Maintenance therapy with ex vivo expanded lymphokine-activated killer cells and rituximab in patients with follicular lymphoma is safe and may delay disease progression.

Anti-cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) have shown promise in follicular lymphoma (FL) as post-induction therapy, by enhancing antibody-dependent cellular cytotoxicity (ADCC). However, cytotoxic cells are reduced after this treatment. We hypothesised that ex vivo expanded lymphokine-activated killer (LAK) cells administered to FL-remission patients are safe and improve anti-CD20 efficacy. This open, prospective, phase II, single-arm study assessed safety and efficacy of ex vivo expanded LAK cells in 20 FL-remission patients following rituximab maintenance. Mononuclear cells were obtained in odd rituximab cycles and stimulated with interleukin 2 (IL-2) for 8 weeks, after which >5 × 108 LAK cells were injected. Patients were followed-up for 5 years. At the end of maintenance, peripheral blood cells phenotype had not changed markedly. Natural killer, LAK and ADCC activities of mononuclear cells increased significantly after recombinant human IL-2 (rhIL-2) stimulation in all cycles. Rituximab significantly enhanced cytotoxic activity. No patients discontinued treatment. There were no treatment-related serious adverse events. Three patients had progressed by the end of follow-up. After a median (interquartile range) follow-up of 59.4 (43.8-70.9) months, 85% of patients remained progression free. No deaths occurred. Quality-of-life improved throughout the study. Post-induction LAK cells with rituximab seem safe in the long term. Larger studies are warranted to confirm efficacy.

The top ten clues to understand the origin of chronic lymphocytic leukemia (CLL).

The fundamental task of the immune system is to protect the individual from infectious organisms without serious injury to self. The essence of acquired immunity is molecular self/non self discrimination. Chronic lymphocytic leukemia is characterized by a global failure of immune system that begins with the failure of immunological tolerance mechanisms (autoimmunity) and finish with the incapacity to response to non-self antigens (immunodeficiency). Immunological tolerance mechanisms are involved in chronic lymphocytic leukemia (CLL) development. During B cell development some self-reactive B cells acquire a special BCR that recognize their own BCR. This self-autoantibody-self BCR interaction promotes survival, differentiation and proliferation of self-reactive B cells. Continuous self-autoantibody-self BCR interaction cross-linking induces an increased rate of surface BCR elimination, CD5+ expression, receptor editing and anergy. Unfortunately, some times this mechanisms increase genomic instability and promote additional genetic damage that immortalize self-reactive B cells and convert them into CLL like clones with the capability of clonal evolution and transformed CLL B cells. This review summarizes the immunological effects of continuous self-autoantibody-self BCR interaction cross-linking in the surface of self-reactive B cells and their role in CLL development.

Serology-based therapeutic strategy in SARS-CoV-2-infected patients.

SARS-CoV-2 infection can be a life-threatening disease. The optimal treatment of patients is not yet standardized. We use a serology-based therapeutic strategy based on the presence of antibodies against the SARS-CoV-2 virus, in which patients with positive serology receive aggressive anti-inflammatory treatment with high-dose dexamethasone and/or tocilizumab and patients with negative serology receive early convalescent plasma therapy. We also analyze the immunological impact of this therapy in the recovery of T cells, B cells and NK cells during hospitalization in a COVID-19 infectious ward. Our results suggest that aggressive therapy with early administration of convalescent plasma and high-dose dexamethasone may be of benefit in patients with SARS-CoV-2 infection and might avoid progression of lung damage or need of admission in intensive care. This strategy did not impair immune responses against SARS-CoV-2, as 93% of the patients generated antibodies against the virus. Independently of previous immunological status of the patients, serology-guided therapy might benefit even patients with a high CIRS-G score, immunosuppressed or medically debilitated individuals and elderly patients. T cell disturbances were most frequent in patients who required high-dose dexamethasone, and B cell depletion was most frequent in patients who received tocilizumab. Early passive immunotherapy with convalescent plasma does not affect lymphoid recovery.

Full donor chimerism without graft-versus-host disease: the key factor for maximum benefit of pre-emptive donor lymphocyte infusions (pDLI).

