Comparación indirecta ajustada de zanubrutinib e ibrutinib en el tratamiento de primera línea de la leucemia linfocítica crónica / Adjusted indirect comparison of zanubrutinib and ibrutinib in first-line treatment of chronic lymphocytic leukemia

Objetivo el objetivo del presente trabajo fue realizar una comparación indirecta ajustada, según el perfil citogenético, en términos de eficacia, entre los distintos inhibidores de la tirosin cinasa de bruton empleados como monoterapia en primera línea para la leucemia linfocítica crónica. Asimismo, se evaluaron los resultados de seguridad considerados de interés para establecer si dichas opciones pueden ser consideras alternativas terapéuticas equivalentes. Método con fecha 10 de noviembre del 2022, se llevó a cabo una búsqueda bibliográfica en las bases de datos de Pubmed y Embase de ensayos clínicos fase III que estudiaran los inhibidores de la tirosin cinasa de Bruton en monoterapia en contexto de primera línea para la leucemia linfocítica crónica. Se incluyeron ensayos en los que se empleara la combinación de bendamustina y rituximab como comparador y que presentaran poblaciones y tiempos de seguimiento semejantes. Se combinaron mediante metaanálisis los resultados de los subgrupos según las características mutacionales clasificando a los pacientes en alto y bajo riesgo citogenético. Se desarrolló una comparación indirecta ajustada utilizando el método de Bucher. Se determinó la posible equivalencia terapéutica aplicando para ello la guía de alternativas terapéuticas equivalentes. Resultado de los 39 estudios obtenidos en la revisión, se seleccionaron 2 ensayos clínicos: uno para zanubrutinib y otro para ibrutinib. El resto de estudios no se incluyeron por incumplimiento de los criterios de inclusión. Los resultados obtenidos en la comparación indirecta ajustada para ambos subgrupos de riesgo citogenético no mostraron diferencias estadísticamente significativas. En cuanto a la seguridad, las diferencias más relevantes se encontraron en la incidencia de fibrilación auricular, hipertensión arterial y eventos cardiovasculares en los pacientes tratados con ibrutinib, y mayor incidencia de cánceres secundarios en los pacientes tratados con zanubrutinib (AU)

Objective The aim of this study was to perform an adjusted indirect treatment comparison, according to the cytogenetic profile, in terms of efficacy between different Bruton tyrosine kinase inhibitors used as first-line monotherapy for chronic lymphocytic leukemia. Safety outcomes considered of interest were also evaluated to establish whether these options can be considered equivalent therapeutic alternatives. Method A literature search was conducted in Pubmed and Embase on 10 November 2022 for phase III clinical trials studying Bruton's tyrosine kinase inhibitors in monotherapy in the first-line setting for CLL. Results were filtered according to whether the combination of bendamustine and rituximab was used as comparator and whether they had similar populations and follow-up times. Subgroup results were meta-analyzed according to mutational characteristics by classifying patients into high and low cytogenetic risk. An adjusted indirect comparison was developed using Bucher's method. Possible therapeutic equivalence was determined by applying the guide to equivalent therapeutic alternatives. Result Of the 39 studies obtained in the review, two clinical trials were selected: one for zanubrutinib and one for ibrutinib. The remaining studies were not included because they did not meet the inclusion criteria. The results obtained in the adjusted indirect treatment comparison for both cytogenetic risk subgroups showed no statistically significant differences. The most relevant safety differences were auricular fibrillation, hypertension and cardiovascular events in patients treated with ibrutinib and higher incidence of secondary cancers in patients treated with zanubrutinib. Applying the ATE guideline criteria, both treatments cannot be considered equivalent therapeutic alternatives (AU)

Adherencia y calidad de vida en los pacientes con leucemia linfocítica crónica tratados con antineoplásicos orales / Adherence and quality of life in patients with chronic lymphocytic leukemia treated with oral antineoplastic drugs

