Infections in patients with chronic lymphocytic leukemia

ABSTRACT Introduction: Infection is a major complication in patients with chronic lymphocytic leukemia (CLL). Newly diagnosed patients are at high risk of developing infection caused by encapsulated bacteria, such as Streptococcus pneumoniae and Haemophylus influenzae. Method and Results: However, once treatment is initiated, the spectrum of pathogens causing infection broadens, depending on the treatment regimens. With disease progression, cumulative immunosuppression occurs as a consequence of multiple treatment lines and the risk of infection further increases. On the other hand, the use of targeted therapies in the treatment of CLL have brought new risks of infection, with an increased incidence of invasive fungal diseases, particularly aspergillosis, in patients receiving Bruton kinase inhibitors. Conclusion: In this article, we review the epidemiology of infection in patients with CLL, taking into account the treatment regimen, and briefly discuss the management of infection.

Zeta-associated protein 70 expression in chronic lymphocytic leukemia: Relevance in Indian context

Background: Chronic lymphocytic leukemia (CLL) is prognosticated using the Rai and the Binet's staging. In the past few years, new parameters have been considered for prognostication. One such marker that has been a subject of speculation and found useful by some western studies is zeta-associated protein 70 (ZAP-70). Aim: To investigate the prevalence of ZAP-70 and find out its association with other prognostic markers like Rai and Binet's stage and CD38 in Indian CLL patients. Materials and Methods: Twenty-nine newly diagnosed cases of CLL were selected over 1 year. Immunophenotyping was done and expression of CD38 and ZAP-70 was evaluated on gated CLL cells. Statistical Analysis: Qualitative data were expressed as frequency and percentage. Differences between groups were evaluated using Student's t-test for quantitative data and Chi-square test/Fisher's exact t-test for qualitative variables. A P value less than 0.05 was considered significant. Results and Conclusion: We found a lower prevalence rate of ZAP-70 (2/29, 6.89%) with no association with any of the conventional poor prognostic factors. A large number of our CLL patients fall into the good prognostic group (22/29, ZAP 70?/CD38?) with a least number in the poor prognostic group (2/29, ZAP-70 + CD38+). Also, no association was found between ZAP-70 and CD38. The findings of the present study suggest that the majority of CLL patients in India have a good prognosis, may not require treatment, and have good overall survival. Geographical variations, genetic makeup, and natural history of the CLL could be the cause of such differences from western literature.

Rare case of multiple primary malignant neoplasms

Multiple Primary Malignant Neoplasms (MPMNs) are rarely reported and are defined as the diagnosis of ?2 independent, primary malignancies of different histologies/ origins in a single individual. In this study, we report a patient with Male Breast Cancer (MBC) and coexisting Small Lymphocytic Lymphoma (SLL) and Chronic Lymphocytic Leukemia (CLL). A 65-year-old male with complaints of a lump in his left breast since 2 years. CT scan findings were a non-homogeneous mass in the left breast along with bilateral axillary lymphadenopathy. Modified radical mastectomy was done. Microscopic examination showed the features of infiltrating duct carcinoma NOS: Modified Nottingham Bloom Richardson抯 Grade II in breast specimen. A peripheral smear of the patient showed features of chronic lymphocytic leukemia (absolute lymphocyte count was 16400 cells/mm3). IHC of breast tumor showed ER/PR positivity with H scores of 350 and 240 respectively and HER- 2/Neu protein expression was negative with a score of (1+). Lymph nodes were immunoreactive for CD 19, CD 23 and CD 5. Cells were non-reactive for Cyclin D1a and CD3. This is probably the first case of MBC with SLL and CLL. The diagnosis is consistent with synchronous MPMNs, which are increasingly reported nowadays.

Current status of diagnosis and treatment of chronic lymphocytic leukemia in China: A national multicenter survey research / 中华血液学杂志

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.

