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This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to Y-90-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m(2) every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42; p > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39, p > .1). Patients receiving Y-90-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively; p = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival (PFS) and overall survival (OS) of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. 103 patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, PFS was significantly better in the transplanted patients than in the non-transplanted group: 63% vs. 48% at 5 years (p=0.042). OS was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year OS: 70% vs. 50%, p=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged PFS (HR 0.57, 95% CI 0.35-0.93) and OS (HR 0.57, 95% CI 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study.

The purpose of this report is to provide long-term follow-up of 38 patients diagnosed of post-transplant lymphoproliferative disease (PTLD) included in a phase 2 clinical trial of first line therapy with rituximab and to evaluate the same therapy in a real world cohort of 21 consecutive patients treated once the trial was closed. Eligible patients were >= 18 years of age with a biopsy-proven CD20 positive B cell PTLD and treatment naive except for reduction of immunosuppression. Treatment consisted in four weekly infusions of rituximab at the standard dose of 375 mg/m(2). Patients in complete remission (CR) were followed without further treatment, and those in partial remission (PR) were treated with another four cycles of weekly rituximab. Median follow-up in the clinical trial was 13.0 years. Disease-specific survival (DSS) at 10 years was 64.7% [95% confidence interval (CI) 48.2-81.2%]. For those patients who achieved CR (61%), DSS at 5 and 10 years was 94.4% (95% CI 83.8-100%) and 88.1% (95% CI 72.6-100%), respectively, and only 1 patient progressed beyond 5 years. The median follow-up of the real world patients was 6.5 years. DSS at 5 years was 75.2% (95% CI 56.4-94.0%). DSS at 5 years of patients who achieved CR (38%) was 87.5% (95% CI 64.6-100%). In conclusion, PTLD patients in CR after rituximab have an excellent long-term outcome. These results not only apply in the clinical trial setting but are also reproducible in the real world. However, those patients who do not respond represent an unmet clinical need and should be included in prospective clinical trials.

El mieloma múltiple (MM) es una neoplasia de células B caracterizada por la expansión y acumulación de células plasmáticas (CPs) patológicas en la médula ósea (MO). El MM constituye el 1% de todas las neoplasias y supone el 10% de las hemopatías malignas. En las últimas dos décadas se han logrado importantes avances en el tratamiento del MM, principalmente con la introducción de inhibidores del proteosoma, fármacos inmunomoduladores y anticuerpos monoclonales (mAb). Sin embargo, el MM sigue siendo una enfermedad altamente resistente dada su propensión a la heterogeneidad clonal y su compleja interacción con el microambiente medular. Son necesarias estrategias terapéuticas novedosas capaces de revertir la resistencia a los tratamientos de primera y otras líneas. Nos propusimos investigar los mecanismos de acción de isatuximab (mAb anti-CD38) y EM801 (anticuerpo biespecífico BCMAxCD3) mediante cultivos con los fármacos, utilizando tanto líneas celulares como muestras primarias de MO de pacientes con MM. Isatuximab es un mAb IgG1κ, que reconoce específicamente un epítopo concreto de CD38. Inicialmente, hemos investigado un efecto directo de este mAb, sobre el receptor CD38, concluyendo que isatuximab no tiene efecto directo sobre las líneas de MM con baja o alta expresión de CD38. Además, este mAb no produce una liberación significativa de la molécula de la superficie de las CPs. A continuación hemos evaluado diferentes mecanismos de acción responsables del efecto de isatuximab. La citotoxicidad celular dependiente de anticuerpo se proclama como mecanismo efector más relevante por el cual elimina las CPs mielomatosas, siendo las células NK la subpoblación más importante para la acción inequívoca del fármaco. Los mecanismos de fagocitosis celular y citotoxicidad dependiente de complemento solo ocurrirían en pacientes con una densidad de CD38 muy elevada en sus CPs, mostrando de esta manera una asociación directa entre los niveles de expresión y los mecanismos desarrollados por el fármaco. Además, isatuximab induce depleción significativa de precursores B, basófilos y células NK. Por último demostramos que isatuximab se une tanto al receptor FcγRIII como a CD38 presente en la superficie de células NK, provocando una activación y posterior depleción de estas células. EM801 es una IgG asimétrica, bivalente para BCMA y monovalente para CD3ε. Con este diseño, se produce una unión preferencial de las CPs con los linfocitos T. Inicialmente, hemos demostrado que la molécula BCMA se expresa de modo selectivo en las CPs, estando ausente en el resto de poblaciones leucocitarias. A continuación, mediante microscopia de fluorescencia y fuerza atómica, hemos verificado que EM801 produce una unión estrecha y selectiva de la CP y el linfocito T. Esta unión provoca una activación de los linfocitos T con expresión de marcadores de activación como son CD69 y CD25. Además, mediante ELISA, hemos observado una secreción significativa de interferón gamma, granzima B y perforina. La eficacia del fármaco se demostró en cultivos de MO de 43 pacientes con MM, obteniendo una lisis significativa en el 79% de los casos. Además, se estudió la toxicidad que podría tener EM801 sobre otras células de la MO, no observando una muerte relevante en células B, T, NK ni neutrófilos. Por último, hemos testado EM801 en un modelo de xenoinjerto subcutáneo en ratones NOG, observando regresión tumoral en 6 de 9 ratones tratados. En el modelo animal de mono cynomolgus, utilizado para evaluar la actividad del fármaco en un ambiente autólogo, se corroboró la lisis significativa de CPs, así como una disminución en los niveles de IgG e IgM. En estos animales, se observó un aumento ligero y transitorio de citoquinas, que regresaba a niveles basales tras 24 horas de la inyección del fármaco, con lo que podemos concluir que EM801 muestra un perfil de toxicidad aceptable y un perfil farmacocinético que permitiría su administración semanal.

