karyotype. During multivariable analysis, leukocytosis ⩾15 × 109/l, palpable splenomegaly and ⩾grade 1 BM reticulin fibrosis remained significant. The current study validates the previously observed association between ⩾grade 1 BM reticulin fibrosis in PV and subsequent fibrotic progression, and identifies leukocytosis and palpable splenomegaly as additional risk factors for fibrotic progression; additional studies are required to clarify the impact of BM fibrosis on thrombosis and that of abnormal karyotype on MFFS.
Asunto(s)
Médula Ósea/patología , Policitemia Vera/diagnóstico , Policitemia Vera/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Biopsia , Médula Ósea/metabolismo , Progresión de la Enfermedad , Femenino , Fibrosis , Humanos , Janus Quinasa 2/genética , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Policitemia Vera/genética , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/mortalidad , Pronóstico , Reticulina/metabolismo , Adulto JovenRESUMEN
In a recent International Working Group on Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) study, prior arterial events and hypertension were predictors of subsequent arterial thrombosis whereas prior venous events and age ≥65 years predicted venous thrombosis in polycythemia vera (PV). In the current study, we sought to validate the above findings and identify additional predictors of arterial versus venous thrombosis. At a median follow up of 109 months, thrombosis after diagnosis occurred in 128 (22%) patients; 82 (14%) arterial and 57 (10%) venous events. On multivariate analysis, prior arterial events (<0.0001), hyperlipidemia (p = 0.03), and hypertension (p = 0.02) predicted subsequent arterial events. In comparison, prior venous events (p = 0.05), leukocytosis ≥11 × 109/L (p = 0.002), and major hemorrhage (p = 0.02) were predictors of subsequent venous events. Salient associations with arterial thrombosis included age ≥ 60 years, hypertension, diabetes, hyperlipidemia and normal karyotype whereas age ≤ 60 years, females, palpable splenomegaly and history of major hemorrhage were associated with venous thrombosis. TET2 or ASXL1 mutations did not impact arterial nor venous thrombosis. In conclusion, we identify distinct associations for arterial versus venous thrombosis in PV and confirm that a prior arterial or venous thrombotic event is the most reliable predictor of subsequent events.
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Policitemia Vera/complicaciones , Trombosis/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de Riesgo , Trombosis/epidemiología , Adulto JovenRESUMEN
Current prognostic models for myelodysplastic syndromes (MDS), including the Revised International Prognostic Scoring System (IPSS-R), do not account for host immunity. We retrospectively examined the prognostic relevance of monocytopenia, lymphocytopenia and lymphocyte-to-monocyte ratio (LMR) in a cohort of 889 patients with primary MDS. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformation were documented. In univariate analysis, subnormal absolute lymphocyte count (ALC) <0.9 × 109/l; P=0.001), ALC<1.2 × 109/l (P=0.0002), subnormal absolute monocyte count (AMC) <0.3 × 109/l (P=0.0003), LMR (P⩽0.0001) and LMR⩾5 (P=0.03) were all associated with inferior overall survival. In multivariable analysis that included other risk factors, significance was retained for LMR (P=0.02) and became borderline for ALC <1.2 × 109/l (P=0.06). Analysis in the context of IPSS-R resulted in P-values of 0.06 for ALC<1.2 × 109/l, 0.7 for monocytopenia and 0.2 for LMR. Leukemia-free survival was not affected by ALC, AMC or LMR. The observations from the current study suggest a possible detrimental role for altered host immunity in primary MDS, which might partly explain the therapeutic benefit of immune-directed therapy, including the use of immune modulators; however, IPSS-R-independent prognostic value for either ALC or AMC was limited.
