RESUMEN
Tenalisib, a selective phosphoinositide-3-kinase δ/γ, and salt-inducible-kinase-3 inhibitor has shown efficacy and was well-tolerated in patients with T-cell lymphoma (TCL). In vitro studies suggest a synergistic anti-tumor potential for the combination of tenalisib with the histone-deacetylase inhibitor, romidepsin. This multicenter, open-label, phase I/II study was designed to characterize the safety, efficacy and pharmacokinetics of oral tenalisib twice-daily and intravenous romidepsin administered on days 1, 8 and 15 in 28-day cycles in adults with relapsed/refractory TCL. Phase I/dose escalation determined the maximum tolerated dose (MTD)/optimal doses of tenalisib and romidepsin. The phase II/dose expansion assessed the safety and anti-tumor activity of the combination at MTD/optimal dose. Overall, 33 patients were enrolled. In dose escalation, no dose-limiting toxicity was identified. Hence, the recommended doses for dose expansion were tenalisib 800 mg twice daily orally, and romidepsin 14 mg/m2 intravenous. Overall treatment-emergent adverse events of any grade reported in >15% of patients were nausea, thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased appetite, neutropenia, vomiting, fatigue, anemia, dysgeusia, weight loss, diarrhea, and hypokalemia. Twenty-three patients (69.7%) had related grade ≥3 treatment-emergent adverse events. The overall objective response rate in evaluable patients was 63.0% (peripheral TCL: 75% and cutaneous TCL: 53.3%), with a complete response and partial response of 25.9% and 37.0% respectively. The median duration of response was 5.03 months. Co-administration of tenalisib and romidepsin did not significantly alter the pharmacokinetics of romidepsin. Overall, tenalisib and romidepsin combination demonstrated a favorable safety and efficacy profile supporting its further development for relapsed/refractory TCL (clinicaltrials gov. Identifier: NCT03770000).
Asunto(s)
Linfoma de Células T Periférico , Linfoma de Células T , Neoplasias Cutáneas , Adulto , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T Periférico/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL-NOS were retained for study. At a median follow-up of 46 months, the median overall survival (OS) and progression-free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1-2), and high risk (HiR, 74 patients, 24%, score 3-4), having a 3-year OS of 76% [95% confidence interval 61-88], 43% [35-51], and 11% [4-21], respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes.
Asunto(s)
Linfoma de Células T Periférico/mortalidad , Modelos Biológicos , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células T Periférico/terapia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II-IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3-4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survival, were 39% (95% confidence interval 21-57) and 60% (95% confidence interval 39-76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21·5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células T Periférico/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Aminopterina/administración & dosificación , Aminopterina/efectos adversos , Aminopterina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) both mobilize CD34(+) stem cells into the blood when administered before apheresis but have distinct effects on dendritic cell (DC) differentiation. We previously demonstrated that the combination of GM+G-CSF results in fewer plasmacytoid DCs (pDCs) when used to mobilize peripheral blood stem cells for autologous transplantation. To test the hypothesis that the content of pDCs in an allograft can be modulated with the cytokines used for mobilization, we randomized the human leukocyte antigen-matched sibling donors of 50 patients with hematological malignancies to a mobilization regimen of either GM+G-CSF (n = 25) or G-CSF alone (n = 25). Primary and secondary endpoints included the cellular constituents of the mobilized grafts, the kinetics of posttransplantation immune reconstitution, and clinical outcomes of the transplantation recipients. Grafts from donors receiving GM+G-CSF contained equivalent numbers of CD34(+) cells with fewer pDCs and T cells, with a higher fraction of Th1-polarized donor T cells than G-CSF mobilized grafts. Immune recovery was enhanced among recipients of GM+G-CSF. Survival was not significantly different between transplantation recipients in the two arms. The use of GM+G-CSF modulates immune function and recovery after allogeneic transplantation and should be explored in larger studies powered to evaluate clinical outcomes.
Asunto(s)
Médula Ósea/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas , Leucemia/terapia , Linfoma/terapia , Adulto , Anciano , Antígenos CD34/genética , Antígenos CD34/inmunología , Eliminación de Componentes Sanguíneos , Células Dendríticas/citología , Células Dendríticas/inmunología , Femenino , Humanos , Leucemia/inmunología , Leucemia/mortalidad , Leucemia/patología , Linfoma/inmunología , Linfoma/mortalidad , Linfoma/patología , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Células TH1/citología , Células TH1/inmunología , Donantes de Tejidos , Trasplante Autólogo , Trasplante HomólogoRESUMEN
Plerixafor with granulocyte colony-stimulating factor (G-CSF) is effective for hematopoietic stem cell (HSC) mobilization in patients with non-Hodgkin Lymphoma and myeloma; however, labeling requires dosing 11 hours before apheresis. Pharmacodynamic studies show peak blood CD34(+) cell counts at 10 to 14 hours; limited data are available for later time points. To address the effect of afternoon plerixafor dosing on CD34(+) cell yields, we conducted a prospective clinical trial in myeloma patients undergoing stem cell collection. Thirty-one patients received plerixafor 17 hours before apheresis; blood CD34(+) cells were measured before the first plerixafor dose and 1, 3, and 17 ± 1 hours after treatment. The target HSC number (≥10 × 106 CD34(+) cells/kg) was collected from 22 subjects (73%) in 1 day and from all subjects within 3 days. Hematopoietic engraftment after transplantation and adverse events were similar to previous studies. Plerixafor given 17 hours before apheresis yields desired HSC collection efficiencies after induction treatment in myeloma patients.