Objetivos: evaluar la adherencia y la calidad de vida de los pacientes con leucemia linfocítica crónica tratados con antineoplásicos orales. Comparar la adherencia y la calidad de vida según el fármaco recibido y según la línea de tratamiento.Métodoestudio descriptivo prospectivo realizado de junio a noviembre de 2021 en un hospital terciario. Se incluyeron pacientes con leucemia linfocítica crónica, atendidos en la consulta de Farmacia Oncológica y tratados con antineoplásicos orales desde al menos 6 meses antes de la inclusión en el estudio. Se estimó la adherencia mediante el cuestionario Morisky’s 8 item Medication Adherence Scale y el recuento de medicación sobrante, considerándose adherentes si su tasa de adherencia era ≥ 90%. Para evaluar la calidad de vida, se utilizó el cuestionario EQ-5D-3L del grupo EuroQol, la escala Functional Assessment of Chronic Illness Therapy – Fatigue y el QLQ-C30 de la European Organization for Research and Treatment of Cancer. Se programaron 2 entrevistas: en el momento de la inclusión y a los 3 meses. Se revisó la historia clínica, recogiéndose variables demográficas y clínicas. El análisis estadístico se realizó con el programa SPSS® 25.0.Resultadosse incluyeron 23 pacientes, todos fueron adherentes según el recuento de medicación, 20 presentaron adherencia alta, y 3 media, según Morisky’s 8 item Medication Adherence Scale. Los resultados del cuestionario EQ-5D-3L mostraron que los pacientes eran autónomos para su cuidado personal y sus actividades cotidianas, el 69,6% no tenían problemas de movilidad, el 78,3% no tenía ansiedad/depresión y el 56,5% presentaba algún tipo de dolor. (AU)

Objective: To evaluate adherence and quality of life to oral antineoplastic treatment in patients with chronic lymphocytic leukemia. To compare adherence and QoL according to treatment subgroups and treatment-line subgroups.MethodsWe conducted a descriptive prospective study from June to November 2021 in a tertiary care hospital. Patients treated at the Oncology Pharmacy with a diagnosis of chronic lymphocytic leukemia and treatment with oral antineoplastics for at least 6 months before inclusion in the study were included. Adherence was assessed using Morisky’s 8 item Medication Adherence Scale and leftover pills counts, considering adherents if their adherence rate was ≥ 90%. Quality of life was assessed with Euro-Qol EQ-5D-3L questionnaire, Functional Assessment of Chronic Illness Therapy – Fatigue scale and QLQ-C30 questionnaire from European Organization for Research and Treatment of Cancer. Two interviews were scheduled: at the time of inclusion and at 3 months. Variable collected: demographic data, clinical data (disease and treatment); and response (scores obtained from questionnaires and adherence rate). The data statistical analysis was carried out with SPSS® 25.0 software.ResultsTwenty three patients were included, all of them showed an adherence rate higher than 90%; 20 patients were considered high adherent, and 3 patients medium adherent to treatment according to Morisky’s 8 item Medication Adherence Scale. (AU)

Síndrome hemofagocítico en pacientes con leucemia linfocítica crónica tratados con ibrutinib. A propósito de dos casos / Haemophagocytic syndrome in patient with chronic lymphocytic leukaemia treated with ibrutinib. Two cases report

Se presentan dos casos de sospecha de síndrome hemofagocítico secundario en pacientes con leucemia linfocítica crónica, tratados con ibrutinib, síndrome que puede ser letal y que tiene lugar por una activación inmune excesiva. En el presente artículo se describe el desarrollo del síndrome, su diagnóstico, el tratamiento y su desenlace, acorde a las guías y protocolos de diagnóstico, actuación y tratamiento. Es destacable por el hecho de ser una reacción adversa rara de la que no se conoce muy bien la causa, multifactorial, de diferente inicio y evolución, como ocurre en los dos casos que se presentan, no recogida en ficha técnica. Se sitúan los casos junto a un pequeño número de casos también publicados. (AU)