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Recuento de Leucocitos , Linfocitos , Linfopenia/sangre , Monocitos , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/metabolismo , Médula Ósea/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/epidemiología , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
Mutations involving epigenetic regulators (TET2~60% and ASXL1~40%) and splicing components (SRSF2~50%) are frequent in chronic myelomonocytic leukemia (CMML). On a 27-gene targeted capture panel performed on 175 CMML patients (66% males, median age 70 years), common mutations included: TET2 46%, ASXL1 47%, SRSF2 45% and SETBP1 19%. A total of 172 (98%) patients had at least one mutation, 21 (12%) had 2, 24 (14%) had 3 and 30 (17%) had >3 mutations. In a univariate analysis, the presence of ASXL1 mutations (P=0.02) and the absence of TET2 mutations (P=0.03), adversely impacted survival; while the number of concurrent mutations had no impact (P=0.3). In a multivariable analysis that included hemoglobin, platelet count, absolute monocyte count and circulating immature myeloid cells (Mayo model), the presence of ASXL1 mutations (P=0.01) and absence of TET2 mutations (P=0.003) retained prognostic significance. Patients were stratified into four categories: ASXL1wt/TET2wt (n=56), ASXL1mut/TET2wt (n=31), ASXL1mut/TET2mut (n=50) and ASXL1wt/TET2mut (n=38). Survival data demonstrated a significant difference in favor of ASXL1wt/TET2mut (38 months; P=0.016), compared with those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (21 months) and ASXL1mut/TET2mut (16 months) (P=0.3). We confirm the negative prognostic impact imparted by ASXL1 mutations and suggest a favorable impact from TET2 mutations in the absence of ASXL1 mutations.
Asunto(s)
Proteínas de Unión al ADN/genética , Epistasis Genética , Estudios de Asociación Genética , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/mortalidad , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dioxigenasas , Femenino , Regulación Leucémica de la Expresión Génica , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
CD123 is the α-subunit of the interleukin-3 receptor; it represents a potential therapeutic target in systemic mastocytosis (SM) given its absent expression on normal/reactive mast cells (MCs) and aberrant expression on neoplastic MCs. We studied 58 SM patients to define CD123 expression patterns by immunohistochemistry and its clinical significance. Two hematopathologists independently scored bone marrow slides using predefined histologic parameters. In all, 23 patients had indolent SM (ISM), 10 aggressive SM (ASM), 23 SM with associated hematological neoplasm (SM-AHN) and 2 had mast cell leukemia (MCL). MC_CD123 expression was demonstrable in 37 (64%) cases; expression rates were 100%, 61%, 57% and 0% in ASM, ISM, SM-AHN and MCL, respectively (P=0.02). Focal proliferation of plasmacytoid dendritic cells (PDCs) around MC aggregates, suggesting a tumor-promoting role for PDCs, was noted in 44 (76%) cases, and was significantly higher in CD123-positive versus -negative cases (87% versus 50%, P=0.005). CD123 expression and its staining intensity had prognostic value in SM-chronic myelomonocytic leukemia and nonindolent SM patients, respectively. These observations suggest that targeting CD123 in SM may have direct (via MCs) and indirect (via PDCs) antitumor effects and clinical trials to that effect require laboratory correlative studies to address the observed target expression heterogeneity.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Hematológicas/metabolismo , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Leucemia de Mastocitos/metabolismo , Mastocitosis Sistémica/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/patología , Humanos , Técnicas para Inmunoenzimas , Leucemia de Mastocitos/patología , Masculino , Mastocitosis Sistémica/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios RetrospectivosRESUMEN
PURPOSE: This study was undertaken to evaluate the tumor targeting, toxicity, and therapeutic potential of the anti-B-cell-reactive monoclonal antibody MB-1 (anti-CD37) labeled with iodine 131 given in a nonmarrow ablative dose range in B-cell lymphoma patients who relapsed after chemotherapy. PATIENTS AND METHODS: Twelve patients with MB-1-reactive tumors were infused first with 40 mg of trace-labeled (3 to 7 mCi) MB-1. Ten patients who had no serious toxicity postinfusion and who had successful tumor imaging on serial gamma scans then received at least one 40-mg radioimmunotherapy (RIT) dose (25 to 161 mCi). Tracer estimates of delivered whole-body dose (WBD) were used in prescribing a millicurie RIT dose for seven patients. RESULTS: Eleven patients had positive tumor imaging after a tracer dose, including patients with bulky tumors and/or large tumor burdens (> or = 1 kg) +/- splenomegaly. However, overall sensitivity for the detection of known tumor sites was only 39%. In six of eight patients with dose-assessable tumors, the radiation dose to at