A novel differential diagnosis algorithm for chronic lymphocytic leukemia using immunophenotyping with flow cytometry

Abstract Introduction The availability of a clinical decision algorithm for diagnosis of chronic lymphocytic leukemia (CLL) may greatly contribute to the diagnosis of CLL, particularly in cases with ambiguous immunophenotypes. Herein we propose a novel differential diagnosis algorithm for the CLL diagnosis using immunophenotyping with flow cytometry. Methods The hierarchical logistic regression model (Backward LR) was used to build a predictive algorithm for the diagnosis of CLL, differentiated from other lymphoproliferative disorders (LPDs). Results A total of 302 patients, of whom 220 (72.8%) had CLL and 82 (27.2%), B-cell lymphoproliferative disorders other than CLL, were included in the study. The Backward LR model comprised the variables CD5, CD43, CD81, ROR1, CD23, CD79b, FMC7, sIg and CD200 in the model development process. The weak expression of CD81 and increased intensity of expression in markers CD5, CD23 and CD200 increased the probability of CLL diagnosis, (p < 0.05). The odd ratio for CD5, C23, CD200 and CD81 was 1.088 (1.050 - 1.126), 1.044 (1.012 - 1.077), 1.039 (1.007 - 1.072) and 0.946 (0.921 - 0.970) [95% C.I.], respectively. Our model provided a novel diagnostic algorithm with 95.27% of sensitivity and 91.46% of specificity. The model prediction for 97.3% (214) of 220 patients diagnosed with CLL, was CLL and for 91.5% (75) of 82 patients diagnosed with an LPD other than CLL, was others. The cases were correctly classified as CLL and others with a 95.7% correctness rate. Conclusions Our model highlighting 4 markers (CD81, CD5, CD23 and CD200) provided high sensitivity and specificity in the CLL diagnosis and in distinguishing of CLL among other LPDs.

Inhibidores de bruton tirosina quinasa. ¿Qué necesita saber el oncohematólogo y el cardiólogo? / Bruton tyrosine kinase inhibitors. What does the oncohematologist and the cardiologist need to know?

Resumen Los avances en el conocimiento incorporados en la última década han modificado en gran parte el paradigma del tratamiento de las enfermedades hematológicas malignas. Particularmente la intro ducción de los inhibidores de la Bruton tirosina quinasa (iBTK) y otras drogas blanco junto a nuevos anticuerpos monoclonales se han transformado en los agentes de elección, tanto para la leucemia linfática crónica (LLC) como para otros linfomas "B" periféricos como el linfoma de células del manto (LCM). Los resultados de eficacia frente a la terapia genotóxica son tan exitosos que el fin de la quimio inmunoterapia, sobre todo para la LLC, es ya un postulado reconocido por los principales grupos de investigación. Por otra parte, los nuevos fármacos modificaron el perfil de eventos adversos lo que obligó al desarrollo de nuevas subespecialidades como la cardio-oncología, la cual constituye actualmente un baluarte para el manejo racional de estos pacientes. La presente revisión tiene como objetivo destacar el estado actual del conocimiento sobre estas enfermedades, los principios farmacológicos junto a los nuevos eventos adversos de los iBTK y el invalorable aporte de la cardiología para un correcto tratamiento y control de estos pacientes.

Abstract Advances in knowledge incorporated in the last decade have modified the treatment paradigm in most of the malignant hematological diseases. In particular, the introduction of Bruton tyrosine kinase inhibitors (BTKi) and other target drugs together with new monoclonal antibodies have become agents of choice for both chronic lym phocytic leukemia (CLL) and other peripheral "B" lymphomas such as mantle cell lymphoma (MCL). The results of efficacy against genotoxic therapy are so successful that the end of chemoimmunotherapy, especially for CLL, is already a postulate recognized by the main research groups. On the other hand, the new drugs modified the profile of adverse events, which forced the development of new subspecialties such as cardio-oncology, which currently constitutes a bastion for the rational management of these patients. This review aims to highlight the current state of knowledge on these pathologies, pharmacological principles together with new adverse events of iBTK and the invaluable contribution of cardiology for correct management of these patients.

