Cross-talk between leukemic and immune cells at the tumor microenvironment in chronic lymphocytic leukemia: An update review.

Chronic lymphocytic leukemia (CLL) is a mature-type B cell malignancy correlated with significant changes and defects in both the innate and adaptive arms of the immune system, together with a high dependency on the tumor microenvironment. Overall, the tumor microenvironment (TME) in CLL provides a supportive niche for leukemic cells to grow and survive, and interactions between CLL cells and the TME can contribute to disease progression and treatment resistance. Therefore, the increasing knowledge of the complicated interaction between immune cells and tumor cells, which is responsible for immune evasion and cancer progression, has provided an opportunity for the development of new therapeutic approaches. In this review, we outline tumor microenvironment-driven contributions to the licensing of immune escape mechanisms in CLL patients.

Clinical Risks for Chronic Lymphocytic Leukemia.

Our understanding of risk factors for the development of chronic lymphocytic leukemia (CLL) is still incomplete and includes genetic and environmental factors. CLL is one of the most familial of all cancers, yet common high-penetrance risk alleles have not been identified. Genome-wide association studies have identified many common variants with low relative risks, whereas exome-wide rare variant analysis has implicated ATM in CLL causation. Environmental factors have also been challenging to identify given the limited understanding of the relevant time period of exposure relative to diagnosis, and the inability to quantify past exposures. Agent Orange and glyphosate herbicides have perhaps the most data to support their role. CLL is preceded by a precursor condition called monoclonal B-cell lymphocytosis (MBL), which could therefore be considered a risk factor, but which itself is likely caused by the same risk factors that ultimately give rise to CLL. Although virtually all people with CLL have a preceding MBL phase, most people with MBL will not develop CLL.

Update on the management of relapsed/refractory chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) predominantly affects older adults, characterized by a relapsing and remitting pattern with sequential treatments available for many patients. Identification of progressive/relapsed CLL should prompt close monitoring and early discussion about the next therapies when treatment indications are present. The intervening period represents an opportunity to optimize patient health, including establishing adequate vaccination and surveillance for second primary malignancies, and treating non-CLL-related comorbidities which may impact well-being and CLL therapy. We now see patients with relapsed/refractory (RR) CLL in the clinic who have been previously treated with chemoimmunotherapy (CIT) and/or one or more novel therapies. Continuous covalent inhibitors of Bruton's tyrosine kinase (cBTKi) and fixed-duration venetoclax (Ven)-anti-CD20 monoclonal antibody (mAb) are preferred over CIT given the survival advantages associated with these therapies, although have never been evaluated head-to-head. While both classes are effective for RR CLL, potential side effects and the logistics of administration differ. Few randomized data demonstrate the sequential use of cBTKi and fixed-duration Ven-anti-CD20 mAb; however, they may be used in either sequence. Newer non-covalent BTKi, active against BTK C481 resistance mutations emerging with continuous cBTKi exposure, and novel approaches such as BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell therapies demonstrate impressive efficacy. In this review of RR CLL we explore relevant investigations, consideration of broader CLL- and non-CLL-related health needs, and evidence for efficacy and safety of B-cell receptor inhibitors and Ven, including available data to support drug sequencing or switching. We describe novel approaches to RR CLL, including rechallenging with fixed-duration therapies, allogeneic stem cell transplant indications in the novel therapy era, and highlight early data supporting the use of T-cell directing therapies and novel drug targets.

Richter's transformation: Transforming the clinical landscape.

Richter transformation (RT) represents an aggressive histological transformation from chronic lymphocytic leukaemia, most often to a large B cell lymphoma. It is characterised by chemo-resistance and subsequent short survival. Drug development has struggled over recent years in light of the aggressive kinetics of the disease, lack of pivotal registrational trials and relative rarity of the phenomenon. In this review we will highlight the diagnostic and therapeutic challenges of managing patients with RT as well as taking a look to the future therapeutic landscape. Highly active therapies developed across B cell malignancies are starting to impact this field, with T-cell activation therapies (CAR-T, bispecific antibodies), antibody-drug conjugates, and novel small molecule inhibitor combinations (e.g. BTKi-BCL2i) being actively studied. We will highlight the data supporting these developments and look to the studies to come to provide hope for patients suffering from this devastating disease.