least one tumor was 1.1 to 3.1 times higher than to any normal organ, excluding the spleen for a 40-mg tracer dose. Tracer-dose toxicities included reversible glossal edema in one patient, grade 3 hepatic transaminasemia in another, and early drops in both circulating B and T cells (with decreases in B cells more pronounced) in nearly all patients. RIT toxicity was primarily myelosuppression (especially thrombocytopenia), which had a delayed onset and protracted recovery (without significant recovery until at least 2 months post-RIT). Grade 3 myelosuppression in two of two patients who were treated at a tracer-projected 50-cGy WBD level (133 and 149 mCi) precluded further planned RIT dose escalation. Less myelosuppression was generally observed in patients who were treated at < or = 40-cGy WBD levels. Antimouse antibodies developed in two patients. Six patients had tumor responses post-RIT. Four had responses that lasted more than 1 month (2 to 6 months), which included one complete response, one partial response, one minor response, and one mixed response. Responses seemed to occur more frequently in imaged tumors than in nonimaged tumors. The most durable response occurred in a patient who had the best antibody targeting to tumor. CONCLUSIONS: Although 131I-MB-1 has limited diagnostic value, it can produce tumor responses at nonmarrow ablative RIT doses. Further studies that focus on improving tumor targeting with this or other B-cell-reactive radiolabeled antibodies and on ameliorating the myelosuppression associated with the RIT-dosing approach used in this trial are warranted.
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Antígenos CD/inmunología , Antígenos de Neoplasias , Glicoproteínas/inmunología , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B/radioterapia , Radioinmunoterapia/métodos , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Radioisótopos de Yodo/uso terapéutico , Linfoma de Células B/inmunología , Masculino , Persona de Mediana Edad , Dosis de Radiación , Radioinmunoterapia/efectos adversos , Cintigrafía , Dosificación Radioterapéutica , Recurrencia , Tetraspaninas , Tomografía Computarizada por Rayos XRESUMEN
This report describes a single institution's recent experience with six patients fulfilling the diagnostic criteria of chronic neutrophilic leukemia. No patient had the Philadelphia chromosome or the BCR/ABL fusion gene. None of the common cytogenetic abnormalities characteristic of myeloid disorders were detected. Two patients demonstrated clonal evolution during the course of the disease. All responded initially to therapy with hydroxyurea with control of leukocytosis and reduction in splenomegaly. Three patients eventually became refractory to hydroxyurea, manifesting progressive neutrophilia without blastic transformation. Aggressive chemotherapy to control progressive leukocytosis resulted in death due to cytopenias in two of these patients. The third patient received less intensive chemotherapy and died of progressive disease. One patient died after transformation of the disease into undifferentiated acute myeloid leukemia. Two patients remain alive with stable disease on hydroxyurea therapy, 12 and 54 months after initial diagnosis. Chronic neutrophilic leukemia is a rare clinicopathologic entity that can be distinguished from chronic myelogenous leukemia, the recently described neutrophilic-chronic myelogenous leukemia, and myelodysplastic syndrome. The clinical course is heterogeneous, with a definite risk of death from either blastic transformation or progressive neutrophilic leukocytosis. Continued study and reporting of these cases must be encouraged.
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Leucemia Neutrofílica Crónica , Humanos , Leucemia Neutrofílica Crónica/genética , Leucemia Neutrofílica Crónica/patología , Leucemia Neutrofílica Crónica/fisiopatologíaRESUMEN
A new human plasma cell line, UMJF-2, has been derived from the bone marrow of a patient with multiple myeloma. Morphological studies disclosed large nucleoli, moderate numbers of mitochondria, and scant endoplasmic reticulum consistent with a plasmablastic morphology. The cells have immunologic characteristics of early plasma cells, including intense expression of cytoplasmic IgG-lambda and weaker, but discernible, expression of surface IgG-lambda. Cell surface antigens defined by the monoclonal antibodies OKT10 (CD38) and PCA-1, characteristic of mature plasma cells, and B1 (CD20), B4 (CD19), and I-2 (HLA-DR), characteristic of earlier stages of B-lymphocyte differentiation, are present on UMJF-2 cells. Cytogenetic studies reveal the presence of trisomy 12. UMJF-2 does not contain the Epstein-Barr virus by Southern blot analysis. Tissue culture media conditioned by these cells contains a soluble immunosuppressive factor, capable of inhibiting pokeweed mitogen induced IgM secretion by normal human B-lymphocytes. UMJF-2 provides a model for the study of the pathogenesis of polyclonal hypogammaglobulinemia in human multiple myeloma.