Impacto orçamentário da incorporação do rituximabe para o tratamento de leucemia linfocítica crônica no SUS / Budget impact of the incorporation of rituximab for the treatment of chronic lymphocytic leukemia in Brazil

Objetivo: O presente estudo objetiva desenvolver um modelo de análise de impacto orçamentário (AIO) relacionada à incorporação do rituximabe no tratamento de primeira linha da leucemia linfocítica crônica (LLC) no Sistema Único de Saúde (SUS). Métodos: A elaboração da AIO foi realizada de acordo com as recomendações metodológicas das diretrizes brasileiras, considerando a perspectiva do SUS, horizonte temporal de cinco anos, população a ser tratada, diferentes cenários de market share do rituximabe e custos diretos envolvidos no tratamento atual e no tratamento proposto, e também foi executada uma análise de sensibilidade para avaliar possíveis incertezas futuras. Resultados: A cada ano e ao final do horizonte temporal de cinco anos, a incorporação do rituximabe promoverá aumento dos custos, quando comparado com o valor de ressarcimento do SUS para o tratamento de primeira linha da LLC. No cenário de maior participação de mercado do rituximabe, os custos totais foram menores em relação ao cenário de menor market share. Dado que a estimativa da AIO é para gastos futuros, incertezas relacionadas como a possível elevação do custo do medicamento foi o fator que promoveu o cenário de maiores gastos. Conclusões: A projeção de custos estimados pela AIO demonstrou menores gastos financeiros no cenário de maior difusão do medicamento, o que pode ter correlação com o atraso da progressão da doença ao utilizar o rituximabe, e consequentemente menos pacientes irão requerer segunda linha de tratamento, que tem custo mais elevado.

Objective: This study aims to develop a budget impact analysis (BIA) model related to the incorporation of rituximab in the first-line treatment of chronic lymphocytic leukemia (CLL) in the Unified Health System (SUS). Methods: The preparation of the BIA was carried out in accordance with the methodological recommendations of the Brazilian guidelines, considering the perspective of the SUS, a time horizon of five years, population to be treated, different market share scenarios for rituximab and direct costs involved in the current treatment and treatment proposed, a sensitivity analysis was also performed to assess possible future uncertainties. Results: Each year and at the end of the five-year time horizon, the incorporation of rituximab will increase costs, when compared to the SUS reimbursement value for the first-line treatment of CLL. In the scenario of higher market share for rituximab, total costs were lower compared to the scenario of lower market share. Given that the BIA estimate is for future expenses, uncertainties related to the possible increase in the cost of the drug were the factor that promoted the scenario of higher expenses. Conclusions: The projection of costs estimated by the BIA showed lower financial expenses in the scenario of greater diffusion of the drug, which may be correlated with the delay in the progression of the disease when using rituximab and, consequently, fewer patients will require second-line treatment, which has a higher cost.

Análise de custo do sequenciamento dos novos agentes para o tratamento de leucemia linfocítica crônica sob a perspectiva do sistema de saúde suplementar brasileiro / Cost analysis of sequencing new agents for the treatment of chronic lymphocytic leukemia from the perspective of the Brazilian supplementary health system

