Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures

Abstract

Disease overview: Chronic lymphocytic leukemia (CLL) is one of the most frequent types of leukemia. It typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and of apoptosis in 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 and staging: The clinical staging systems provide prognostic information by using the results of physical examination and blood counts. Various biological and genetic markers provide additional prognostic information. 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. The CLL international prognostic index integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL. Therapy: Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist: a combination of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax with obinutuzumab, monotherapy with inhibitors of Bruton tyrosine kinase (BTK) such as ibrutinib and acalabrutinib, or chemoimmunotherapy. 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 usually resistant to chemotherapy and should, therefore, be treated with targeted agents.Future challenges: Combinations of targeted agents are now being investigated to create efficient, potentially curative therapies of CLL with fixed duration. One of the most relevant questions currently addressed in clinical trials is the comparison of monotherapies with BTK inhibitors with fixed duration combination therapies. Moreover, the optimal sequencing of targeted therapies remains to be determined.

Reliable one-step assessment of IGHV mutational status and gene mutations in Chronic Lymphocytic Leukemia by capture-based high throughput sequencing

“…This is an important advantage in patient management by providing in one-step all necessary information to decide for the optimal therapeutic strategy. Indeed, IGHV and TP53 mutational status are currently the major theranostic markers in CLL, orienting treatment towards immunochemotherapy or chemo-free (BTKi, iBCL2) schedules (2,27,28). It would moreover be very easy to include other targets such as ATM, NOTCH1, SF3B1, BIRC3 (29) or others, should they become significant indicators of response or prognosis.…”

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

“…BTK inhibitors have unique toxicities that require monitoring. As such, it is essential to provide optimal management to achieve the best possible outcomes for patients [110,111]. The most common reason for discontinuing ibrutinib is toxicity, particularly the AEs specific for this group of drugs, such as atrial fibrillation (AF), bleeding events, arthralgias, rash, diarrhea, and cytopenias [112].…”

HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia

“…Ibrutinib resistance is a major challenge in the treatment of CLL [17]. To further investigate whether molidustat has the same inhibitory effects on ibrutinib-resistant strains of CLL, we intermittently treated MEC-1 with low concentrations of ibrutinib and gradually increased ibrutinib concentrations to induce ibrutinib resistance in MEC-1 cells [18].…”