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Linfocitos B/inmunología , Inmunoglobulina M/metabolismo , Mieloma Múltiple , Anciano , Antígenos de Superficie/análisis , Línea Celular , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Inmunofenotipificación , Cariotipificación , Masculino , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Mieloma Múltiple/patologíaRESUMEN
We have found a single 4p+ chromosomal abnormality, 46,XX, -4, +der(4)t(3;4)(q13.3;p16), in a patient with an unusual B cell leukemia of mature phenotype characterized by a high white cell count, tartrate-resistant acid phosphatase-positive malignant cells, splenic white pulp proliferation, and a serum IgM monoclonal gammopathy. The malignant cells were characterized by surface expression of CD19 (B4), CD20 (B1), IgM, IgD, kappa, and HLA-DR. They were weakly positive for CD21 (B2) and negative for CD25 (interleukin-2 receptor). The malignant cells also showed clonal rearrangement of the immunoglobulin heavy chain and kappa light chain genes. A cell line, designated HCLW-3B, was derived from unstimulated peripheral blood obtained during the leukemic phase and was found to contain the same 4p+ chromosomal abnormality as well as genomic sequences of the Epstein-Barr virus nuclear antigen. A somatic cell hybrid constructed from HCLW-3B containing the derivative chromosome 4 was used to confirm that chromosome 3q was the source of the translocated material. The availability of a cell line which is clonally derived from the patient's circulating leukemia cells should permit further characterization of this translocation at the molecular level.
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Aberraciones Cromosómicas/genética , Cromosomas Humanos Par 4 , Leucemia de Células B/genética , Southern Blotting , Aberraciones Cromosómicas/patología , Bandeo Cromosómico , Trastornos de los Cromosomas , Sondas de ADN , ADN Viral/análisis , Femenino , Reordenamiento Génico de Linfocito B , Genes de Inmunoglobulinas , Herpesvirus Humano 4/genética , Humanos , Persona de Mediana Edad , Translocación Genética , Células Tumorales CultivadasRESUMEN
Initial work has shown that clonal B cells from B-chronic lymphocytic leukemia (B-CLL) are able to synthesize pro-angiogenic molecules. In this study, our goal was to study the spectrum of angiogenic factors and receptors expressed in the CLL B cell. We used ELISA assays to determine the levels of basic fibroblast growth factors (bFGF), vascular endothelial growth factor (VEGF), endostatin, interferon-alpha (IFN-alpha) and thrombospondin-1 (TSP-1) secreted into culture medium by purified CLL B cells. These data demonstrated that CLL B cells spontaneously secrete a variety of pro- and anti-angiogenic factors, including bFGF (23.9 pg/ml +/- 7.9; mean +/- s.e.m.), VEGF (12.5 pg/ml +/- 2.3) and TSP-1 (1.9 ng/ml +/- 0.3). Out of these three factors, CLL B cells consistently secreted bFGF and TSP-1, while VEGF was expressed in approximately two-thirds of CLL patients. Of interest, hypoxic conditions dramatically upregulated VEGF expression at both the mRNA and protein levels. We also employed ribonuclease protection assays to assay CLL B cell expression of a variety of other angiogenesis-related molecules. These analyses revealed that CLL B cells consistently express mRNA for VEGF receptor 1 (VEGFR1), thrombin receptor, endoglin, and angiopoietin. Further analysis of VEGFR expression by RT-PCR revealed that CLL B cells expressed both VEGFR1 mRNA and VEGFR2 mRNA. In summary, these data collectively indicate that CLL B cells express both pro- and anti-angiogenic molecules and several vascular factor receptors. Because of the co-expression of angiogenic molecules and receptors for some of these molecules, these data suggest that the biology of the leukemic cells may also be directly impacted by angiogenic factors as a result of autocrine pathways of stimulation.