We presented two cases of suspected secondary haemophagocytic syndrome in patients with chronic lymphocytic leukaemia treated with ibrutinib, syndrome that could be letal and that occurs due to excessive immune activation. This article describes the evolution, diagnosis, treatment, and denouement, according to protocols and guidelines for diagnosis and therapeutic decision-making. It is noteworthy, because is a rare adverse event, not present in product monograph, whose cause is not weel known, multifactorial, with different onset and evolution, as in the two cases presented. The cases are placed next to a small number of publicated cases. (AU)

Knockdown of Bcl-3 alleviates psoriasis and dyslipidemia comorbidity by regulating Akt pathway

Background Psoriasis is considered as an inflammatory skin disease accompanied by dyslipidemia comorbidity. B-cell leukemia-3 (Bcl-3) belongs to IκB (inhibitor of nuclear factor kappa B [NF-κB]) family, and regulates inflammatory response through associating with NF-κB. The role of Bcl-3 in psoriasis was investigated in this study. Methods Apolipoprotein E (ApoE)-deficient mice were treated with imiquimod to induce psoriasis and dyslipidemia. Mice were injected intradermally in the back with lentiviral particles encoding Bcl-3 small hairpin RNA (shRNA). Hematoxylin and eosin were used to detect pathological characteristics. The blood lipid levels were determined by automatic biochemical analyzer, and inflammation was assessed by enzyme-linked-immunosorbent serologic assay and real-time quantitative reverse transcription polymerase chain reaction. Results Bcl-3 was elevated in imiquimod-induced ApoE-deficient mice. Injection with lentiviral particles encoding Bcl-3 shRNA reduced Psoriasis area and severity index (PASI) score in ApoE-deficient psoriatic mice. Knockdown of Bcl-3 also ameliorated imiquimod-induced psoriasiform skin lesions in ApoE-deficient mice. Moreover, loss of Bcl-3 enhanced expression of loricrin, an epidermal barrier protein, reduced expression of proliferating cell nuclear antigen (PCNA) and lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1) in imiquimod-induced ApoE-deficient mice. The enhanced levels of blood lipid in ApoE-deficient mice were attenuated by silencing of Bcl-3 with increase of high-density lipoprotein, and reduction of total cholesterol, triglycerides, and low-density lipoprotein cholesterol. Knockdown of Bcl-3 attenuated imiquimod-induced decrease of transforming growth factor beta (TGF-β), and increase of Interleukin (IL)-17A, IL-23, IL-6, and tumor necrosis factor-α (TNF-α) in ApoE-deficient mice. Protein expression of phospho-Akt (p-Akt) and p-GSK3β in ApoE-deficient psoriatic mice was decreased by silencing of Bcl-3 (AU)

Análisis de minimización de costes de la leucemia linfocítica crónica en España en la era de las terapias orales dirigidas / Cost-minimisation analysis of chronic lymphocytic leukemia in Spain in the era of oral targeted therapies

Objetivo: La leucemia linfocítica crónica supone una carga económica considerable para el Sistema Nacional de Salud español. Este estudioestimó los costes directos de las terapias orales dirigidas para leucemia linfocítica crónica desde 2011 a 2025, inclusive, en un escenario conterapias orales de duración fija y en un escenario sin ellas.Método: Se representó el curso clínico de pacientes adultos con leucemia linfocítica crónica mediante un modelo de Markov con cuatro estados de salud: vigilancia activa, tratamiento de primera línea, recaída y muerte. Patrón de tratamiento definido por tipo de paciente: estado o situación dela enfermedad, edad, presencia o no de deleción en el brazo corto del cromosoma 17, estado mutacional de la cadena pesada de inmunoglobulinasy año de tratamiento. Algoritmo de tratamiento simulado desde 2011a 2025, incluyendo terapias financiadas por el Sistema Nacional deSalud español y su uso en práctica clínica habitual, validado por expertosde referencia. Se asumió una opción de tratamiento por tipo de pacientey periodo de tiempo (la más ampliamente utilizada en cada momento).Se incluyeron costes directos: farmacológicos, administración, pruebasrealizadas, visitas rutinarias, hospitalizaciones y acontecimientos adversos.Resultados: Se estimó una prevalencia media anual de leucemia linfocíticacrónica desde 2011 a 2025 de 16.436 pacientes en el escenariosin terapias orales de duración fija y 16.413 en el escenario con terapias orales de duración fija. Los costes totales desde 2011 a 2025 en el escenariosin terapias orales de duración fija ascendieron a 4.676,7 millonesde € y a 4.111,8 millones de € en el escenario con terapias orales deduración fija. Así, la introducción de las terapias orales de duración fijasupondría un ahorro de 564,9 millones de € (12,1% del total del costede atención de los pacientes con leucemia linfocítica crónica durante elperiodo evaluado).

