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1.
JCI Insight ; 9(10)2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38775157

RESUMEN

Redundant tumor microenvironment (TME) immunosuppressive mechanisms and epigenetic maintenance of terminal T cell exhaustion greatly hinder functional antitumor immune responses in chronic lymphocytic leukemia (CLL). Bromodomain and extraterminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T cell function and differentiation. Herein, we report that blocking BET protein function alleviates immunosuppressive networks in the CLL TME and repairs inherent CLL T cell defects. The pan-BET inhibitor OPN-51107 reduced exhaustion-associated cell signatures resulting in improved T cell proliferation and effector function in the Eµ-TCL1 splenic TME. Following BET inhibition (BET-i), TME T cells coexpressed significantly fewer inhibitory receptors (IRs) (e.g., PD-1, CD160, CD244, LAG3, VISTA). Complementary results were witnessed in primary CLL cultures, wherein OPN-51107 exerted proinflammatory effects on T cells, regardless of leukemic cell burden. BET-i additionally promotes a progenitor T cell phenotype through reduced expression of transcription factors that maintain terminal differentiation and increased expression of TCF-1, at least in part through altered chromatin accessibility. Moreover, direct T cell effects of BET-i were unmatched by common targeted therapies in CLL. This study demonstrates the immunomodulatory action of BET-i on CLL T cells and supports the inclusion of BET inhibitors in the management of CLL to alleviate terminal T cell dysfunction and potentially enhance tumoricidal T cell activity.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Linfocitos T , Microambiente Tumoral , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Humanos , Animales , Ratones , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Proliferación Celular/efectos de los fármacos , Proteínas que Contienen Bromodominio , Proteínas
2.
Cancer Res Commun ; 4(5): 1328-1343, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38687198

RESUMEN

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacologic agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NFκB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its antileukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NFκB signaling and the UPR, culminating in profound antitumor properties independent of TME stimuli. SIGNIFICANCE: SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NFκB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NFκB pathway and UPR) highlighting its use in drug-resistant CLL.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Transducción de Señal , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Humanos , Animales , Ratones , Transducción de Señal/efectos de los fármacos , Piperidinas/farmacología , Piperidinas/uso terapéutico , Línea Celular Tumoral , Respuesta de Proteína Desplegada/efectos de los fármacos , Adenina/análogos & derivados , Adenina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , FN-kappa B/metabolismo , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Receptores de Antígenos de Linfocitos B/metabolismo , Proliferación Celular/efectos de los fármacos
3.
Br J Haematol ; 202(1): 116-121, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37096954

RESUMEN

Improved maintenance treatments are needed for patients with relapsed/refractory aggressive lymphomas after autologous haematopoietic stem cell transplantation (ASCT). Several studies with lenalidomide have been found to have activity in the treatment of relapsed/refractory aggressive lymphomas. In the present phase I/II, single-arm, open-label study, 59 patients with high-risk relapsed non-Hodgkin lymphoma received pretransplant BEAM chemotherapy and ASCT followed by 12 months of maintenance lenalidomide once daily on Days 1-21 (28-day cycles) beginning at post-transplantation Day 100. The most common histologies were mantle cell lymphoma (56%) and diffuse large B-cell lymphoma (24%). The maximum tolerated dose in the dose-finding part of the study was 15 mg, but cytopenias led to the subsequent adoption of a 10 mg dose in the final study. Sixteen patients (27%) completed 12 cycles of lenalidomide maintenance. The most common reason for discontinuation was adverse events (31%). These were primarily haematologic, and 56% of patients experienced Grade 3-4 events. Two-year PFS rates (95% CIs) were 70% (56%-80%), 45% (19%-68%) and 81% (66%-90%); 2-year OS rates (95% CIs) were 91% (80%-96%), 93% (61%-99%) and 90% (76%-96%) in all patients, patients completing and patients not completing 12-month maintenance respectively. These results do not support the use of lenalidomide maintenance in this setting.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Linfoma de Células del Manto , Linfoma no Hodgkin , Humanos , Adulto , Lenalidomida , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del Tratamiento
4.
Future Oncol ; 18(3): 311-321, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34761681