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Inhibidores de la Angiogénesis/biosíntesis , Linfocitos B/metabolismo , Sustancias de Crecimiento/biosíntesis , Leucemia Linfocítica Crónica de Células B/metabolismo , Antígenos CD , Comunicación Autocrina , Linfocitos B/patología , Células Clonales/metabolismo , Células Clonales/patología , Estudios de Cohortes , Colágeno/análisis , Colágeno/metabolismo , Endoglina , Endostatinas , Factores de Crecimiento Endotelial/análisis , Factores de Crecimiento Endotelial/metabolismo , Factor 2 de Crecimiento de Fibroblastos/análisis , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Mutación de Línea Germinal , Humanos , Interferón-alfa/análisis , Interferón-alfa/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Linfocinas/análisis , Linfocinas/metabolismo , Fragmentos de Péptidos/análisis , Fragmentos de Péptidos/metabolismo , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Superficie Celular , Receptores de Factores de Crecimiento/biosíntesis , Receptores de Factores de Crecimiento/genética , Receptores de Trombina/genética , Receptores de Factores de Crecimiento Endotelial Vascular , Trombospondina 1/análisis , Trombospondina 1/metabolismo , Células Tumorales Cultivadas , Molécula 1 de Adhesión Celular Vascular/genética , Factor A de Crecimiento Endotelial Vascular , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Although KITD816V occurs universally in adult systemic mastocytosis (SM), the clinical heterogeneity of SM suggests presence of additional phenotype-patterning mutations. Because up to 25% of SM patients have KITD816V-positive eosinophilia, we undertook whole-exome sequencing in a patient with aggressive SM with eosinophilia to identify novel genetic alterations. We conducted sequencing of purified eosinophils (clone/tumor sample), with T-lymphocytes as the matched control/non-tumor sample. In addition to KITD816V, we identified a somatic missense mutation in ethanolamine kinase 1 (ETNK1N244S) that was not present in 50 healthy controls. Targeted resequencing of 290 patients showed ETNK1 mutations to be distributed as follows: (i) SM (n=82; 6% mutated); (ii) chronic myelomonocytic leukemia (CMML; n=29; 14% mutated); (iii) idiopathic hypereosinophilia (n=137; <1% mutated); (iv) primary myelofibrosis (n=32; 0% mutated); and (v) others (n=10; 0% mutated). Of the 82 SM cases, 25 had significant eosinophilia; of these 20% carried ETNK1 mutations. The ten mutations (N244S=6, N244T=1, N244K=1, G245A=2) targeted two contiguous amino acids in the ETNK1 kinase domain, and are predicted to be functionally disruptive. In summary, we identified novel somatic missense ETNK1 mutations that were most frequent in SM with eosinophilia and CMML; this suggests a potential pathogenetic role for dysregulated cytidine diphosphate-ethanolamine pathway metabolites in these diseases.
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Eosinofilia/genética , Leucemia Mielomonocítica Crónica/genética , Mastocitosis Sistémica/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adulto , Anciano , Anciano de 80 o más Años , Eosinofilia/complicaciones , Eosinofilia/patología , Exoma/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mielomonocítica Crónica/complicaciones , Leucemia Mielomonocítica Crónica/patología , Masculino , Mastocitosis Sistémica/complicaciones , Mastocitosis Sistémica/patología , Persona de Mediana Edad , MutaciónRESUMEN
In patients with chronic myelomonocytic leukemia (CMML), age>65 years is an adverse prognostic factor. Our objective in the current study was to examine risk factors for survival and treatment outcome in 261 'young' adults with CMML, as defined by age ⩽65 years. In multivariable analysis, lower HB (P=0.01), higher circulating blast % (P=0.002), ASXL1 (P=0.0007) and SRSF2 mutations (P=0.008) and Mayo-French cytogenetic stratification (P=0.04) negatively impacted survival. Similarly, leukemia-free survival was independently affected by higher circulating blast % (P<0.0001), higher bone marrow blast % (P=0.0007) and the presence of circulating immature myeloid cells (P=0.0002). Seventy-five (29%) patients received hypomethylating agents (HMA), with the median number of cycles being 5, and the median duration of therapy being 5 months. The over-all response rate was 40% for azacitidine and 30% for decitabine. Fifty-three (24%) patients underwent an allogeneic hematopoietic stem cell transplant (AHSCT), with a response rate of 56% and a non-relapse mortality of 19%. Survival in young adults with CMML, although higher than in older patients, is poor and even worse in the presence of ASXL1 and SRSF2 mutations. Treatment outcome was more impressive with AHSCT than with HMA and neither was influenced by ASXL1/SRSF2 mutations or karyotype.