Objective: Chronic lymphocytic leukaemia places a considerable economicburden on the Spanish National Health System. This study estimatedthe direct costs of chronic lymphocytic leukaemia oral targetedtherapies from 2011 to 2025, inclusive, in a scenario with fixed treatmentoral targeted therapies and in a scenario without them.Method: The clinical course of adult chronic lymphocytic leukaemiapatients was represented by a Markov model with four health states: watchfulwaiting, first-line treatment, relapse, and death. The treatment patternwas defined according to patient type by disease status or situation, age,presence or absence of deletion in the short arm of chromosome 17,immunoglobulin heavy chain mutation status, and year of treatment. Thetreatment algorithm was simulated from 2011 to 2025, and includedtherapiesfunded by the Spanish National Health System and their use inroutine clinical practice, validated by leading experts. A single treatmentoption was assumed for each type of patient and time period (the mostwidely option used at each time point). Direct costs were included: pharmacological,administration, tests performed, routine visits, hospitalizations,and adverse events.Results: From 2011 to 2025, there would be a mean annual chronic lymphocyticleukaemia prevalence of 16,436 patients in the scenario withoutfixed treatment oral targeted therapies and 16,413 in the scenario with fixed treatment oral targeted therapies. In the same period, the total costsin the scenario without fixed treatment oral targeted therapies would be€4,676.7 million and in the scenario with fixed treatment oral targetedtherapies they would be €4,111.8 million. Thus, the introduction of fixedtreatment oral targeted therapies would entail a saving of €564.9 million(12.1% of the total cost of care of chronic lymphocytic leukaemia patientsduring the period assessed).

PD-1 and PD-L1 gene expressions and their association with Epstein-Barr virus infection in chronic lymphocytic leukemia

PurposeThe PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells. Its ligand, programmed cell death ligand-1 (PD-L1), is expressed on the surface of dendritic cells or macrophages. The PD-1/PD-L1 interaction ensures prevention of autoimmunity by activating the immune system only when needed. In cancers, PD-L1 expressed on the tumour cells binds to PD-1 receptors on the activated T cells, leading to inhibition of the cytotoxic T cells and immunosuppression. PD-1/PD-L1 pathway is upregulated in EBV infection that is known to worsen the CLL prognosis. Therefore, we aimed to study the association between PD-1 and PD-L1 expressions, EBV status and the CLL prognosis.Methods and patientsThe study was conducted on 80 newly diagnosed CLL patients and 80 controls. We analyzed PD-1 and PD-L1 expressions and EBV-DNA load by real-time PCR. The cytogenetic abnormalities and expression of ZAP70 and CD38 were detected by FISH and Flow cytometry, respectively.ResultsPD-1/PD-L1 expressions were significantly upregulated in CLL patients compared to controls. In addition, their mRNA levels were significantly higher in EBV( +) versus EBV( −) patients. High expression of PD-1/PD-L1 was associated with poor prognostic markers (RAI stages of CLL, del 17p13, ZAP70, and CD38 expression), failure of complete remission, shorter progression-free survival, and overall survival.ConclusionHigh expression of PD-1 and PD-L1, together with high EBD-DNA load were linked to worse prognosis in CLL. In addition, PD-1 and PD-L1 might represent suitable therapeutic targets for patients suffering from aggressive CLL. (AU)