RESUMEN

Background: We used the Therapy Preference Scale, a 30-item questionnaire, to determine cancer treatment preferences of adults with cancer. Methods: We used Wilcoxon's rank sum test and Fisher's exact test to compare the preferences of younger (<60 years) versus older adults (≥60 years). Results: While 56% of patients would accept treatment offering increased life expectancy at an expense of short-term side effects, 75% preferred maintenance of cognition, functional ability and quality of life to quantity of days. Oral instead of intravenous treatment (p = 0.003), shorter hospital stay (p = 0.03), preservation of cognitive function (p = 0.01) and avoidance of pain (p = 0.02) were more important to older patients compared with younger patients. Conclusion: Many patients prioritized maintenance of cognition, functional ability and quality of life; older patients valued oral treatment, shorter hospital stay, preservation of cognitive function and avoidance of pain.


Lay abstract Understanding the preferences of adults with cancer is important for physicians to develop personalized cancer treatment plans. We used a self-reported 30-item questionnaire, the Therapy Preference Scale, to help patients express their preferences with regard to safety, efficacy and other aspects of therapy. While 56% of the patients in our study would accept treatment offering increased life expectancy at an expense of short-term side effects, 75% preferred maintenance of cognition, functional ability and quality of life to quantity of days. Compared with younger patients, older patients preferred oral instead of intravenous treatment, shorter hospital stay, preservation of cognitive function and avoidance of pain.


Asunto(s)
Antineoplásicos/administración & dosificación , Dolor en Cáncer/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Prioridad del Paciente/estadística & datos numéricos , Administración Intravenosa , Administración Oral , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Dolor en Cáncer/etiología , Dolor en Cáncer/psicología , Cognición/efectos de los fármacos , Toma de Decisiones , Humanos , Esperanza de Vida , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/psicología , Prioridad del Paciente/psicología , Calidad de Vida , Encuestas y Cuestionarios/estadística & datos numéricos , Adulto Joven
5.
Ann Hematol ; 101(2): 335-340, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34668982

RESUMEN

Peripheral T-cell lymphomas (PTCL) are a unique subset of lymphomas with a poor prognosis due to limited treatment options. We performed a phase 1 study of carfilzomib in patients with relapsed/refractory PTCL to determine the safety profile and the maximum tolerated dose (MTD) of this agent. The study was a classical 3 + 3 phase 1 design with intra-patient dose escalation allowed beginning on day 8 of cycle 1 and subsequently. Dose-limiting toxicity (DLT) was defined as the occurrence of any grade 3/4 adverse event. Carfilzomib was given on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Fifteen patients were enrolled from 3 centers. The median age of patients was 62. The median number of prior therapies for subjects on this trial was five. The MTD of carfilzomib was 36 mg/m2. Dose-limiting toxicities included anemia and sepsis. Serious adverse events were seen in 45% of patients. Single-agent carfilzomib leads to a complete response in one patient and a partial response in one patient. Overall, the drug was reasonably tolerated for a heavily pretreated population, but the limited response rate and short duration of response demonstrate a lack of promise for carfilzomib as a single agent in this patient population.


Asunto(s)
Antineoplásicos/uso terapéutico , Linfoma de Células T Periférico/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Adulto , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oligopéptidos/administración & dosificación , Oligopéptidos/efectos adversos , Supervivencia sin Progresión , Resultado del Tratamiento
8.
Hum Pathol ; 80: 192-200, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29902576

