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1.
Haematologica ; 103(3): 514-521, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29217776

RESUMEN

Melphalan at a dose of 200 mg/m2 is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m2 and melphalan 140 mg/m2 are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m2 (n=245) and melphalan 200 mg/m2 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m2 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m2versus melphalan 140 mg/m2: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m2 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m2 and melphalan 140 mg/m2 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m2 or melphalan 140 mg/m2 for key transplant outcomes (NCT01362972).


Asunto(s)
Melfalán/administración & dosificación , Mieloma Múltiple/terapia , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Recurrencia , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo/métodos , Resultado del Tratamiento
2.
Clin Immunol ; 183: 91-98, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28780376

RESUMEN

Invariant natural killer T (iNKT) cells are cytotoxic T cells that respond to glycolipid antigens presented by CD1d. Therapeutic activation of iNKT cells with α-galactosylceramide (α-GalCer) can prevent and reverse tumor growth in mice and clinical trials involving α-GalCer-stimulated iNKT cells are ongoing in humans. B cells express CD1d, however, we show that CD1d expression is reduced on B cells from patients with chronic lymphocytic leukemia (CLL). B cells from CLL patients pulsed with α-GalCer failed to stimulate cytolytic degranulation by iNKT cell lines, but could present the more potent glycolipid analogue, 7DW8-5. Retinoic acid receptor-α (RAR-α) agonists induced CD1d expression by CLL B cells, restoring their ability to present α-GalCer to CD8α+ iNKT cells, resulting in cytolytic degranulation. Thus, RAR-α agonists can augment the anti-tumor activities of iNKT cells against CLL cells in vitro. Their inclusion in iNKT cell-based therapies may benefit patients with CLL.


Asunto(s)
Presentación de Antígeno/efectos de los fármacos , Antígenos CD1d/efectos de los fármacos , Antineoplásicos/farmacología , Linfocitos B/efectos de los fármacos , Benzoatos/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Galactosilceramidas/farmacología , Células T Asesinas Naturales/efectos de los fármacos , Tetrahidronaftalenos/farmacología , Tretinoina/farmacología , Anciano , Anciano de 80 o más Años , Antígenos CD1d/inmunología , Linfocitos B/inmunología , Femenino , Humanos , Técnicas In Vitro , Leucemia Linfocítica Crónica de Células B , Masculino , Persona de Mediana Edad , Receptor alfa de Ácido Retinoico/agonistas
3.
Life Sci ; 290: 120236, 2022 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-34953891

RESUMEN

AIMS: We have recently described a novel guanidinium-based compound, VP79s, which induces cytotoxicity in various cancer cell lines. Here, we aim to investigate the activity of VP79s and associated mechanisms of action in multiple myeloma (MM) cells in vitro and ex vivo. MAIN METHODS: The effects of VP79s on cell viability and induction of apoptosis was examined in a panel of drug-sensitive and drug-resistant MM cell lines, as well as ex vivo patient samples and normal donor lymphocytes and platelets. Cell signaling pathways associated with the biological effects of VP79s were analysed by immunoblotting and flow cytometry. Gene expression changes were assessed by quantitative real-time PCR analysis. KEY FINDINGS: VP79s was found to rapidly inhibit both constitutively active and IL-6-induced STAT3 signaling with concurrent downregulation of the IL-6 receptors, CD130 and CD126. VP79s induced a rapid and dose-dependent downregulation of anti-apoptotic Bcl-2 family member, myeloid cell leukaemia-1 (MCL-1). VP79s enhanced bortezomib induced cell death and was also found to overcome bone marrow stromal cell induced drug resistance. VP79s exhibited activity in ex vivo patient samples at concentrations which had no effect on peripheral blood mononuclear cells, lymphocytes and platelets isolated from healthy donors. SIGNIFICANCE: As VP79s resulted in rapid inhibition of the key IL-6/STAT3 signaling pathway and downregulation of MCL-1 expression with subsequent selective anti-myeloma activity, VP79s may be a potential therapeutic agent with a novel mechanism of action in MM cells.


Asunto(s)
Guanidina/farmacología , Mieloma Múltiple/tratamiento farmacológico , Factor de Transcripción STAT3/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Expresión Génica/genética , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/genética , Guanidina/análogos & derivados , Humanos , Interleucina-6/metabolismo , Janus Quinasa 1/metabolismo , Quinasas Janus/metabolismo , Leucemia/tratamiento farmacológico , Leucocitos Mononucleares/metabolismo , Mieloma Múltiple/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/efectos de los fármacos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Células Mieloides , Factor de Transcripción STAT3/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
6.
Haematologica ; 91(3): 417-8, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16531269

RESUMEN

Autofluorescence is an immunophenotypic characteristic of leukemic blasts in acute promyelocytic leukemia (APL). We examined the fluorescent intensity of isotype controls in 25 cases of APML and 25 controls with acute myeloid leukemia. The fluorescence of the FITC- and PE-conjugated controls was consistently higher in APML. Autofluorescence may therefore represent a helpful diagnostic marker in APML.