Long intergenic non-coding RNA-p21 is associated with poor prognosis in chronic lymphocytic leukemia

Long non-coding RNAs (LncRNAs) are RNA transcripts longer than 200 nucleotides. They are new players in transcriptional regulation and cancer research. LincRNA-p21 is a p53-regulated lncRNA involved in the p53 transcriptional network. It has an important role in regulating cellular proliferation and apoptosis. Chronic lymphocytic leukemia is derived by a typical defect in apoptosis and characterized by clonal proliferation and accumulation of mature B cells. The aim of the present study was to assess the expression pattern of the lincRNA-p21 and investigate its potential role as a new prognostic marker in CLL. Methods The study was conducted on 80 newly diagnosed CLL patients and 80 age- and sex-matched controls. The analysis of LincRNA-p21 and the p53 downstream proapoptotic target genes (MDM2, PUMA, BAX, and NOXA) was performed by real-time PCR. The cytogenetic abrasions and expression of ZAP70 and CD38 were detected by FISH and Flow cytometry, respectively. Results LincRNA-p21 was significantly downregulated in CLL patients compared to controls. The downstream proapoptotic targets were significantly downregulated in CLL patients and positively correlated with lincRNA-p21. Low expression of lincRNA-p21 was associated with poor prognostic markers (advanced stages of CLL, del 17p13, ZAP70, and CD38 expression), failure of complete remission, shorter progression free survival, and overall survival. Low lincRNA-p21 expression was independently prognostic for shorter time to treatment. Conclusion Low expression of lincRNA-p21 demarcates a more aggressive form of CLL with poor prognosis. Therefore, it could be considered as a new prognostic marker to predict disease outcome in CLL (AU)

Estudio de un paciente con esplenomegalia: a propósito de un caso / Study of a splenomegaly: a case report

El crecimiento patológico del bazo se denomina esplenomegalia. Su detección supone un reto en las consultas de Atención Primaria por el amplio abanico de posibilidades diagnósticas que supone, siendo las principales causas a descartar: infecciosas, tumorales y hematológicas. En nuestro trabajo presentamos un paciente varón de mediana edad que acude a consulta por vez primera porque presenta una tumoración abdominal palpable y no dolorosa de larga evolución. Su diagnóstico se basa en la obtención de imagen a través de alguna prueba de imagen para confirmar la presencia de esplenomegalia, siendo la ecografía la técnica de elección en Atención Primaria. Mediante la sospecha clínica y la realización de la ecografía en consulta llegamos al diagnóstico clínico

The pathological growth of the spleen is called splenomegaly. Its detection is a challenge in Primary Care due to the wide range of diagnostic possibilities involved, including as the main causes to be ruled out: infections, tumors, and hematological causes. We present the case of a middle-aged male patient who seeks care for the first time because he presents a palpable, painless abdominal lump of long evolution. The diagnosis is based on imaging tests to confirm the presence of splenomegaly, with ultrasound as the technique of choice in Primary Care. Clinical suspicion and ultrasound testing in the office lead to clinical diagnosis

Subglottic stenosis due to chronic lymphocytic leukemia / Estenosis subglótica debida a leucemia linfocítica crónica

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Vitrectomía diagnóstica: serie de casos en un centro de referencia / Diagnostic vitrectomy: a case series in a single referral center