Objetivo: Estimar o custo do sequenciamento de tratamentos e por desfecho dos novos agentes disponíveis para o tratamento de pacientes com leucemia linfocítica crônica (LLC) em primeira linha (1L) e segunda linha (2L) em um horizonte temporal de 15 anos sob a perspectiva do sistema de saúde suplementar brasileiro. Métodos: Foi desenvolvido um modelo de sobrevida particionada com quatro transições de estados de saúde (sem progressão em 1L, sem progressão em 2L, pós-progressão e morte), considerando os seguintes regimes: venetoclax + obinutuzumabe (VenO), venetoclax + rituximabe (VenR), ibrutinibe (Ibru) e acalabrutinibe (Acala). Foram consideradas na análise as posologias em bula e as curvas de sobrevida livre de progressão (SLP) dos respectivos estudos pivotais em cada uma das linhas terapêuticas. O custo total de cada sequência considerou a soma dos custos dos regimes utilizados em 1L e 2L, baseado no preço fábrica de cada medicamento. Resultados: As sequências de tratamento iniciadas com VenO apresentaram menores custos, especialmente o regime VenO>VenR (R$ 982.447), que apontou redução de aproximadamente R$ 3 milhões em 15 anos, quando comparada às sequências de Ibru>VenR ou Acala>VenR. Na análise de custo por desfecho, a sequência VenO>VenR apresentou o menor custo por ano de SLP (R$ 104.437), até 76% inferior em relação ao sequenciamento com maior custo por ano de SLP (Ibru>VenR). Conclusões: Os resultados desta análise demonstram o impacto significativo que a 1L de tratamento possui na jornada do paciente com LLC. Adicionalmente, o presente estudo aponta o menor custo de tratamento acumulado para o sequenciamento dos regimes VenO>VenR, sugerindo que os regimes de tratamento à base de venetoclax podem contribuir de maneira substancial em uma maior eficiência na alocação de recursos pelo gestor do sistema de saúde suplementar brasileiro.

Objective: To estimate the cost of treatment sequencing and per outcome of the new agents available for the treatment of patients with chronic lymphocytic leukemia (CLL) in 1st line (1L) and 2nd line (2L) in a 15-years time horizon from the perspective of the Brazilian supplementary health system. Methods: A partitioned survival model including four health state transitions (no progression in 1L, no progression in 2L, post-progression and death) was developed, considering the following regimens: venetoclax + obinutuzumab (VenO), venetoclax + rituximab (VenR), ibrutinib (Ibru) and acalabrutinib (Acala). The package insert dosages and progression-free survival (PFS) curves of the respective pivotal studies in each of the therapeutic lines were considered in the analysis. The total cost of each sequence considered the sum of the costs of the regimens used in 1L and 2L, based on the factory price of each drug. Results: Lower costs were observed when treatment sequences were initiated with VenO, especially the VenO>VenR regimen (R$ 982,447), which showed a reduction of approximately R$ 3 million in 15 years when compared to the Ibru>VenR or Acala>VenR sequences. In the cost per outcome analysis, the sequence VenO>VenR had the lowest cost per year of PFS (R$ 104,437), up to 76% lower than the sequencing with the highest cost per year of PFS (Ibru>VenR). Conclusions: Results show the significant impact that 1L treatment has on the CLL patient's journey. Additionally, the present study points to the lowest accumulated treatment cost for the sequencing of VenO>VenR regimens, suggesting that venetoclax-based treatment regimens can substantially contribute to greater efficiency in the allocation of resources by the manager of the Brazilian supplementary health system.

Application of modified Matutes score containing CD200 in diagnosis of chronic lymphocytic leukemia / 中南大学学报(医学版)

OBJECTIVES@#Immunophenotyping technique is a powerful tool for the diagnosis and differential diagnosis of chronic lymphocytic leukemia (CLL) and other B-cell chronic lymphoproliferative diseases (B-CLPD). CD200 is strongly expressed in CLL. This study aims to analyze the clinical value of modified Matutes score (MMS) containing CD200 in the diagnosis of CLL.@*METHODS@#We retrospectively analyzed 103 B-CLPD patients diagnosed from January 2020 to July 2021, including 64 CLL patients, 11 follicular lymphoma (FL) patients, 14 mantle cell lymphoma (MCL) patients, 6 marginal zone lymphoma (MZL) patients, 1 hairy cell leukemia (HCL) patient, and 7 lymphoplasmic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) patients. The expression of CD markers between the CLL group and the non-CLL group was compared, and the sensitivity, specificity, and clinical consistency of MMS and Royal Marsden Hospital (RMH) immunophenotyping score system were analyzed.@*RESULTS@#There were significant differences in the expressions of CD5, CD23, FMC7, CD22, CD79b, CD200, and sIg between the CLL group and the non-CLL group (χ2 values were 37.42, 54.98, 30.71, 11.67, 55.26, 68.48, and 17.88, respectively, all P<0.01). When the RMH immunophenotyping score≥4, the sensitivity was 79.7%, and the specificity was 100%. When the MMS≥3, the sensitivity was 95.3%, and the specificity was 100%. The Kappa coefficient of RMH immunophenotyping system was 0.677, and the Kappa coefficient of MMS system was 0.860.@*CONCLUSIONS@#The MMS system containing CD200 has better sensitivity and same specificity compared with RMH immunophenotyping system, and MMS system may be more useful in the diagnosis of CLL.