Compared to standard-conditioned regimens, reduced-intensity conditioning and T-cell depletion deliver lower transplant-related mortality and decreased graft-vs-host disease after allogeneic hematopoietic stem-cell transplantation. These advantages may however be mitigated by increased relapse rates and delays in achievement of full donor chimerism (FDC). Pre-emptive donor lymphocyte infusions (pDLI) facilitate the conversion of mixed (MDC) to FDC. However, there is a lack of published data on the risk/benefit analysis of this intervention. We performed a retrospective analysis of 119 patients who received 276 pDLI doses for falling CD3 chimerism, CD3 < 50% or mixed XX/XY karyotype. 71/119(60%) Patients achieved FDC, with only one reverting to MDC. Cumulative incidence (CI) of relapse at 5 years was significantly lower in the FDC group (16.0 vs 41.4%, p < 0.001). Those patients who achieved FDC had improved EFS (p < 0.001) and OS (p < 0.001). Interestingly, patients with FDC who developed DLI-induced graft-vs-host disease (GvHD) showed a similar outcome to those with MDC. The majority of patients who receive pDLI convert to FDC and retain that status. Achievement of FDC after pDLI impacts on survival, and those patients who achieve FDC without GvHD, experience maximum clinical benefit. Strategies to minimise DLI-induced GvHD should be considered to maximise the therapeutic potential of this intervention.

Battle of Thermopylae: 300 Spartans (natural killer cells plus obinutuzumab) versus the immortal warriors (chronic lymphocytic leukemia cells) of Xerxes' army.

AIM: To analyze the effects of subcutaneous or intravenous rituximab + lymphokine-activated killer cells, obinutuzumab or ibrutinib on natural killer (NK) cell levels in chronic lymphocytic leukemia and follicular lymphoma patients. PATIENTS & METHODS: The distribution of peripheral blood NK cells of 31 patients was analyzed by flow cytometry. RESULTS: We detected a decrease of NK cells in peripheral blood below normal range after obinutuzumab treatment. During maintenance treatment with subcutaneous rituximab, an NK cell reduction was less pronounced than after intravenous rituximab treatment, despite lymphokine-activated killer cell infusions. CONCLUSION: After one dose of obinutuzumab, each NK cell in peripheral blood destroys 25 leukemic cells.

Obinutuzumab induces depletion of NK cells in patients with chronic lymphocytic leukemia.

AIM: Obinutuzumab induces NK cell antibody-dependent cell-mediated cytotoxicity. OBJECTIVE: Investigate the effects on the human immune system after obinutuzumab monotherapy treatment in patients with chronic lymphocytic leukemia (CLL). METHOD: To evaluate these effects, we analyzed the distribution of CD4+ and CD8+ T cells, B cells and NK cells in the peripheral blood of eight CLL patients who were treated with obinutuzumab in monotherapy. The distribution of peripheral blood lymphocytes was examined prior to each dose of obinutuzumab and 24-72 h after the first 1000 mg complete dose (cycle 1 day 2). We also repeated measurements 3 months after the last obinutuzumab dose. In total we obtained ten samples of each patient. Analyses were performed by flow cytometry with monoclonal antibodies against CD3, CD4, CD8, CD19 and CD56+. RESULTS: After the first 1000 mg obinutuzumab infusion (cycle 1 day 2), CD4+ T cells and CD8+ T cells were significantly decreased in peripheral blood compared with prior to therapy. This reduction in the CD4+ T cells persisted after six cycles of obinutuzumab (1235 cells/µl basal vs 662 cells/µl after six cycles, p ≤ 0.05), but not in CD8+ T cells (987 cells/µl basal vs 837 cells/µl after six cycles). Interestingly, we also observed significant differences in the NK cell compartment after the first 1000 mg drug infusion (490 cells/µl basal vs 23 cells/µl postinfusion, p ≤ 0.05), and after cycle 6 (490 cells/µl basal vs 149 cells/µl after six cycles, p ≤ 0.05). CONCLUSION: Obinutuzumab induces depletion of NK cells in CLL.

[Venous thromboembolism in patients with cancer]. / Tromboembolia venosa en pacientes con cáncer.

