Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment

Abstract

Disease overview Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B‐cells. Diagnosis The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B‐lymphocytes, which identify a clonal B‐cell population carrying the CD5 antigen, as well as typical B‐cell markers. Prognosis The two similar clinical staging systems, Rai and Binet, create prognostic information by using results of physical examination and blood counts. Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 (del [17p]) and/or mutations of the TP53 gene, predict resistance to chemoimmunotherapy and a shorter time to progression, with most targeted therapies. A comprehensive, international prognostic score (CLL‐IPI) integrates genetic, biological and clinical variables to identify distinct risk groups of CLL patients. Therapy Only patients with active or symptomatic disease, or with advanced Binet or Rai stages require therapy. When treatment is indicated, several options exist for most CLL patients: a combination of venetoclax with obinutuzumab, ibrutinib monotherapy, or chemoimmunotherapy. For physically fit patients younger than 65 (in particular when presenting with a mutated IGVH gene), chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab remains a standard therapy, since it may have curative potential. At relapse, the initial treatment may be repeated, if the treatment‐free interval exceeds 3 years. If the disease relapses earlier, therapy should be changed using an alternative regimen. Patients with a del (17p) or TP53 mutation are a different, high‐risk category and should be treated with targeted agents. An allogeneic SCT may be considered in relapsing patients with TP53 mutations or del (17p), or patients that are refractory to inhibitor therapy. Future Challenges Targeted agents (ibrutinib, idelalisib, venetoclax, obinutuzumab) will be increasingly used in combination to allow for short, but potentially definitive therapies of CLL. It remains to be proven that they generate a superior outcome when compared to monotherapies with inhibitors of Bruton tyrosine kinase, which can also yield long‐lasting remissions. Moreover, the optimal sequencing of drug combinations is unknown. Therefore, CLL patients should be treated in clinical trials whenever possible.

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

“…According to most practice guidelines today, TP53 disruption remains the lone predictive biomarker in CLL [38][39][40][41] and should be analyzed prior to treatment initiation in all patients owing to the large body of evidence demonstrating that patients either do not respond to initial chemoimmunotherapy (CIT) or experience relapse soon after remission [42] (Table 2). The most comprehensive data addressing the predictive capacity of TP53 disruption comes from an analysis of the CLL-8 trial [43], a phase 3, randomized (1:1) study comparing treatment with fl a phase and cyclophosphamide (FC) or FC with rituximab (FCR) in 817 previously untreated patients in which Stilgenbauer et al, showed that patients with TP53 disruption experienced poorer clinical responses, minimal residual disease (MRD) negativity, progression-free survival (PFS) and OS after treatment with FC and FCR [44] and that anti-CD20 therapy added no OS benefit.…”

Myocardial contractility dysfunction in patients with chronic lymphocytic leukemia receiving chemotherapy and their treatment with enalapril

“…Применение новых современных методов лечения с включением таргетных препаратов позволило совершить прорыв в терапии многих онкогематологических заболеваний, что привело к значительному увеличению продолжительности жизни пациентов [1]. Однако все более актуальными становятся вопросы качества жизни этой категории больных, своевременное выявление и коррекция осложнений химиотерапевтического лечения [2].…”

Cell-free IgG-aggregates in plasma of patients with chronic lymphocytic leukemia cause chronic activation of the classical complement pathway

“…Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, accounts for 30% of all leukemia cases. CLL is characterized by �5000 monoclonal B lymphocytes/μl in peripheral blood, which co-express the antigens CD5, CD19, CD20 and CD23 [1], and exhibit mature phenotype. The lymphocytes accumulate in peripheral blood, bone marrow, spleen, and secondary lymphoid organs.…”

“…CLL is a heterogenous disease, with a survival that depends on several factors, including the genomic landscape of CLL, with long known (such as del[13q14], del[17p], del[11q] and others) and more recently described (NOTCH1, MYD88, TP53, ATM, SF3B1, FBXW7, POT1, CHD2, RPS15 and others) mutations [1]. CLL is also associated with an inherent immune dysfunction that is related to morbidity and mortality as well as to infections, which account for 50 to 60% of all deaths [1,2]. The infections in CLL are related both to the disease and to the immuno-suppressive effects of the therapy.…”

“…The infections in CLL are related both to the disease and to the immuno-suppressive effects of the therapy. The therapeutic approach in fit CLL patients includes therapeutic monoclonal antibodies (mAbs), commonly used in combination with chemotherapy [1][2][3], so that the mAb drugs trigger immune responses against the leukemic B-cells that synergize with cytotoxic chemotherapeutic agents. The most clinically used immunotherapeutic drugs are Rituximab (RTX), Obinutuzumab, Ofatumumab (which target the CD20) and Alemtuzumab (anti CD52), expressed on B-CLL cell surface [4,5].…”