Leucemia linfocítica crônica associada a melanoma metastático em homem de 53 anos / Metastatic melanoma in a 53-year-old male with relapsed chronic lymphocytic leukemia

Introdução: A associação de leucemia linfocítica crônica (LLC) e melanoma tem sido estudada nos últimos anos. Acredita-se que a imunossupressão causada pelo tratamento da doença seja o fator de risco mais importante para o aumento da susceptibilidade ao desenvolvimento e disseminação do câncer de pele. Relato de Caso: Este relato de caso descreve homem de 53 anos, em tratamento de leucemia linfocítica crônica desde 2018, já submetido a diversos ciclos de quimioterapia com fludarabina. Apresentou histórico de exérese de melanoma nodular epitelioide no couro cabeludo em 2019, removido com margens livres. Um ano após a cirurgia, paciente evoluiu com piora do estado geral com necessidade de hospitalização. Investigação adicional revelou focos de metástase em pulmões, fígado, rins, estômago, sistema nervoso central e linfonodos. Análise histopatológica foi positiva para melanoma. A possibilidade de tratamento foi descartada pela equipe de oncologia, que sugeriu cuidados paliativos. Discussão: Um dos mecanismos mais discutidos para explicar esta associação de neoplasias é a imunossupressão resultante do tratamento da LLC, que deixa o paciente suscetível ao desenvolvimento e à disseminação do melanoma. Além disso, a fludarabina, quimioterápico geralmente usado para remissão da LLC, é conhecida por depletar células T-helper e tem sido descrita como cofator deste processo. A associação de leucemia e melanoma cutâneo têm sido descrita nos últimos anos, porém não há nenhum protocolo de tratamento para esta condição.

BACKGROUND: The association of Chronic Lymphocytic Leukemia (CLL) and melanoma have been studied in the last years. The immunosuppression caused by the treatment of CLL seems to be the major factor of increasing patients' susceptibility to the development and spread of skin cancer. CASE REPORT: This case report describes a 53-year-old male patient, in CLL treatment since 2018, already submitted to many cycles of chemotherapy with fludarabine. History of an exeresis of epithelioid nodular melanoma of the scalp in 2019, which was removed with a clear margin. One year later, he presented with a poor general condition with hospitalization indication. Additional investigation revealed metastatic lesions in lungs, liver, kidneys, stomach, central nervous system, and lymph nodes. Histopathologic analysis positive for melanoma. The possibility of treatment was discarded by the Oncology team, which suggested palliative care. DISCUSSION: One of the most discussed mechanisms to explain this cancer association is the immunosuppression developed during the treatment of CLL, increasing patients' susceptibility to the development and spread of melanoma. In addition, the use of fludarabine, a chemotherapy commonly used in relapsed CLL, is known to deplete T-helper cells and has been described as a cofactor of this process. The association of leukemia and cutaneous melanoma has been reported in the last years, yet there is no surveillance protocol.