RESUMEN

High-grade B-cell lymphomas with MYC, BCL2, and/or BCL6 rearrangements, "double-hit" or "triple-hit" lymphomas (DTHL), are aggressive neoplasms associated with a poor prognosis. A t(3;8)(q27;q24) rarely occurs in B-cell lymphomas that results in a unique "pseudo-double-hit" BCL6-MYC fusion, indistinguishable by interphase fluorescence in situ hybridization (FISH) from more conventional DTHL with independent MYC and BCL6 translocations. Reports of t(3;8)(q27;q24) lymphomas are sparse, and to better characterize their pathologic, cytogenetic, and clinical features, 6 new cases from 2 institutions and 19 previously published cases were reviewed. All new cases displayed aggressive morphologic features, and most previously published cases were classified as aggressive lymphomas. Collectively, all t(3;8)(q27;q24) cases had a germinal center (GC) phenotype, and most had complex karyotypes (22/24, 92%), including frequent concomitant BCL2 rearrangements (17/24, 71%). When compared to two large published DTHL cohorts, t(3;8)(q27;q24) lymphomas less often expressed BCL2 (P < .01), had a greater likelihood of extranodal involvement (P < .01), and more frequently appeared triple-hit by FISH analysis (P < .01). Despite presenting with aggressive clinicopathologic features, 100% (6/6) of t(3;8;)(q27;q24) patients achieved complete remission after intensive induction regimens, and 2- and 3-year overall survival rates were 63% (10/16) and 57% (8/14), respectively. These findings suggest that lymphomas with t(3;8)(q27;q24) may represent a subset of GC B-cell lymphomas distinct from conventional DTHL. Our results further highlight the value of routine karyotype assessment in aggressive B-cell lymphomas, and the importance of recognizing the t(3;8)(q27;q24) so that its clinical significance can be more fully explored.


Asunto(s)
Reordenamiento Génico/genética , Centro Germinal/patología , Inmunofenotipificación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Adulto , Anciano , Femenino , Humanos , Hibridación Fluorescente in Situ/métodos , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Fenotipo , Proteínas Proto-Oncogénicas c-myc/genética , Translocación Genética/genética
9.
Blood ; 132(1): 40-48, 2018 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-29703778

RESUMEN

Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline chemotherapy. Achievement of complete remission (CR) with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT. This phase 1/2 study evaluated the combination of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory HL. A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled. Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m2) on days 1 and 2 of a 21-day cycle for up to 6 cycles. Patients could undergo ASCT any time after cycle 2. Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy. After a median of 2 cycles of combination therapy (range, 1-6), the objective response rate among 53 efficacy-evaluable patients was 92.5%, with 39 patients (73.6%) achieving CR. Forty patients underwent ASCT. Thirty-one patients (25 of whom underwent ASCT) received BV monotherapy (median, 10 cycles; range, 1-14). After a median of 20.9 months of follow-up, the estimated 2-year progression-free survival was 69.8% and 62.6% for patients who received ASCT and all patients, respectively. Thirty-one patients (56.4%) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy. A protocol amendment requiring premedication reduced IRR severity. BV plus bendamustine as first salvage therapy in relapsed/refractory HL is highly active with a manageable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT01874054.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Terapia Recuperativa , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Brentuximab Vedotina , Supervivencia sin Enfermedad , Femenino , Enfermedad de Hodgkin/patología , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Masculino , Persona de Mediana Edad , Recurrencia , Tasa de Supervivencia , Factores de Tiempo
11.
Clin Lymphoma Myeloma Leuk ; 17(9): 569-574, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28709798

RESUMEN

BACKGROUND: With the improving outcomes of patients with follicular lymphoma (FL), it is imperative to focus on survivorship issues, including the development of second primary malignancies (SPMs). We used a large US database to measure the risk of SPMs among FL survivors. MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results-13 registry to identify FL patients from 1992 to 2011. We calculated the risk of SPMs, developing ≥ 6 months after diagnosis, using the standardized incidence ratio (SIR) and absolute excess risk. We calculated the cumulative incidence of SPMs using the competing risk method and risk factors for SPMs using univariate and multivariate methods. RESULTS: Of a total of 15,517 patients with FL followed up for a median of 71 months, 1540 (9.9%) developed SPMs, with a SIR of 1.08 and absolute excess risk of 11.3 per 10,000 person-years. A significantly increased risk was noted for Hodgkin lymphoma (SIR, 5.85), acute myeloid leukemia (SIR, 4.88), and the following sites: oral cavity and pharynx (SIR, 1.43), stomach (SIR, 1.43), lung and bronchus (SIR, 1.35), melanoma of skin (SIR, 1.38), other nonepithelial cancers of the skin (SIR, 2.88), urinary bladder (SIR, 1.24), and kidney/renal pelvis (SIR, 1.43). The cumulative incidence of SPMs was 11.06% at 10 years. Multivariate regression showed that age > 65 years (SIR, 1.57; P < .001), male gender (SIR, 1.43; P < .001), and receipt of radiation (SIR, 1.24; P = .001) predicted a higher rate of SPMs. CONCLUSION: Patients with FL have increased risk of both hematologic and solid malignancies. Risk factors for SPMs include advanced age, male gender, and receipt of radiation therapy.