Asunto(s)
Citometría de Flujo/métodos , Leucemia Promielocítica Aguda/diagnóstico , Crisis Blástica/diagnóstico , Crisis Blástica/patología , Separación Celular , Transformación Celular Neoplásica/patología , Fluorescencia , Humanos , Inmunofenotipificación , Leucemia Promielocítica Aguda/patología
7.
Leuk Lymphoma ; 47(11): 2371-9, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17107912

RESUMEN

Chronic lymphocytic leukemia (CLL) follows a variable clinical course which is difficult to predict at diagnosis. We assessed somatic mutation (SHM) status, CD38 and ZAP-70 expression in 87 patients (49 male, 38 female) with stage A CLL and known cytogenetic profile to compare their role in predicting disease progression, which was assessed by the treatment free interval (TFI) from diagnosis. Sixty (69%) patients were SHM+, 24 (28%) were CD38+ and ten (12%) were ZAP-70+. The median TFI for: (i) SHM + versus SHM- patients was 124 versus 26 months; hazard ratio (HR) = 3.6 [95% confidence interval (CI) = 1.8 - 7.3; P = 0.001]: (ii) CD38- versus CD38+ patients was 120 versus 34 months; HR = 2.4 (95% CI = 1.4 - 5.3; P = 0.02); and (iii) ZAP70- versus ZAP70+ was 120 versus 16 months; HR = 3.4 (95% CI = 1.4 - 8.7; P = 0.01). SHM status and CD38 retained prognostic significance on multivariate analysis whereas ZAP-70 did not. We conclude that ZAP-70 analysis does not provide additional prognostic information in this group of patients.


Asunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , ADP-Ribosil Ciclasa 1/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Tasa de Supervivencia , Proteína Tirosina Quinasa ZAP-70/metabolismo
8.
Case Rep Hematol ; 2013: 513049, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23653869

RESUMEN

Since the initial report of the BRAF V600E mutation in hairy cell leukemia, numerous investigators have demonstrated the presence of this activating mutation in nearly all cases of this disease. A case of hairy cell leukemia is documented with a classical clinical, morphological, immunophenotypic, and cytochemical profile in which the BRAF V600E was not detected. The diagnostic and therapeutic implications are discussed.

9.
Int J Oncol ; 42(1): 239-46, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23135704

RESUMEN

Although recent decades have seen an improved cure rate for newly diagnosed paediatric acute lymphoplastic leukaemia (ALL), the treatment options for adult ALL, T-cell ALL (T-ALL) and relapsed disease remain poor. We have developed a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds and established their anticancer efficacy in a variety of human tumour cell types. Here, we demonstrate that PBOX-15 inhibits cell growth, and induces G2/M cell cycle arrest and apoptosis in both T-ALL and B-cell ALL (B-ALL) cells. In addition, prior to PBOX-15-induced apoptosis, PBOX-15 decreases ALL cell adhesion, spreading and migration. Concurrently, PBOX-15 differentially down-regulates ß1-, ß2- and α4-integrin expression in ALL cells and significantly decreases integrin-mediated cell attachment. PBOX-15 interferes with the lateral mobility and clustering of integrins in both B-ALL and T-ALL cells. These data suggest that PBOX-15 is not only effective in inducing apoptosis in ALL cells, but also has the potential to disrupt integrin-mediated adhesion of malignant lymphocytes, which represents a novel avenue for regulating leukaemic cell homing and migration.