En la actualidad las vacunas contra el cáncer se conciben como armas terapéuticas, en contraste con las preventivas que se administran frente a enfermedades infecciosas. Entre las más potentes vacunas terapéuticas se encuentra la vacunación anti-idiotipo, que emplea como diana la inmunoglobulina tumor-específica, el único antígeno completo tumor-específico conocido que se expone en la membrana de ciertas enfermedades hematológicas de extirpe B. La vacunación idiotípica ha demostrado ya beneficios clínicos y en la actualidad existen dos ensayos clínicos fase III que abordan esta opción terapéutica. Asímismo se van desarrollando otras estrategias que incluyen el empleo de células dendríticas o la producción de vacunas idiotípicas por mecanismos moleculares, que sin duda aportarán en los próximos años conclusiones beneficiosas para el tratamiento de los pacientes con cáncer.

SP-004 Introducción: La combinación de anticuerpos monoclonales anti CD20 con varios regimenes de quimioterapia se considera el tratamiento estándar en pacientes con linfoma folicular (LF). A pesar de los buenos resultados de este tratamiento, un porcentaje importante de los pacientes no se beneficia de esta terapia ensombreciendo de manera considerable su pronóstico. Nuestra hipótesis es que el tratamiento con una suspensión de linfocitos efectores autólogos expandidos ex vivo (células LAK) podría potenciar el efecto biológico del tratamiento con rituximab (R) mediante el incremento de la actividad ADCC. Investigamos la toxicidad y eficacia de dicho tratamiento con un ensayo clínico fase II. Métodos: Entre 2010 y 2012 se reclutaron 20 pacientes con LF en respuesta tras una primera línea de tratamiento con R-CHOP. El objetivo primario de este ensayo, multicéntrico, prospectivo y de un solo brazo fue evaluar la seguridad y eficacia de la infusión de células LAK (administradas cuatrimestralmente en los ciclos pares de R) en combinación con la pauta estándar de R de mantenimiento bimestral durante 2 años. La producción de células LAK se realizó a partir de células de sangre periférica extraídas en los ciclos impares de R para aislar células mononucleadas y estimularlas y expandirlas en cultivo con interleukina-2 durante 8 semanas. Uno de los objetivos secundarios del ensayo fue la evaluación de los fenotipos celulares y de la potencia biológica de las células LAK midiendo su actividad citotóxica. Este ensayo está registrado en ClinicalTrials.gov con número NCT01329354 Resultados: Se registraron 29 eventos adversos (EA) relacionados con la infusión de las células LAK. Las artralgias y las ...