THE COURSE OF CHRONIC LYMPHOCYTIC LEUKEMIA AFTER SARS-COV-2 VIRUS INFECTION. / ПЕРЕБІГ ХРОНІЧНОЇ ЛІМФОЦИТАРНОЇ ЛЕЙКЕМІЇ НА ТЛІ ІНФЕКЦІЇ ВІРУСОМ SARS-COV-2.

Objective - to investigate the course of B-cell chronic lymphocytic leukemia (CLL) in patients after SARS-CoV-2 virus infection taking into account anamnestic exposure to the ionizing radiation (IR).Methods. The study was performed in a group of 51 CLL patients who were admitted to the Department of Radiation hematology of the National Research Center for Radiation Medicine of NAMS of Ukraine, Kyiv, from January 2020 (the beginning of SARS-CoV-2 epidemic) to August 2023. The group included 19 (37.3 %) clean-up workers of the Chornobyl NPP accident, 15 (29.4 %) inhabitants of radionuclide contaminated areas and 17 (33.3 %) IR non-exposed patients. The diagnosis of CLL was based on clinical history, lymphocyte morphology, and immunophenotypic criteria. Statistical studies were performed using the SPSS software package, version 20.0.Results. The diagnosis of CLL was established for the first time in 14 patients, in seven of them, CLL was diagnosed after 2-17 months after SARS-CoV-2 infection. In contrast to patients who did not suffer from a coronavirus infection, they had pronounced lymphadenopathy, which in some cases was accompanied by hyperleukocytosis, and needed early treatment. Thirteen patients with a previously established CLL were diagnosed with COVID-19 by PCR test. In seven of them (53.8 %) starting treatment was needed, or CLL has progressed. Seven of 51 patients (13.5 %) were vaccinated against SARS-CoV-2. Then, four of them were diagnosed with SARS-CoV-2 infection, confirmed by a positive PCR test, and two patients had a relapse of CLL within 1-2 months after vaccination. Most of patients with signs of the influence of SARS-CoV-2 infection on CLL belonged to sufferers of the Chornobyl NPP accident Conclusions. The clinical features of CLL that developed after SARS-CoV-2 were characterized firstly. The negative impact of SARS-CoV-2 infection on previously established CLL was established. The question about vaccination of CLL patients remains debatable.

Patogénesis de la leucemia linfática crónica / Pathogenesis of the chronic lymphocytic leukemia

La leucemia linfática crónica (LLC) es la leucemia de mayor prevalencia en adultos mayores. Se caracteriza por la acumulación progresiva de linfocitos B con morfología madura y un fenotipo particular con expresión de CD5, CD23 y bajos niveles de inmunoglobulina en la membrana. El linfocito leucémico en LLC presenta numerosas aberraciones cromosómicas, pero no se ha podido atribuir a una mutación o deleción particular la responsabilidad de la transformación maligna. Las alteraciones epigenéticas también juegan un papel en LLC, en particular la baja o nula expresión de ciertos microARN que controlan la transcripción de genes anti-apoptóticos. La inmunoglobulina clonal en LLC representa una molécula clave para entender la patología. Alrededor del 30% de los pacientes expresan inmunoglobulinas que reconocen autoantígenos intracelulares que se exponen en las células apoptóticas. En estos casos, la estimulación a través del receptor antigénico sería la responsable de la iniciación y/o progresión leucémica. Tradicionalmente se consideró a la LLC como una patología causada por defectos en la maquinaria apoptótica. En años recientes se demostró que las células leucémicas proliferan en forma activa en los tejidos linfáticos, donde se encuentran en íntimo contacto con linfocitos T, células estromales y de estirpe mieloide. Este microambiente particular provee a las células LLC de señales de supervivencia y activación a través de factores solubles y contacto celular. Uno de los objetivos terapeúticos actuales es lograr compuestos que rompan la interacción de las células LLC con su microambiente para interferir con estas señales de supervivencia. En esta revisión se discuten los aportes realizados desde la investigación básica para entender la etiopatología de la LLC.