Asunto(s)
Linfoma Folicular/epidemiología , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Incidencia , Linfoma Folicular/diagnóstico , Linfoma Folicular/terapia , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/terapia , Vigilancia de la Población , Modelos de Riesgos Proporcionales , Sistema de Registros , Riesgo , Programa de VERF , Estados Unidos/epidemiología , Adulto Joven
13.
Am J Hematol ; 91(11): E468-E472, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27489982

RESUMEN

The optimal management of hematologic malignancy-associated venous thromboembolism (VTE) in patients with moderate-to-severe thrombocytopenia is unclear. This is a retrospective study of 128 adult patients with hematologic malignancies who were diagnosed with VTE. The outcome of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Forty-seven patients (36.7%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 10,000/µL (range 2,000-45,000/µL) versus 165,000/µL (50,000-429,000/µL) in those without (P < 0.001). The median duration of significant thrombocytopenia in the first group was 10 days (1-35 days). Therapy during the period of significant thrombocytopenia included prophylactic-dose low-molecular-weight heparin (LMWH) (47%), therapeutic-dose LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%), and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At a median follow-up of more than 2 years, the risk of clinically significant bleeding (11% vs 6%, P = 0.22) including major bleeding (6% vs 2%) and clot progression or recurrence (21% vs 22%, P = 1.00) were similar in patients with or without significant thrombocytopenia. In a multivariate analysis, the risk of recurrence/progression (hazard ratio, HR 0.59, 95% CI 0.21-1.66, P = 0.31) and hemorrhage rate (HR 0.29, 95% CI 0.05-1.56, P = 0.15) did not differ based on the presence of significant thrombocytopenia. Within the limits of this retrospective study, cautious use of prophylactic-dose LMWH may be safe in thrombocytopenic patients with hematologic malignancy-associated VTE. Am. J. Hematol. 91:E468-E472, 2016. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Neoplasias Hematológicas/complicaciones , Heparina de Bajo-Peso-Molecular/uso terapéutico , Trombocitopenia/etiología , Tromboembolia Venosa/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/uso terapéutico , Femenino , Hemorragia/inducido químicamente , Heparina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Premedicación , Recurrencia , Estudios Retrospectivos , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/patología , Tromboembolia Venosa/patología , Warfarina/uso terapéutico , Adulto Joven
14.
Clin Lymphoma Myeloma Leuk ; 16(7): 373-8, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27349764

RESUMEN

BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare entity with no previous population-based study. MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results 18 database to identify adult patients with SPTCL and peripheral T-cell lymphoma not otherwise specified (PTCL NOS) diagnosed between 1973 and 2011. The actuarial survival of SPTCL was compared with a propensity-matched cohort of PTCL NOS. Multivariate analysis was conducted using weighted Cox proportional hazard regression model. RESULTS: Patients with SPTCL (n = 118), compared with PTCL NOS (n = 3296), were more likely to be younger (median age of 47 vs. 62 years; P < .01), women (67% vs. 40%, P < .01), and diagnosed with stage I/II disease (46% vs. 36%; P = .01). The 5-year actuarial, relative, and cause-specific survival for SPTCL was 40%, 57%, and 64%, respectively. After propensity-matching, the 5-year overall survival (OS) of SPTCL was better than that of PTCL NOS (57% vs. 40%; P < .01). In a multivariate analysis, mortality was significantly lower among SPTCL versus PTCL NOS (hazard ratio, 0.54; 95% confidence interval, 0.39-0.75; P < .01). Among patients with SPTCL, advanced age (P < .01) and diagnosis before the year 2008 (P = .02) were predictors of worse OS. CONCLUSION: Our study provides characteristics and OS of a large cohort of SPTCL. Compared with PTCL NOS, SPTCL patients were more likely to be younger, female, and diagnosed at an early stage. The OS of SPTCL was better than PTCL NOS.