Chronic Lymphocytic Leukemia (CLL): evaluation of AKT protein kinase and microRNA gene expression related to disease pathogenesis

Abstract The present study evaluated 56 patients diagnosed with Chronic Lymphocytic Leukemia (CLL) and a control group of 44 clinically healthy subjects with no previous history of leukemia. Genetic expressions of AKT and microRNAs were evaluated by quantitative PCR (qPCR). A significant increase in AKT gene expression in patients when compared to controls was observed (p = 0.017). When the patients were stratified according to Binet subgroups, a significant difference was observed between the subgroups, with this protein kinase appearing more expressed in the B+C subgroup (p = 0.013). Regarding miRNA expression, miR-let-7b and miR-26a were reduced in CLL patients, when compared to controls. However, no significant differences were observed in these microRNA expressions between the Binet subgroups (A versus B+C). By contrast, miR-21 to miR-27a oncogenes showed no expression difference between CLL patients and controls. AKT protein kinase is involved in the signaling cascade that occurs with BCR receptor activation, leading to increased lymphocyte survival and protection against the induction of cell death in CLL. Thus, increased AKT protein kinase expression and the reduction of miR-let-7b and miR-26a, both tumor suppressors, may explain increased lymphocyte survival in CLL patients and may be promising markers for the prognostic evaluation of this disease.

Injuria subendocárdica sin evidencia de aterosclerosis relacionada con infusión de obinutuzumab / Subendocardial injury with no evidence of atherosclerosis associated with obinutuzumab infusión

Resumen El obinutuzumab es un anticuerpo monoclonal completamente humanizado contra CD20, empleado en el tratamiento de leucemia linfocítica crónica. Los eventos cardiovasculares fatales han sido des critos, pero solo en pacientes con antecedentes cardiovasculares conocidos. Presentamos el caso de un hombre adulto con diagnóstico de leucemia linfocítica crónica de alto riesgo que desarrolló injuria subendocárdica, sin evidencia de aterosclerosis coronaria, durante la primera infusión de obinutuzumab.

Abstract Obinutuzumab is a fully humanized monoclonal antibody against CD20 used in the treat ment of chronic lymphocytic leukemia. Fatal cardiovascular events have been described, but only in patients with known cardiovascular records. We report the case of an adult male with a high-risk chronic lymphocytic leukemia who developed subendocardial injury, with no evidence of coronary atherosclerosis, during the first administration of obinutuzumab.

Leucemias crónicas y SARS-CoV-2 / Chronic leukemias and SARS-CoV-2

Resumen El 30 de enero del año 2020, la Organización Mundial de la Salud declaró emergencia internacional de Salud Pública la pandemia causada por el coronavirus 2 del síndrome respiratorio agudo grave (SARS-CoV-2). Al inicio surgieron muchas dudas relacionadas con los ajustes al tratamiento y el seguimiento de los pacientes con leucemias crónicas y diversas asociaciones internacionales emitieron recomendaciones. El uso de la telemedicina y la selección de estrategias de tratamiento que permitan un menor acercamiento de los pacientes a los centros hospitalarios ha sido una de las principales técnicas de protección de los pacientes con leucemias crónicas. La experiencia internacional nos describe que al parecer los pacientes con leucemia mieloide crónica son menos susceptibles a contraer la infección y a morir, al contrario de los pacientes con leucemia linfocítica crónica.

Abstract On January 30 of the 2020 year, the World Health Organization declared an international public health emergency the pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initially, many doubts arose regarding treatment adjustments and follow-up of patients with chronic leukemias, and various international associations issued recommendations. The use of telemedicine and the selection of treatment strategies that allow care without patients going to hospital centers, has been one of the main techniques for protecting patients with chronic leukemias. International experience describes that it seems that patients with chronic myeloid leukemia are less susceptible to infection and death, unlike patients with chronic lymphocytic leukemia.