The association between neoplastic diseases and venous thromboembolism (VTE) is known since long time ago. The nature of this association is bidirectional. On one hand, cancer increases the incidence of venous thrombosis and, on the other hand, the hemostatic system does play a key role in the tumorigenesis process. However, despite recent advances in the field, prophylaxis and treatment of VTE in cancer patients is still a challenge, due to the complexity of this type of patients. This review is focused on some important points regarding management of VTE in cancer patients such as physiopathology, epidemiology, search for hidden malignancy, prognostic impact, prophylaxis in the medical and surgical setting, or initial and long-term treatment.

Follicular lymphoma: in vitro effects of combining lymphokine-activated killer (LAK) cell-induced cytotoxicity and rituximab- and obinutuzumab-dependent cellular cytotoxicity (ADCC) activity.

Follicular lymphoma (FL) is a disease of paradoxes-incurable but with a long natural history. We hypothesized that a combination of lymphokine-activated killer (LAK) cells and monoclonal antibodies might provide a robust synergistic treatment and tested this hypothesis in a phase II clinical trial (NCT01329354). In this trial, in addition to R-CHOP, we alternated the administration of only rituximab with rituximab and autologous LAK cells that were expanded ex vivo. Our objective was to determine the in vitro capability of LAK cells generated from FL patients to produce cytotoxicity against tumor cell lines and to determine rituximab- and obinutuzumab-induced cytotoxicity via antibody-dependent cellular cytotoxicity (ADCC) activity. We analyzed the LAK cell-induced cytotoxicity and rituximab (R)- and obinutuzumab (GA101)-induced ADCC activity. We show that LAK cells generated from FL patients induce cytotoxicity against tumor cell lines. R and GA101 enhance cytolysis through ADCC activity of LAK cells. Impaired LAK cell cytotoxicity and ADCC activity were detected in 50 % of patients. Percentage of NK cells in LAK infusions were correlated with the R- and GA101-induced ADCC. Our results indicate that the combination of R or GA101 and LAK cells should be an option as frontline maintenance therapy in patients with FL.

[New strategies in the secondary prevention of relapsing venous thromboembolism]. / Nuevas estrategias en la prevención secundaria de la recurrencia de la tromboembolia venosa.

Treatment of venous thromboembolism includes an acute phase treatment, followed by a secondary prophylaxis period. Oral anticoagulants have been the usual treatment for secondary prophylaxis of VTE. However, some issues regarding oral anticoagulant treatment (OAT), such as length or intensity are controversial. The appropriate duration of OAT depends on the individual risk of both, thrombotic recurrence and hemorrhagic complications. Recent studies suggest that full-dose OAT is more effective and as safe as low-dose OAT. On the other hand, low-molecular-weight heparins are an alternative for the secondary prophylaxis of VTE, being the treatment of choice in patients with cancer or during pregnancy. Probably, new antithrombotic drugs such as idraparinux or ximelagatran, will be considered as another therapeutic alternative in a near future.

[Decreased transfusion requirements in acquired severe bleeding with recombinant activated factor VII]. / Reducción de las necesidades transfusionales en hemorragias adquiridas graves mediante factor VII activo recombinante.

BACKGROUND AND OBJECTIVE: Patients with severe and persistent bleeding have high mortality rates despite standard therapy, including blood transfusion support. The aim of the study was to evaluate the role of rFVIIa in the management of severe bleeding, refractory to other treatments. PATIENTS AND METHODS: All cases with severe bleeding and failure of previous treatments who received rFVIIa (n = 21) at one single center were retrospectively included in the study. RESULTS: A response after the administration of rFVIIa was reported in 16 of 21 patients (76.2%). Hemorrhage was completely halted in 14 cases, and 12 patients (57.1%) were alive 30 days after treatment. The use of rFVIIa was associated with a normalization of coagulation tests, especially the prothrombin time (p = 0.001). A marked reduction in blood requirements, red cell units (p = 0.003), fresh frozen plasma (p = 0.009) and platelets (p = 0.017) was also observed. CONCLUSIONS: rFVIIa may have an important role in the achievement of an adequate hemostasis and reduces blood requirements in patients with severe bleeding, emerging as an alternative to blood transfusion.