Asunto(s)
Linfoma de Células T Periférico/mortalidad , Linfoma de Células T/mortalidad , Paniculitis/mortalidad , Vigilancia de la Población , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Bases de Datos Factuales , Femenino , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Linfoma de Células T/diagnóstico , Linfoma de Células T/epidemiología , Linfoma de Células T/historia , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/epidemiología , Linfoma de Células T Periférico/historia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Paniculitis/diagnóstico , Paniculitis/epidemiología , Paniculitis/historia , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Programa de VERF , Estados Unidos/epidemiología , Adulto Joven
15.
Haematologica ; 101(8): 968-75, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27151994

RESUMEN

Classical Hodgkin lymphoma treatment is evolving rapidly with high response rates from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response, therefore development of novel therapies is warranted to improve patient outcomes. In this phase II study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat, an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled: 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week); 16 patients on Schedule B (15 mg oral entinostat once weekly in 3 of 4 weeks). Patients received a median of 3 prior treatments (range 1-10), with 80% of the patients receiving a prior stem cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention-to-treat analysis, the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease beyond 6 months) was 24%. Seven patients did not complete the first cycle due to progression of disease. Tumor reduction was observed in 24 of 38 (58%) evaluable patients. Median progression-free survival and overall survival was 5.5 and 25.1 months, respectively. The most frequent grade 3 or 4 adverse events were thrombocytopenia (63%), anemia (47%), neutropenia (41%), leukopenia (10%), hypokalemia (8%), and hypophosphatemia (6%). Twenty-five (51%) patients required dose reductions or delays. Pericarditis/pericardial effusion occurred in one patient after 12 cycles of therapy. Future studies are warranted to identify predictive biomarkers for treatment response and to develop mechanism-based combination strategies. (clinicaltrials.gov identifier: 00866333).


Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Piridinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Terapia Combinada , Citocinas/sangre , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/farmacocinética , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Imagen Multimodal , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/farmacocinética , Recurrencia , Retratamiento , Resultado del Tratamiento , Adulto Joven
16.
Future Oncol ; 12(13): 1565-75, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27079926

RESUMEN

BACKGROUND: This large population-based study determined the epidemiology and outcomes of secondary acute myeloid leukemia (sAML) developing in Hodgkin lymphoma survivors. METHODS: We utilized the Surveillance Epidemiology and End Results (SEER) 9 database to identify 104 cases of sAML. RESULTS: Patients with sAML (median age: 47 years; 82% <60 years) were significantly younger than de novo AML cases (66 years; p < 0.01). sAML had worse overall survival (OS) than de novo AML (p < 0.01). OS was better in younger patients and in more recent years. CONCLUSION: Older patients with sAML have a dismal OS and should be enrolled in trials of novel therapies. Younger patients have improved OS and hence may benefit from curative intent intensive therapy and allogeneic transplant.


Asunto(s)
Enfermedad de Hodgkin , Leucemia Mieloide Aguda/epidemiología , Neoplasias Primarias Secundarias/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Femenino , Enfermedad de Hodgkin/terapia , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Programa de VERF , Sobrevivientes/estadística & datos numéricos , Adulto Joven
17.
Blood ; 127(19): 2310-21, 2016 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-26809508

