Síndromes linfoproliferativos crónicos

El objetivo de la presente guía es confeccionar pautas de diagnóstico y tratamiento de los síndromes linfoproliferativos, teniendo en cuenta las recomendaciones de expertos así como las publicaciones internacionales relacionadas al tema, la disponibilidad de recursos locales y la experiencia de los especialistas convocados. La misma contempla: establecer pautas diagnósticas, clasificar y establecer factores pronósticos, unificar recomendaciones terapéuticas y contribuir a la toma de decisiones terapéuticas.Fil: Bezares, Raimundo F.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Dr. Teodoro Álvarez"; ArgentinaFil: Bistmas, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Borge, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Cabrejo, María del Rosario. Sanatorio Méndez; ArgentinaFil: Custidiano, Rosario. Instituto Alexander Fleming.; ArgentinaFil: Dupont, Juan. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; ArgentinaFil: Ferini, Gonzalo. Hospital Italiano; ArgentinaFil: Fernandez Grecco, Horacio. No especifíca;Fil: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Kornblihtt, Laura Inés. Hospital de Clínicas, Uba; ArgentinaFil: Kruss, Mariana. Hospital Italiano; ArgentinaFil: Miroli, Augusto. Hospital Italiano; ArgentinaFil: Pavlovsky, Miguel A.. Fundación Para Combatir la Leucemia; ArgentinaFil: Riveros, Dardo Alberto. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; ArgentinaFil: Rodríguez, Cecilia. Gobierno de la Provincia de Cordoba. Hospital de Clinicas.; ArgentinaFil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Venetoclax resistance induced by activated T cells can be counteracted by sphingosine kinase inhibitors in chronic lymphocytic leukemia

The treatment of chronic lymphocytic leukemia (CLL) patients with venetoclax-based regimens has demonstrated efficacy and a safety profile, but the emergence of resistant cells and disease progression is a current complication. Therapeutic target of sphingosine kinases (SPHK) 1 and 2 has opened new opportunities in the treatment combinations of cancer patients. We previously reported that the dual SPHK1/2 inhibitor, SKI-II enhanced the in vitro cell death triggered by fludarabine, bendamustine or ibrutinib and reduced the activation and proliferation of chronic lymphocytic leukemia (CLL) cells. Since we previously showed that autologous activated T cells from CLL patients favor the activation of CLL cells and the generation of venetoclax resistance due to the upregulation of BCL-XL and MCL-1, we here aim to determine whether SPHK inhibitors affect this process. To this aim we employed the dual SPHK1/2 inhibitor SKI-II and opaganib, a SPHK2 inhibitor that is being studied in clinical trials. We found that SPHK inhibitors reduce the activation of CLL cells and the generation of venetoclax resistance induced by activated T cells mainly due to a reduced upregulation of BCL-XL. We also found that SPHK2 expression was enhanced in CLL cells by activated T cells of the same patient and the presence of venetoclax selects resistant cells with high levels of SPHK2. Of note, SPHK inhibitors were able to re-sensitize already resistant CLL cells to a second venetoclax treatment. Our results highlight the therapeutic potential of SPHK inhibitors in combination with venetoclax as a promising treatment option for the patients

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors

COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated

The evolving landscape of COVID‐19 and post‐COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Impact of Ibrutinib in Quality of Life (QoL) in Patients with Chronic Lymphocytic Leukemia (CLL): Preliminary Results of Real-World Experience

Context: Clinical data from controlled trials report an improvement in QoL in patients with CLL in ibrutinib monotherapy. Reallife evidence is necessary to confirm this data. Objective: The disease control when treatment is initiated could lead to decreasedfatigue. It is likely that treatment with ibrutinib could result in animprovement in QoL in our real-world population. Primaryobjective: evaluate impact of ibrutinib treatment in QoL. Wedefined a clinically meaningful improvement 3 points in FACITfatigue score. Secondary Endpoints: Detect a 10% improvement byEQ5D VAS. Correlate baseline and follow-up hemoglobin levels(meaningful improvement 1g/dL). Design: This is a prospective,longitudinal, single arm study enrolling consecutive CLL patientsunder ibrutinib monotherapy either as first or further line oftreatment. Median follow-up was 7 months (range 1-28). Setting:Patients are recruited in an academic referral center in BuenosAires. Interventions: QoL was explored with FACIT-fatigue andEQ5D visual-analogue-scale (VAS) questionnaires (with copyrightpermission). Assessment by results reported by patient questionnaires are completed on months 0-1-3-6 and 12 since the beginningof treatment. Main Outcomes Measures: We are reporting preliminary results after 3 months of treatment compared to baseline.Statistical Analysis: data was analyzed with the Sign Test (BinomialTest). Results: A total of 21 CLL patients who started ibrutinibbetween 2016 and 2018 were included. Median age was 75 years(range 57-84); 12 patients (57%) were males. Ibrutinib was first-linetherapy in 7 patients (33%), second-line in 7 patients (33%) and 7patients (33%) received 3 previous lines. After 3 months oftreatment, the median change in FACIT-fatigue score 3 pointswas reached in 13 patients (62%) as compared to baseline(p=0.024). After 3 months of treatment there was no evidence of amedian change >10% on the EQ5D VAS (p=0.593) nor a significant improvement on hemoglobin level (p=0.105).Conclusions: These results suggest an early improvement of fatiguewithin the first 3 months of treatment with ibrutinib. Longerfollow-up and larger number of patient are necessary to confirm thisdata and determine the further improvements of QoL withcontinuous treatment and correlation with hemoglobin changes.Fil: Mela Osorio, Maria Jose. Fundación Para Combatir la Leucemia; ArgentinaFil: Pavlovsky, Carolina. Fundación Para Combatir la Leucemia; ArgentinaFil: Pavlovsky, Astrid. Fundación Para Combatir la Leucemia; ArgentinaFil: Fernandez, Isolda. Fundación Para Combatir la Leucemia; ArgentinaFil: Massa, Federico Sackmann. Fundación Para Combatir la Leucemia; ArgentinaFil: Ferrari, Luciana. Fundación Para Combatir la Leucemia; ArgentinaFil: Juni, Mariana. Fundación Para Combatir la Leucemia; ArgentinaFil: Riddick, Maximiliano Luis. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Matemáticas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pavlovsky, Miguel A.. Fundación Para Combatir la Leucemia; Argentin