Tiempos modernos: retorno al pasado, regreso al futuro / Modern times: back to past, back to future

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Tromboembolia venosa en pacientes con cáncer / Venous thromboembolism in patients with cancer

La asociación entre las enfermedades neoplásicas y la tromboembolia venosa (TEV) es conocida desde antiguo. La naturaleza de esta asociación es bidireccional, ya que, por un lado, el cáncer se asocia con una mayor incidencia de trombosis venosa, mientras que, por el otro, el sistema hemostático desempeña un papel importante en los procesos de progresión tumoral. Sin embargo, a pesar de los avances recientes en esta especialidad, hoy día la profilaxis y el tratamiento de la TEV en los pacientes con cáncer constituyen todavía un reto, debido a la complejidad de este tipo de pacientes. En esta revisión se recogen importantes puntos a tener en cuenta en el tratamiento de la TEV en pacientes neoplásicos, como la fisiopatología, la epidemiología, la búsqueda de neoplasia oculta, las implicaciones pronósticas, la profilaxis en situaciones médicas y quirúrgicas o el tratamiento inicial y a largo plazo

The association between neoplastic diseases and venous thromboembolism (VTE) is known since long time ago. The nature of this association is bidirectional. On one hand, cancer increases the incidence of venous thrombosis and, on the other hand, the hemostatic system does play a key role in the tumorigenesis process. However, despite recent advances in the field, prophylaxis and treatment of VTE in cancer patients is still a challenge, due to the complexity of this type of patients. This review is focused on some important points regarding management of VTE in cancer patients such as physiopathology, epidemiology, search for hidden malignancy, prognostic impact, prophylaxis in the medical and surgical setting, or initial and long-term treatment

Nuevas estrategias en la prevención secundaria de la recurrencia de la tromboembolia venosa / New strategies in the secondary prevention of relapsing venous thromboembolism

En el tratamiento de la tromboembolia venosa se distinguen una etapa inicial de tratamiento de la fase aguda y otra posterior de prevención secundaria, dirigida a evitar la recurrencia trombótica. Clásicamente esta prevención secundaria se ha realizado mediante el empleo de anticoagulantes orales. Sin embargo, diversos aspectos del tratamiento anticoagulante oral, como la duración o la intensidad, son motivo de debate. La duración apropiada de dicho tratamiento varía según el riesgo de recurrencia y de complicaciones hemorrágicas de cada paciente. En cuanto a su intensidad, las dosis convencionales parecen ser más eficaces e igual de seguras que dosis reducidas. Por otra parte, las heparinas de bajo peso molecular se presentan como una alternativa para la profilaxis secundaria de la tromboembolia venosa y son el tratamiento de elección en pacientes con cáncer o en embarazadas. Posiblemente, nuevos fármacos antitrombóticos como el idraparinux o el ximelagatrán sean una alternativa en un futuro próximo

Treatment of venous thromboembolism includes an acute phase treatment, followed by a secondary prophylaxis period. Oral anticoagulants have been the usual treatment for secondary prophylaxis of VTE. However, some issues regarding oral anticoagulant treatment (OAT), such as length or intensity are controversial. The appropiate duration of OAT depends on the individual risk of both, thrombotic recurrence and hemorragic complications. Recent sudies suggest that full-dose OAT is more effective and as safe as low-dose OAT. On the other hand, low-molecular-weight heparins are an alternative for the secondary prophylaxis of VTE, being the treatment of choice in patients with cancer or during pregnancy. Probably, new antithrombotic drugs such as idraparinux or ximelagatran, will be considered as another therapeutic alternative in a near future

Reducción de las necesidades transfusionales en hemorragias adquiridas graves mediante factor VII activo recombinante / Decreased transfusion requirements in acquired severe bleeding with recombinant activated factor VII

Fundamento y objetivo: Los pacientes con hemorragias graves y persistentes presentan una elevada mortalidad pese a los tratamientos convencionales, entre ellos el soporte transfusional. El objetivo del estudio ha sido evaluar el papel del factor VII activo recombinante (rFVIIa) en el tratamiento de hemorragias graves, refractarias a otros tratamientos. Pacientes y métodos: En el estudio se incluyeron retrospectivamente todos los casos (n = 21) tratados en un único centro con rFVIIa debido a hemorragias graves, en las que previamente habían fracasado otras medidas terapéuticas. Resultados: La tasa de respuesta al tratamiento fue del 76,2%, cediendo completamente la hemorragia en 14 pacientes. La supervivencia a los 30 días tras la administración del fármaco fue del 57,1% (12 de 21 pacientes). La utilización de rFVIIa se asoció con una mejoría de los parámetros de la coagulación, especialmente del tiempo de protrombina (p = 0,001), así como con una marcada reducción de los requerimientos transfusionales, concentrados de hematíes (p = 0,003), plasma fresco (p = 0,009) y plaquetas (p = 0,017). Conclusiones: El rFVIIa consigue una adecuada hemostasia y disminución de requerimientos de hemoderivados en hemorragias graves, por lo que representa una alternativa a la transfusión en estos pacientes