Asunto(s)
Apoptosis/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Integrinas/metabolismo , Microtúbulos/efectos de los fármacos , Oxazepinas/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pirroles/farmacología , Western Blotting , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Células Tumorales Cultivadas
10.
Leuk Res ; 36(4): 483-4, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22230299

RESUMEN

The spectrum of underlying molecular abnormalities of clinically and biologically heterogeneous chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL) has yet to be identified. While whole genome sequencing has identified several genes implicated in the pathogenesis and progression of CLL, the molecular lesions in a substantial proportion of patients remain to be elucidated. The incidence of the BRAF V600E mutation, widely implicated in solid tumours and other B-cell malignancies, was sought in a cohort of patients with CLL and related disorders. One CLL patient and one patient with B-prolymphocytic leukaemia (PLL) were found to harbour this mutation. Although present at a low frequency, the finding of BRAF V600E has biological and clinical implications for CLL and PLL.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Leucemia Prolinfocítica/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Secuencia de Bases , Western Blotting , Genotipo , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa
11.
Leuk Lymphoma ; 51(6): 1035-9, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20443674

RESUMEN

T-lymphoblastic leukemia/lymphoma (LBL and ALL) is a rare lymphoid malignancy typically presenting in adolescent and young adult males. Patients are traditionally treated with ALL-type protocols, with no consensus on the role of maintenance therapy, or allogeneic or autologous transplant. Outcome results are thus difficult to interpret. The successful use of intensified ALL protocols in patients <25 years with lymphoblastic malignancies without transplant prompted the Haematology Unit at St James's Hospital (SJH) to change practice in 2005 from transplanting in first complete remission (CR1) to treating patients <25 years with chemotherapy alone. We reviewed the outcome of patients treated before 2005 in order to compare the pre- and post-2005 management approaches in the future. This retrospective study included 31 patients with T-LBL treated from 1980 to 2004. The patients were divided into group A (16-25 years) and group B (>25 years). Twenty-one patients had an allograft in CR1 (group A, n = 12 and group B, n = 9). For the allografted patients the 5-year EFS and OS was 57%, with a treatment related mortality of 10%. In conclusion, this series confirms that allograft in CR1 has an acceptable cure rate, and we will use these results to benchmark outcomes using pediatric-type protocols in the future.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Terapia Combinada , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
12.
Cancer Res ; 69(21): 8366-75, 2009 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-19826055

RESUMEN

Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC(50) of 0.55 micromol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV(H) genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15-induced apoptosis. Pharmacologic inhibition of c-jun NH(2)-terminal kinase inhibited PBOX-15-induced apoptosis in mutated IgV(H) and ZAP-70(-) CLL cells but not in unmutated IgV(H) and ZAP-70(+) cells. PBOX-15 exhibited selective cytotoxicity in CLL cells compared with normal hematopoietic cells. Our data suggest that PBOX-15 represents a novel class of agents that are toxic toward both high-risk and low-risk CLL cells. The need for novel treatments is acute in CLL, especially for the subgroup of patients with poor clinical outcome and drug-resistant disease. This study identifies a novel agent with significant clinical potential.


Asunto(s)
Apoptosis/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B/patología , Oxazepinas/farmacología , Pirroles/farmacología , Tubulina (Proteína)/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Caspasa 8/metabolismo , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Immunoblotting , Cadenas Pesadas de Inmunoglobulina/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Microtúbulos/efectos de los fármacos , Persona de Mediana Edad , Pronóstico , Vidarabina/análogos & derivados , Vidarabina/farmacología , Proteína Tirosina Quinasa ZAP-70/metabolismo
13.
Hum Mol Genet ; 16(24): 3117-27, 2007 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-17901044

RESUMEN

Cytogenetic analysis in myeloma reveals marked chromosomal instability. Both widespread genomic alterations and evidence of aberrant class switch recombination, the physiological process that regulates maturation of the antibody response, implicate the DNA repair pathway in disease pathogenesis. We therefore assessed 27 SNPs in three genes (XRCC3, XRCC4 and XRCC5) central to DNA repair in patients with myeloma and controls from the EpiLymph study and from an Irish hospital registry (n = 306 cases, 263 controls). For the haplotype-tagging SNP (htSNP) rs963248 in XRCC4, Allele A was significantly more frequent in cases than in controls (86.4 versus 80.8%; odds ratio 1.51; 95% confidence interval 1.10-2.08; P = 0.0133), as was the AA genotype (74 versus 65%) (P = 0.026). Haplotype analysis was performed using Unphased for rs963248 in combination with additional SNPs in XRCC4. The strongest evidence of association came from the A-T haplotype from rs963248-rs2891980 (P = 0.008). For XRCC5, the genotype GG from rs1051685 was detected in 10 cases from different national populations but in only one control (P = 0.015). This SNP is located in the 3'-UTR of XRCC5. Overall, these data provide support for the hypothesis that common variation in the genes encoding DNA repair proteins contributes to susceptibility to myeloma.


Asunto(s)
ADN Helicasas/genética , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Mieloma Múltiple/genética , Estudios de Casos y Controles , Frecuencia de los Genes , Humanos , Autoantígeno Ku , Polimorfismo de Nucleótido Simple , Sistema de Registros
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