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Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/genética , Proteínas Nucleares/genética , Pronóstico , Ribonucleoproteínas/genética , Adulto , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mielomonocítica Crónica/epidemiología , Leucemia Mielomonocítica Crónica/patología , Masculino , Persona de Mediana Edad , Mutación , Factores de Empalme Serina-Arginina , Resultado del Tratamiento , Adulto JovenRESUMEN
The nature of T cells contained within cutaneous lesions of cutaneous T-cell lymphoma (CTCL) has not been studied at the clonal level. T cells extracted from skin lesions of two CTCL patients were cloned by limiting dilution and propagated in interleukin-2 (IL-2) containing medium with periodic lectin stimulation. Twelve T-cell clones were derived from each patient. In both cases, genotypic analysis of the T-cell clones revealed that these clones had T-cell receptor (TCR) beta- and gamma-chain gene rearrangements distinct from the predominant, presumably malignant, clone present in the skin, lymph nodes, or blood. This suggests that they were derived from presumably reactive (non-malignant) T cells. Furthermore, these clones had gene rearrangements different from each other, indicating their multiple clonal origins. The failure to propagate in vitro the CTCL T-cell clone suggests that CTCL cells may have growth requirements different from normal T cells. Thus, conventional T-cell culturing methods using IL-2 and lectins as mitogen may selectively propagate the presumably reactive T cells contained within the skin lesions. The ability to selectively grow these reactive lesional T cells (so-called tumor infiltrating lymphocytes) raises the possibility that these cells could be used in adoptive immunotherapy.
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Linfoma/patología , Neoplasias Cutáneas/patología , Piel/patología , Linfocitos T/fisiología , División Celular , Células Clonales , Reordenamiento Génico , Genotipo , Humanos , Linfoma/genética , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T alfa-beta , Receptores de Antígenos de Linfocitos T gamma-delta , Neoplasias Cutáneas/genética , Linfocitos T/patologíaRESUMEN
Acute lymphoblastic leukemia with eosinophilia is a rare but distinctive clinical entity. The eosinophilia in these patients can present before, concomitantly, or after the diagnosis of leukemia. Patients with this syndrome often suffer from the cardiovascular complications of severe eosinophilia, suffering excess morbidity and mortality as a result of their eosinophilia. Treatment of the eosinophilia in this syndrome consists of administration of induction chemotherapy, followed by prednisone and hydroxyurea if required for persistent eosinophilia. Eosinophilia often resolves with remission of leukemia, only to return at the time of relapse in a high percentage of cases. Patients with this syndrome characteristically have cytogenetic abnormalities involving the long arms of chromosomes 5 and 14. These cytogenetic abnormalities are not commonly seen in acute lymphoblastic leukemia and suggest that this syndrome may have a distinct pathophysiology and etiology. The affected region on chromosome 5 contains genes that control hematopoiesis, including eosinophilopoiesis. Further investigations into these cytogenetic abnormalities may provide insight into the etiology of the leukemia and eosinophilia characteristic of this syndrome.
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Cromosomas Humanos Par 5 , Eosinofilia/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Aberraciones Cromosómicas , Eosinofilia/sangre , Eosinofilia/genética , Eosinófilos/fisiología , Femenino , Humanos , Cariotipificación , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , SíndromeRESUMEN
It is likely that a significant number of cases of THL will continue to be misdiagnosed unless appropriate cytochemical and immunologic markers are incorporated into the panel of studies performed at diagnosis. The clinical findings are nonspecific. With the possible exception of skin infiltration, the frequency of symptoms and signs appear to approximate those of intermediate grade lymphomas. Most commonly, it is the histopathological features that suggest the histiocytic nature of a malignant process, but these alone are not sufficient to secure the diagnosis. Thus, in the absence of a clearly defined lymphoid origin, it is the detection of specific histiocytic markers that establishes a lymphoma as THL. Only the recognition and careful study of additional cases will potentially enable clinical investigators to identify any unique characteristics and distinguish this disease from other lymphomas. For the present, it would appear that the treatment indicated for a patient with diffuse large cell lymphoma would also be appropriate for a comparable patient with THL. Although long-term disease-free survival in THL is possible, there are presently inadequate data to estimate curability.
