Current Treatment of Chronic Lymphocytic Leukemia

Abstract

A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab. Most of these agents are already included into treatment algorithms defined by international practice guidelines, but more clinical investigations are needed to answer still remaining questions. Ibrutinib was proven as a primary choice for patients with the TP53 gene deletion/mutation, who otherwise have no active treatment available. Idelalisib with rituximab is also an active therapy, but due to increased risk of serious infections, its use in first-line treatment is limited to patients for whom ibrutinib is not an option. A new indication for ibrutinib was recently approved for older patients with comorbidities, as an alternative to the already existing indication for chlorambucil with obinutuzumab. The use of kinase inhibitors is already well established in recurrent/refractory disease. Immunochemotherapy with fludarabine, cyclophosphamide, rituximab (FCR) remains a major first-line option for many CLL patients without the TP53 gene deletion/mutation, and who have no significant comorbidities or history of infections, and is particularly effective in patients with favorable features including mutated IGHV status. There are a number of issues regarding novel therapies for CLL that need further investigation such as optimum duration of treatment with kinase inhibitors, appropriate sequencing of novel agents, mechanisms of resistance to inhibitors and response to class switching after treatment failure, along with the potential role of combinations of targeted agents.

Wnt signalling pathways in chronic lymphocytic leukaemia and B‐cell lymphomas

“…CLL patients are typically not treated unless/until they suffer from an aggressive form of the disease. Treatment options involve immunochemotherapy (typically fludarabine/cyclophosphamide/rituximab – regimen) and, more recently, also novel inhibitors that target pro‐survival B‐cell receptor or anti‐apoptotic B‐cell lymphoma 2 (BCL2) signalling (Jamroziak et al ., ). Despite the fact that new treatment options have significantly improved patient response, this therapy needs to be mostly infinite to prevent relapse (Burger et al ., ; Jain et al ., ).…”

Enhanced CDC of B cell chronic lymphocytic leukemia cells mediated by rituximab combined with a novel anti-complement factor H antibody

“…Despite recent advances in the treatment of chronic B-CLL, this leukemia remains essentially incurable [20, 21]. The development of Bruton tyrosine kinase (ibrutinib), phosphoinositide 3-kinase (idelalisib), and B-cell lymphoma 2 (bcl-2) (venetoclax) inhibitors, as well as novel anti-CD20 antibodies (obinutuzumab and ofatumumab), have provided new options for therapy [20].…”

“…The development of Bruton tyrosine kinase (ibrutinib), phosphoinositide 3-kinase (idelalisib), and B-cell lymphoma 2 (bcl-2) (venetoclax) inhibitors, as well as novel anti-CD20 antibodies (obinutuzumab and ofatumumab), have provided new options for therapy [20]. Guidelines for therapy vary, but most divide patients based on their general "fitness," and presence of the p53 gene (17p) deletion or p53 mutation [20, 21]. For fit individuals without 17p deletion, most recommend combination therapy with fludarabine, cyclophosphamide, and rituximab (FCR) if < 65 years old, or bendamustine and rituximab if > 65 years old.…”

“…If 17p deletion is present and the patient is fit, they are given ibrutinib alone (or idelalisib with rituximab if unable to receive ibrutinib) or considered for a stem cell transplant. If 17p deletion is present and the patient is considered unfit, they are generally treated the same but considered for a drug clinical trial (and not a transplant) [20, 21]. Other options after failure include treatment with the bcl-2 inhibitor venetoclax.…”

Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia

“…Chronic lymphocytic leukemia (CLL) is an incurable clonal proliferation of small CD5/CD19-positive lymphocytes accumulating in blood, bone marrow and lymphoid tissues accounting for approximately 25% of all leukemias in Europe and North America [1,2]. The median age of diagnosis is 70 years, and the disease is incurable in majority of cases [3,4]. The disease has a heterogenous clinical course, and numerous studies aimed at identifying novel prognostic and predictive factors are being intensively performed.…”