Objetivo: Estudiar la eficacia y perfil de seguridad de la vitretomía diagnóstica en pacientes con uveítis no filiada. Métodos: Estudio observacional descriptivo retrospectivo de 29 pacientes (37 ojos) con panuveítis no filiada en los que se realizó vitrectomía diagnóstica. Las características clínicas y demográficas fueron recogidas. Se estudiaron los métodos de extracción de muestras y las técnicas de procesado aplicadas para el diagnóstico. Resultados: De los 29 pacientes analizados 18 (62%) eran hombres. La media de edad fue de 63,11 años (desviación estándar: 14,55). El síntoma inicial más frecuente fue la disminución de agudeza visual, la agudeza visual media fue de 20/40 excluyendo 8 ojos en los que resultó inferior a 20/200. Veintiún pacientes presentaban alteración unilateral. Se realizó extracción de muestra en seco a todos los pacientes. Además, fueron empleadas las siguientes técnicas de toma de muestras: 5 biopsias retinianas, 5 muestras diluidas, 1 aspirado de absceso subretiniano, 1 aspirado de humor acuoso. Con respecto al procesado de las muestras la técnica más utilizada fue la citología en 25 ojos, seguida de la reacción en cadena de la polimerasa en 11 ojos, el cultivo en 10 ojos. El diagnóstico etiológico fue encontrado en 94,5% de los casos, siendo el principal linfoma, seguido de toxoplasmosis. Conclusión: La vitrectomía diagnóstica es útil para la identificación de la inflamación oftalmológica. Pueden utilizarse diferentes técnicas de obtención de muestras y procesado de las mismas

Objective: To study the results and safety of diagnostic vitrectomy in patients with unknown etiology panuveitis. Methods: A retrospective descriptive observational study was carried out in which a total of 29 patients (37 eyes) were included, who underwent a vitreous biopsy due to acute intraocular inflammatory processes. In all, demographic and clinical data were collected. We studied the specific samples extraction methods and their diagnosic processing. Results: Of the 29 patients analyzed, 18 were men. Mean of age was 63.11 years old (standard deviation: 14.55). The most frequent initial symptom was visual acuity decrease, with mean initial visual acuity being 20/40, excluding 8 eyes that had vision lower than 20/200. 21 presented unilateral ocular involvement. Vitrectomy was performed in all of them obtaining a dry sample. Vitrectomy was performed in all of the patients obtaining a dry sample. Moreover, the following techniques were done: 5 retinal biopsies, obtaining 5 muestras diluidas, 1 subretinal abscess aspirate and 1 aqueous humor aspirate. The most frequent processing technique that was used was cytology in 25 eyes, followed by PCR (polymerase chain reaction) in 11 eyes and culture in 10 eyes. Diagnosis was achieved in 94.5% of patients. Main diagnosis found was lymphoma, followed by toxoplasmosis. Conclusions: Diagnostic vitrectomy is very important in ophthalmic inflammation identification. Different techniques for obtaining and processing can be used

Miastenia gravis y leucemia de linfocitos T grandes granulares / Myasthenia gravis and large granular lymphocytic leukemia

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Reactivación del virus varicela-zóster en dos pacientes inmunodeprimidos / Reactivation of varicella-zoster virus in two immunosuppressed patients

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Enfermedad residual mínima en la leucemia linfática crónica / Minimal residual disease in chronic lymphocytic leukaemia

La evaluación de la enfermedad mínima residual (EMR) es un objetivo importante en el tratamiento de la leucemia linfocítica crónica (LLC). Su obtención es predictiva de una supervivencia libre de progresión (SLP) y una supervivencia global prolongadas y podría considerarse una variable subrogada de la SLP en el contexto del tratamiento con quimioinmunoterapia. La evaluación de la EMR mediante citometría de flujo o técnicas moleculares en la era de los nuevos inhibidores de BCR o Bcl-2 podría identificar la secuencia de tratamiento más coste-efectiva y la duración de la misma. Una aproximación terapéutica guiada por el nivel de EMR también podría determinar qué pacientes se beneficiarían de un tratamiento de consolidación o de una finalización precoz del mismo. En esta revisión discutimos los diferentes métodos de análisis de la EMR, qué muestras deben ser analizadas, el papel futuro de la detección del ADN tumoral circulante y el papel potencial de la negatividad de la EMR en la práctica clínica en la era moderna del tratamiento de la LLC (AU)

Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost-effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy. In this review, we discuss the different MRD methods of analysis, which source of tumour samples must be analysed, the future role of the detection of circulating tumour DNA, and the potential role of MRD negativity in clinical practice in the modern era of CLL therapy (AU)