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Linfoma de Células B Grandes Difuso/diagnóstico , Adulto , Anciano , Anticuerpos Monoclonales , Antígenos de Superficie/análisis , Niño , Femenino , Humanos , Inmunohistoquímica , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
Lymphocyte-predominant Hodgkin's disease (LPHD) is a subtype of Hodgkin's disease characterized by an indolent clinical course and by distinctive histological and immunological features. Coexistence of diffuse or nodular LPHD with large-cell non-Hodgkin's lymphoma (NHL) distant from the presenting site has rarely been reported. We studied three cases of simultaneous LPHD and large-cell NHL. Two cases involved men, aged 66 and 20 years, with neck and axillary masses, respectively. Biopsy of each mass revealed nodular LPHD. In one case the spleen contained areas of both LPHD and large-cell NHL, whereas only large-cell NHL was found in the spleen of the other patient. The patients are alive 49 months and 29 months after diagnosis. The third case was from a 4-year-old boy with a neck mass that revealed both diffuse LPHD and areas of large-cell NHL. Local recurrence prompted therapy, and the boy is in complete remission 31 months after diagnosis. Immunophenotyping in all three cases showed the Reed-Sternberg variant lymphocytic and histiocytic cells to be B-lymphocytes. The NHL cells in two cases were B-cells; in the child, the cells reacted only with leukocyte common antigen. Immunoglobulin heavy- and light-chain genes were rearranged in the NHL cells in the spleen of one case, and heavy-chain genes were rearranged in the lymph node of the child. It appears that when large-cell NHL and LPHD occur simultaneously, even when the large-cell NHL occurs at a site distant from the LPHD, the patient's clinical course is like the indolent course of LPHD rather than like the typically aggressive course of large-cell NHL. This clinical course, together with immunophenotyping and genotyping studies, suggests a developmental relationship between these two lymphomas when they occur simultaneously.
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Enfermedad de Hodgkin/complicaciones , Linfocitos/patología , Linfoma de Células B Grandes Difuso/complicaciones , Adulto , Anciano , Preescolar , Genotipo , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Humanos , Inmunoglobulinas/metabolismo , Inmunohistoquímica , Inmunofenotipificación , Ganglios Linfáticos/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/patología , MasculinoRESUMEN
Hairy cell leukemia is a distinct chronic lymphoproliferative disorder composed of morphologically unique B-lymphocytes. The diagnosis of hairy cell leukemia is usually based on the morphology of blood/bone marrow aspirate smears and bone marrow sections. We report three cases of hairy cell leukemia that had an unusual multilobated nuclear appearance seen on both smears and tissue sections. Many of the hairy cells exhibited marked nuclear lobulations and convolutions, giving rise to clover leaf-like nuclear configurations. The nuclear chromatin was finely reticular and characteristic of hairy cell leukemia. Bone marrow sections were hypercellular and the leukemic infiltrate was loosely distributed. A leukemic infiltrate was also seen in splenic sections in two cases in which splenectomy was carried out. Tartrate-resistant acid phosphatase cytochemistry was positive in all three cases. Flow cytometric analysis and paraffin section immunoperoxidase studies confirmed the B-cell lineage of the leukemic cells in all cases. The multilobulated nuclei described in these three cases are quite unusual in hairy cell leukemia; they could potentially lead to an erroneous diagnosis of T-cell lymphoma or leukemia. Features typical of hairy cell leukemia, such as the nuclear chromatin distribution and pattern of bone marrow infiltration, together with the clinical history, are helpful in establishing a correct diagnosis of these variant cases of hairy cell leukemia.