Chronic lymphocytic leukemia (CLL) is the commonest leukemia in elderly. It is characterized by the progressive accumulation of B lymphocytes, with a mature morphology and a particular phenotype, expressing CD5, CD23 and low levels of surface immunoglobulin. Although the leukemic lymphocyte in CLL presents a variety of chromosomic aberrations, none of them was demonstrated to be responsible for the malignant transformation. Epigenetic alterations have also a place in CLL, particularly the low or absent expression of a number of microRNA that normally control the transcription of anti-apoptotic genes. Around 30% of CLL cases express clonal immunoglobulin that recognizes intracellular autoantigens which are exposed in apoptotic cells. In these cases, stimulation through the antigenic receptor would be responsible for the initiation and/or progression of the disease. The traditional point of view considered CLL as a pathology caused by defects in the apoptotic machinery. However, in recent years it was demonstrated that leucemic cells actively proliferate in lymphoid tissues, where they are found in intimate contact with T lymphocytes, myeloid and stromal cells. This particular microenvironment provides CLL cells with survival and activation signals through the release of soluble factors and cell contact interactions. Today, one of the therapeutic goals in CLL is the development of agents capable of disturbing the interaction of leukemic cells with their mileu in order to interfere with pro-survival signals. This review discusses the novel evidence from basic research directed to understand the etiopathology of CLL.

Análisis de factores pronósticos en leucemia linfática crónica. Valor predictivo del inmunofenotipo, el CD23 soluble y la morfología / Predictive factors in chronic lymphocytic leukemia. Value of immunophenotype, SCD23 and morphology

En LLC se reconocen factores pronósticos útiles como la duplicación linfocitaria, el estadio clínico y el patrón de infiltración medular. Otros, como el porcentaje de células CD38+, están en estudio y requieren confirmación. El objetivo del presente trabajo fue evaluar si existe asociación entre morfología, inmunofenotipo linfocitario, CD23 soluble (SL) y sobrevida libre de eventos (SLE). Se evaluaron prospectivamente 36 pacientes sin tratamiento. Se determinaron: morfología típica, mixta y LLC-PL; inmunofenotipo linfocitario (score de Matutes); niveles plasmáticos de CD23 SL; estadio clínico, duplicación linfocitaria; ß2 microglobulina y alteraciones citogenéticas. Se consideró evento: progresión de enfermedad (necesidad de tratamiento, evolución a estadios avanzados, desarrollo de organomegalia voluminosa) y muerte por enfermedad. Mediana de seguimiento 24 meses. Resultados: estadio 0: 11/36, SLE 80 por ciento; I: 10/36 SLE 90 por ciento; II: 13/36: III y IV: 2/36. SLE >= II 37 por ciento. p= 0.023. Duplicación linfocitaria: <12m 7/31, >12m 24/31. SLE 28 por ciento vs 80 por ciento p<0.001. Citogenético: normal 13/28; anormal 15/28. SLE 92 por ciento vs 54 por ciento p=0.053. +12 positiva 7/30, negativa 23/30. SLE 65 por ciento vs 66 por ciento. ß2 microglobulina normal 9/35, elevada 26/35; SLE 100 por ciento vs 53 por ciento p=0.006. D23 SL < 350 Ul/ml 15/32, > 350 Ul/ml 17/32. SLE 92 por ciento vs 53 por ciento p=0.005. Inmunofenotipo: Score 5: 15/36, Score 4: 19/36, SLE 64 por ciento. Score 3: 2/36. p=0.516. Morfología típica 17/35, mixta 17/35. SLE 81 por ciento vs. 57 por ciento p=0.099. LLC-PL 1/35. El CD 23 SL resultó adecuado para predecir SLE, particularmente útil en estadios iniciales sin otros marcadores de actividad. La morfología y el fenotipo linfocitario, dos variables accesibles, no fueron útiles para el propósito del estudio.