Diagnóstico por citometría de flujo de paciente con leucemia linfoide crónica / Flow cytometry diagnosis of a patient with chronic lymphocytic leukemia

Introducción: La citometría de flujo es una técnica de avanzada, objetiva y altamente sensible que permite el análisis y la cuantificación simultánea de múltiples parámetros celulares, muy utilizada en el estudio de la leucemia linfoide crónica, entidad caracterizada como un trastorno proliferativo maligno de linfocitos de aspecto maduro e incompetentes. Objetivo: Describir la estrategia de diagnóstico del inmunofenotipaje por citometría de flujo de la leucemia linfoide crónica. Métodos: Se analizó una muestra de médula ósea para la citometría de flujo de un paciente con sospecha clínica y morfológica de la leucemia linfoide crónica. El inmunofenotipaje celular se realizó con el empleo de anticuerpos monoclonales dirigidos contra los antígenos de diferenciación linfoides B y T. Se procedió a la lectura de la muestra en un citómetro GALLIOS, Beckman Coulter y los datos obtenidos se analizaron con el empleo del programa informático Kaluza. Resultados: Los antígenos con expresión positiva fueron el CD19 (99,94 por ciento), CD20 (81,56 por ciento), CD5 (80,25 por ciento), así como la coexpresión de CD5+/CD19+ (96,56 por ciento), CD5+/CD20+ (80,56 por ciento), CD19+/CD20+ (84,86 por ciento), CD23 (62,65 por ciento), CD49d (65,18 por ciento), CD38 (52,17 por ciento). Se encontró monoclonalidad de la cadena ligera k en un 44,27 por ciento. La expresión de los antígenos CD3, CD4, CD8y CD25 resultó negativa. Conclusiones: La estrategia diagnóstica propuesta permitió identificar los antígenos más frecuentemente expresados en pacientes con leucemia linfoide crónica, así como la coexpresión de los mismos y la monoclonalidad de la cadena k, los cuales son marcadores celulares que permiten realizar el diagnóstico inmunofenotípico de la leucemia linfoide crónica, por citometría de flujo(AU)

Introduction: Flow cytometry is an advanced, objective, highly sensitive technique for the simultaneous analysis and quantification of multiple cellular parameters. This technique is very common in the study of chronic lymphocytic leukemia, a condition defined as a malignant proliferative disorder of mature, incompetent lymphocytes. Objective: Describe the diagnostic strategy for flow cytometry immunophenotyping of chronic lymphocytic leukemia. Methods: Flow cytometry testing was performed of a bone marrow sample taken from a patient with clinical and morphological suspicion of chronic lymphocytic leukemia. Cell immunophenotyping was based on monoclonal antibodies targeted against lymphoid differentiation antigens B and T. The sample was read in a GALLIOS Beckman Coulter cytometer, and the data obtained were analyzed with the software Kaluza. Results: Antigens with a positive expression were CD19 (99.94 percent), CD20 (81.56 percent), CD5 (80.25 percent), as well as the co-expression of CD5+/CD19+ (96.56 percent), CD5+/CD20+ (80.56 percent), CD19+/CD20+ (84.86 percent), CD23 (62.65 percent), CD49d (65.18 percent), CD38 (52.17 percent). Monoclonality of the k light chain was present in 44.27 percent. Expression of antigens CD3, CD4, CD8 and CD25 was found to be negative. Conclusions: The diagnostic strategy proposed made it possible to identify the antigens most frequently expressed in patients with chronic lymphocytic leukemia, as well as their co-expression and the monoclonality of the k chain, all of which are cell markers allowing flow cytometry-based immunophenotypical diagnosis of chronic lymphocytic leukemia(AU)

Multidisciplinary diagnostics of chronic lymphocytic leukemia: European Research Initiative on CLL - ERIC recommendations

ABSTRACT Recent advances in chronic lymphocytic leukemia (CLL) includes description of disease genomic landscape, inclusion of prognostic relevant genetic tests in CLL workflow and evaluation of minimal residual disease (MRD)1 in parallel with the increase availability of novel therapy agents.In this review, the theoretical and practical aspects of response assessment have been discussed. These are based on updated recommendations of the European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) for genetic tests (TP53 mutation and IGHV status) and flow cytometry analysis for CLL. Methodological approaches and interpretation of results were also discussed.2,3

Detection of somatic TP53 mutations and 17p deletions in patients with chronic lymphocytic leukemia: a review of the current methods