Background and objective: Patients with severe and persistent bleeding have high mortality rates despite standard therapy, including blood transfusion support. The aim of the study was to evaluate the role of rFVIIa in the management of severe bleeding, refractory to other treatments. Patients and methods: All cases with severe bleeding and failure of previous treatments who received rFVIIa (n = 21) at one single center were retrospectively included in the study. Results: A response after the administration of rFVIIa was reported in 16 of 21 patients (76.2%). Hemorrhage was completely halted in 14 cases, and 12 patients (57.1%) were alive 30 days after treatment. The use of rFVIIa was associated with a normalization of coagulation tests, especially the prothrombin time (p = 0.001). A marked reduction in blood requirements, red cell units (p = 0.003), fresh frozen plasma (p = 0.009) and platelets (p = 0.017) was also observed. Conclusions: rFVIIa may have an important role in the achievement of an adequate hemostasis and reduces blood requirements in patients with severe bleeding, emerging as an alternative to blood transfusion

Neumonías en pacientes con leucemia linfática crónica. Estudio de 30 episodios / Pneumonias in patients with chronic lymphocytic leukemia. Study of 30 episodes

FUNDAMENTOS: Analizar la etiología, los métodos diagnósticos y la respuesta al tratamiento en 30 episodios de neumonía diagnosticados en 17 pacientes con leucemia linfática crónica (LLC) entre 1995 y 2000. PACIENTES Y MÉTODO: En cada episodio se registraron los siguientes parámetros: edad, sexo, tratamiento de la LLC, profilaxis antiinfecciosa, granulocitopenia, cociente de linfocitos CD4 y CD8, hipogammaglobulinemia, tipo de neumonía (intra o extrahospitalaria), localización, insuficiencia respiratoria, necesidad de ventilación mecánica, tratamiento antimicrobiano y respuesta. Se realizaron hemocultivos, cultivo de esputo, fibrobroncoscopia y detección de antígenos en orina (Legionella pneumophila serogrupo 1, galactomanano y Streptococcus pneumoniae). RESULTADOS: La edad mediana de la serie fue de 60 años (límites, 50-86); 12 eran varones. La combinación de clorambucilo y prednisona fue el tratamiento más utilizado para la LLC (13 pacientes) seguido de la fludarabina (8 casos). Existía granulocitopenia en 14 episodios, había hipogammaglobulinemia en 22 y el cociente de linfocitos CD4 y CD8 fue inferior a uno en 8 de 14 determinaciones. Se estableció la etiología de las neumonías en 16 episodios (53 por ciento). La fibrobroncoscopia fue la prueba con mayor rentabilidad diagnóstica (83 por ciento), seguida de los hemocultivos (38 por ciento). Dos pacientes fueron diagnosticados en la autopsia de aspergilosis pulmonar. El neumococo fue el germen aislado con mayor frecuencia (5) seguido de Pseudomonas aeruginosa (4), Pneumocystis carinii (2) y Aspergillus fumigatus (2). De los 2 pacientes con neumocistosis uno había recibido fludarabina y el otro glucocorticoides de forma prolongada. Diez pacientes (30 por ciento) fallecieron a causa de los siguientes gérmenes: P. aeruginosa (3), P. carinii (2), A. fumigatus (2), Mycobacterium xenopi (1) y germen no identificado (2). CONCLUSIONES: En esta serie de pacientes con LLC la tasa global de diagnóstico etiológico de las neumonías fue aceptable. El germen más frecuente fue el neumococo. Las neumonías por microorganismos oportunistas se relacionaron con la administración de fludarabina o el tratamiento prolongado con glucocorticoides y tuvieron una elevada mortalidad (AU)