Lymphoma patients with persistent disease undergoing autologous transplantation have a very poor prognosis in the rituximab era. The addition of radioimmunotherapy to the conditioning regimen may improve the outcome for these patients. In a prospective, phase 2 study, we evaluated the safety and efficacy of the addition of Y-90-ibritumomab tiuxetan to the conditioning chemotherapy in patients with refractory diffuse large B-cell lymphoma. Thirty patients with induction failure (primary refractory; n=18) or refractory to salvage immunochemotherapy at relapse (n=12) were included in the study. The median age of the patients was 53 years (range, 25-67). All patients were given Y-90-ibritumomab tiuxetan at a fixed dose of 0.4 mCi/kg (maximum dose 32 mCi) 14 days prior to the preparative chemotherapy regimen. Histological examination showed that 22 patients had de novo diffuse large B-cell lymphoma and eight had transformed diffuse large B-cell lymphoma. All patients had persistent disease at the time of transplantation, with 25 patients considered to be chemorefractory. The median time to neutrophil recovery (>500 white blood cells/mu L) was 11 days (range, 9-21), while the median time to platelet recovery (>20,000 platelets/mu L) was 13 days (range, 11-35). The overall response rate at day +100 was 70% (95% CI, 53.6-86.4) with 60% (95% CI, 42.5-77.5) of patients obtaining a complete response. After a median follow-up of 31 months for alive patients (range, 16-54), the estimated 3-year overall and progression-free survival rates are 63% (95% CI, 48-82) and 61% (95% CI, 45-80), respectively. We conclude that autologous transplantation with conditioning including Y-90-ibritumomab tiuxetan is safe and results in a very high response rate with promising survival in this group of patients with refractory diffuse large B-cell lymphoma with a very poor prognosis.

In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can be circumvented remain undetermined. We previously reported the frequent inactivation of the proapoptotic BIM gene in B-cell lymphomas. Here we show that BIM epigenetic silencing by concurrent promoter hypermethylation and deacetylation occurs frequently in primary BL samples and BL-derived cell lines. Remarkably, patients with BL with hypermethylated BIM presented lower complete remission rate (24% vs 79%; P = .002) and shorter overall survival (P = .007) than those with BIM-expressing lymphomas, indicating that BIM transcriptional repression may mediate tumor chemoresistance. Accordingly, by combining in vitro and in vivo studies of human BL-xenografts grown in immunodeficient RAG2(-/-)γc(-/-) mice and of murine B220(+)IgM(+) B-cell lymphomas generated in Eμ-MYC and Eμ-MYC-BIM(+/-) transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible on BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors. We suggest that the combination of histone-deacetylase inhibitors and high-dose chemotherapy may overcome chemoresistance, achieve durable remission, and improve survival of patients with BL.

Anemia is a common complication in the clinical course of chronic lymphocytic leukemia. Low hemoglobin levels both correlate with an adverse prognosis and adversely affect the quality of life of chronic lymphocytic leukemia patients. Different physiopathological phenomena may lead to anemia: marrow infi ltration, hypersplenism, immune hemolysis or toxicity of chemotherapy. Treatment with human recombinant erythropoietic agents has been shown to be effective for anemia associated with different lymphoproliferative syndromes. This paper analyses the available evidence on erythropoietic agent treatment for chronic lymphocytic leukemia associated anemia. The comparative effect of different dosage schemes, the role of possible response-prediction factors such as the endogenous erythropoietin level and the results achieved using darbopoietin alpha are reviewed.

Cancer vaccines are conceived as therapeutic tools, in contrast to the prophylactic vaccines used to fight against infectious diseases. Among the most potent therapeutic vaccines, anti-idiotype vaccination is directed against the tumor idiotype, the only well-characterized tumor antigen displayed in neoplastic B-cells. Anti-idiotype vaccines have demonstrated clinical benefit against follicular lymphoma and are currently being evaluated in two different phase III clinical trials. Additional emerging strategies, which include the use of dendritic cells and the production of vaccines via molecular means will surely allow us to draw important conclusions concerning the treatment of cancer patients.

Acute promyelocytic leukemia (APL) represents a biologic and clinically well-defined subtype of acute nonlymphocytic leukemia with specific morphologic and karyotypic characteristics. Although secondary leukemia and myelodysplastic syndromes (MDS) are the most frequent secondary neoplasms following chemotherapy for acute leukemia, their development after complete remission in patients with APL is uncommon. We describe the clinical and genetic features of two APL patients who achieved CR after chemotherapy and all-trans retinoid acid treatment and subsequently developed a MDS. Therapy-related MDS karyotype changes such as abnormalities of chromosomes 5 and 7 were found in the cytogenetic analysis. Since TP53 alteration was detected in one case, possible implications of these findings in the onset of MDS are discussed.