ABSTRACT Chronic lymphocytic leukemia is the most common hematologic malignancy among adults in Western countries. Several studies show that somatic mutations in the TP53 gene are present in up to 50% of patients with relapsed or refractory chronic lymphocytic leukemia. This study aims to review and compare the methods used to detect somatic TP53 mutations and/or 17p deletions and analyze their importance in the chronic lymphocytic leukemia diagnosis and follow-up. In chronic lymphocytic leukemia patients with refractory or recurrent disease, the probability of clonal expansion of cells with the TP53 mutation and/or 17p deletion is very high. The studies assessed showed several methodologies able to detect these changes. For the 17p deletion, the chromosome G-banding (karyotype) and interphase fluorescence in situ hybridization are the most sensitive. For somatic mutations involving the TP53 gene, moderate or high-coverage read next-generation sequencing and Sanger sequencing are the most recommended ones. The TP53 gene mutations represent a strong adverse prognostic factor for patient survival and treatment resistance in chronic lymphocytic leukemia. Patients carrying low-proportion TP53 mutation (less than 20-25% of all alleles) remain a challenge to these tests. Thus, for any of the methods employed, it is essential that the laboratory conduct its analytical validation, documenting its accuracy, precision and sensitivity/limit of detection.

How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation

ABSTRACT: The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

Synchronous high-grade bladder carcinoma associated with chronic lymphocytic leukemia: A rare entity in Indian literature

B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is one of the common lymphoproliferative disorders with an increased risk of developing subsequent neoplasms of epithelial and mesenchymal origin. The decreased immunity and B-cell dysfunction in CLL probably accounts for this emergence of secondary malignancy. Breast, brain, skin and prostate tumors have been reported as usual coincident malignancies of CLL, while in occasional cases CLL may occur with malignancies of other solid organs, such as skin, lung, heart, and prostate. Synchronous CLL with urothelial carcinoma (UC) is an infrequent occurrence. We report this case because of its rarity in Indian literature and interesting hematological, immunophenotypic, histopathological, and cytopathological features of metastatic high-grade UC in a 61-year-old male with CLL

Acute liver failure secondary to chronic lymphocytic leukemia

Chronic lymphocytic leukemia is an indolent malignancy of lymphocytes commonly seen in elderly. Dissemination of malignancy is a rare cause of acute liver failure and has rarely been reported. Here we describe the case of a sixty five year old male presenting with acute liver failure. He is a diabetic with no known history of seropositive hepatitis, drug intake or any addictions. Bone marrow and liver biopsy suggestive of chronic lymphocytic leukemia. He eventually succumbed to his illness.

Bioanalytical Method Development And Validation Of Ibrutinib In Biological Matrices By Lc-Ms/Ms

Objective: The main aim of the research was to develop a fast and highly sensitive bioanalytical LC-MS/MS technique for the quantitation of ibrutinib in human plasma. Methods: Chromatography has achieved on a reverse phase-symmetry C18 (75 mm × 4.6 mm, 3.5 µm) column with gradient elution by acetonitrile, methanol and 0.1%v/v formic acid as the mobile phase. Chromatographic peaks were resolved with 0.7 ml/min flow rate. Drug was extracted with ethyl acetate solvent by liquid-liquid extraction method. Monitoring of transition of m/z 441.2 and 55.01 for ibrutinib and 446.5 and 60.01 for Ibrutinib-D5 were made on multiple reaction monitoring. Results: Calibration curve of ibrutinib was linear over 1-600 ng/ml concentration range with a regression coefficient (r2) value of>0.99. The % RSD values were less than 8.5% for inter-day and intra-day precision and accuracy. The method has excellent recovery and the percentage recovery values of lower quality control (LQC), median quality control (MQC) and higher quality control (HQC) samples were 101.86%, 102.8%, and 99.28% respectively. Conclusion: The drug was stable for more time at variable stability conditions and method was successfully applicable to the regular analysis of ibrutinib in biological matrices.