Asunto(s)
Movilización de Célula Madre Hematopoyética/métodos , Compuestos Heterocíclicos/administración & dosificación , Mieloma Múltiple/terapia , Adulto , Anciano , Bencilaminas , Eliminación de Componentes Sanguíneos/métodos , Ciclamas , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Diffuse large B-cell lymphoma (DLBCL) occasionally presents with circulating malignant cells. The clinical characteristics and long-term outcomes of these patients have not been described. Twenty-nine newly diagnosed DLBCL presenting in leukaemic phase were identified between 1996 and 2010, at two institutions. Median age was 48 years, and patients presented with leucocytosis, high lactate dehydrogenase levels, B symptoms, and high International Prognostic Index score. Extra nodal site involvement was observed in all patients and affected the bone marrow (100%), spleen (62%), pleura/lung (41%), liver (21%), bone (17%), bowels (7%) and cerebrospinal fluid (14%). Blood lymphomatous cells co-expressed CD19, CD20, CD22, CD38, CD45, HLA-DR and FMC7 in >90%, and kappa or lambda light chain restriction in >50%. Ninety per cent received rituximab and anthracycline-based chemotherapy. Overall, remission was complete in 54% and partial in 31%; 15% had resistant disease. Median follow-up was 47 months; 13 (45%) patients remain alive in complete remission. Median progression-free and overall survivals were 11·5 and 46·7 months, respectively. In summary, patients with DLBCL in leukaemic phase present with high tumour burden and frequent involvement of extra nodal sites. In this uncommon DLBCL subgroup, anthracycline-based regimens with rituximab are associated with early morbidity and mortality, but yield approximately 50% 4-year survival.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso/patología , Células Neoplásicas Circulantes/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
We sought to evaluate the performance of the cutaneous lymphoma international prognostic index (CLIPI), a prognostic index for mycosis fungoides (MF), and Sézary syndrome (SS), in our cohort of patients seen at Emory University between 1998 and 2013. Additionally, we examined the prognostic significance of lactate dehydrogenase (LDH), B0a/b, and CD30 status. A total of 390 patients were included in analysis: 78.2% early stage (IA-IIA), 7.2% with SS, 53.1% male, mean age 53.5 years. CLIPI stratified patients into low, intermediate, and high-risk groups for overall survival (OS) and progression free survival (PFS) for early stage patients (p < 0.0001), but was not significant for late stage patients. On multivariable analysis for early stage patients, age >60, plaques, folliculotropic disease was significant for OS and age >60, plaques, N1/Nx was significant for PFS. In the overall cohort, CD30+, elevated LDH, and B0b were significant for worse OS and PFS.
Asunto(s)
Micosis Fungoide/diagnóstico , Micosis Fungoide/mortalidad , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/mortalidad , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/mortalidad , Adulto , Anciano , Biomarcadores , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Antígeno Ki-1/metabolismo , Lactato Deshidrogenasas/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Análisis de SupervivenciaRESUMEN
Rapid and accurate differential diagnosis between Burkitt lymphoma (BL) and CD10+ diffuse large B-cell lymphoma (DLBCL) is imperative because their treatment differs. Recent studies have characterized several antigens differentially expressed in these 2 types of lymphoma. Our goal was to determine whether use of these markers would aid in the differential diagnosis of BL vs CD10+ DLBCL by flow cytometric immunophenotyping (FCI). Twenty-three cases of CD10+ B-cell lymphomas with available cryopreserved samples were identified (13 BL and 10 CD10+ DLBCL). Multiparameter FCI was performed using the following antibodies: CD18, CD20, CD43, CD44, and CD54 and isotype controls. Expression of CD44 and CD54 was detected at a significantly lower level in BL compared with CD10+ DLBCL (P = .001 and P = .01, respectively). There was not a significant difference in expression of CD18 and CD43. Our data show that expression of CD44 and CD54 differs significantly between BL and CD10+ DLBCL.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Antineoplásicos/inmunología , Linfoma de Burkitt/patología , Citometría de Flujo/métodos , Linfoma de Células B Grandes Difuso/patología , Neprilisina/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Linfoma de Burkitt/inmunología , Linfoma de Burkitt/metabolismo , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Inmunofenotipificación , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: We did a randomized phase I/II trial designed to evaluate the safety and efficacy of combining the proteasome inhibitor bortezomib with high-dose melphalan as the conditioning for high-dose therapy and autologous transplant for myeloma. EXPERIMENTAL DESIGN: Enrolled patients were limited to those who did not achieve a very good partial remission (VGPR) following one or more induction regimens, and were randomized to receive a single escalating dose of bortezomib (1.0, 1.3, or 1.6 mg/m(2)) either 24 hours before or 24 hours after high-dose melphalan. Dose escalation was based on the escalation with overdose control (EWOC), a Bayesian statistical model. Bone marrow aspirates were collected before initiation of therapy and at the time of transplant to evaluate which sequence resulted in maximal plasma cell apoptosis, and response to transplant was assessed by the International Myeloma Working Group criteria. RESULTS: Among 39 randomized patients, 20 received bortezomib after melphalan and 19 received bortezomib before melphalan. Toxicities and posttransplant hematopoietic recovery rates were similar between arms. The overall response rate for all patients was 87%, with 51% achieving a VGPR or better. Pharmacodynamic studies showed greater plasma cell apoptosis among patients who received bortezomib following melphalan. CONCLUSIONS: The use of bortezomib in conjunction with high-dose melphalan is safe, with data suggesting improved efficacy. A single dose of bortezomib administered after high-dose melphalan is the recommended dose and schedule for future clinical investigation.