RESUMEN

Clinical heterogeneity is a major barrier to effective treatment of chronic lymphocytic leukemia (CLL). Emerging evidence suggests that constitutive activation of various signaling pathways like mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-Erk) signaling plays a role in the heterogeneous clinical outcome of CLL patients. In this study, we have investigated the role of Sprouty (SPRY)2 as a negative regulator of receptor and nonreceptor tyrosine kinase signaling in the pathogenesis of CLL. We show that SPRY2 expression is significantly decreased in CLL cells, particularly from poor-prognosis patients compared with those from good-prognosis patients. Overexpression of SPRY2 in CLL cells from poor-prognosis patients increased their apoptosis. Conversely, downregulation of SPRY2 in CLL cells from good-prognosis patients resulted in increased proliferation. Furthermore, CLL cells with low SPRY2 expression grew more rapidly in a xenograft model of CLL. Strikingly, B-cell-specific transgenic overexpression of spry2 in mice led to a decrease in the frequency of B1 cells, the precursors of CLL cells in rodents. Mechanistically, we show that SPRY2 attenuates the B-cell receptor (BCR) and MAPK-Erk signaling by binding to and antagonizing the activities of RAF1, BRAF, and spleen tyrosine kinase (SYK) in normal B cells and CLL cells. We also show that SPRY2 is targeted by microRNA-21, which in turn leads to increased activity of Syk and Erk in CLL cells. Taken together, these results establish SPRY2 as a critical negative regulator of BCR-mediated MAPK-Erk signaling in CLL, thereby providing one of the molecular mechanisms to explain the clinical heterogeneity of CLL.


Asunto(s)
Linfocitos B/metabolismo , Proliferación Celular , Regulación Leucémica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas de la Membrana/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Animales , Apoptosis/genética , Linfocitos B/patología , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Proteínas de la Membrana/genética , Ratones , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Quinasa Syk/genética , Quinasa Syk/metabolismo
19.
Leuk Lymphoma ; 57(6): 1327-34, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26377137

RESUMEN

The objective of this retrospective study (N = 169) was to compare the overall survival (OS) of different subtypes of mantle cell lymphoma (MCL) treated by the Nebraska Lymphoma Study Group between 1984 and 2012. The overall response rate to various therapies including stem cell transplant (SCT) was similar (p = 0.44) between blastoid, diffuse and nodular subtypes. At 5 years, blastoid and diffuse subtypes had worse OS (overall p = 0.005) compared to nodular subtype. In multivariate analysis, the blastoid and diffuse subtypes had similar risk of death (p = 0.14) whereas the nodular subtype had a lower risk compared to blastoid (HR 0.48, 95% CI 0.27-0.87, p = 0.01). The use of SCT was associated with lower risk of death. In univariate analysis, blastoid subtype had better OS with intensive upfront therapy. In conclusion, the OS of blastoid subtype is worse than nodular MCL but may improve with the use of SCT and probably intensive induction therapy.


Asunto(s)
Linfocitos B/metabolismo , Linfocitos B/patología , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/terapia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Manejo de la Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Linfoma de Células del Manto/mortalidad , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Evaluación del Resultado de la Atención al Paciente , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento
20.
Ther Adv Hematol ; 6(5): 223-7, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26425335

RESUMEN

BACKGROUND: Cancer therapy and outcomes are known to be affected by various demographic features and hospital types. We aimed to identify the characteristics of non-Hodgkin's lymphoma (NHL) patients associated with receipt of care at academic centers. METHOD: This is a retrospective study of all patients diagnosed with nodal NHL between 2000 and 2011 in the National Cancer Database (NCDB), who received the diagnosis, and all or part of their initial therapy in the reporting hospital (n = 243,436). Characteristics of patients receiving care in academic versus nonacademic centers were compared using the Chi-square test. RESULTS: Approximately 27% received care in academic centers. Patients receiving care in nonacademic centers, compared with academic centers, were more likely to be ⩾60 years (69% versus 58%, p < .0001), White (89% versus 80%, p < .0001) and have lower educational attainment (>12% without high school diploma: 72% versus 69%, p < .0001) and economic status (household income <$49,000: 66% versus 61%, p < 0.0001). Patients receiving care in nonacademic centers were less likely to travel ⩾25 miles (21% versus 26%, p < 0.0001). White patients, compared with non-Whites, were more likely to be ⩾60 years (70% versus <50%, p < 0.0001), which probably explains less care in academic centers. CONCLUSIONS: Patients ⩾60 years and those with poorer educational attainment and economic status were less likely to receive care in academic centers. Care in academic centers required a longer commute. Elderly patients frequently have inferior outcomes and may benefit from clinical trials with novel agents and expertise at academic centers.

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