Current and future treatment strategies in chronic lymphocytic leukemia

Abstract

Treatment decisions for patients with chronic lymphocytic leukemia (CLL) are dependent on symptoms and classification into high-, medium-, or low-risk categories. The prognosis for CLL hinges, in part, on the presence or absence of less-favorable genetic aberrations, including del(17p), del(11q), TP53 dysfunction, and IGHV mutations, as these markers are associated with worse treatment response. Promising results from multiple clinical trials show emerging therapies targeting Burton tyrosine kinase, B-cell leukemia/lymphoma 2, and phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta result in better outcomes and prolonged progression-free survival for patients both with and without certain high-risk aberrations. Favorable outcomes using these novel oral targeted therapies, either alone or in combination with other treatments such as anti-CD20 antibodies, has led to their use almost entirely supplanting chemoimmunotherapy in the treatment of CLL. In this narrative review, we summarize the current clinical evidence for the use of targeted mono- and combination therapies for CLL, discuss new and next-generation treatment approaches currently in development, and provide insight into areas of unmet need for the treatment of patients with CLL.

Use of BTK Inhibitors in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Practical Guidance

“…Patients with a TP53 mutation or del(17p) generally have a poor response to chemotherapy, with a historical median PFS of 9 months. 3 , 60 , 61 In the phase III CLL14 trial, median PFS for TP53 mutated disease was approximately 18 months in patients treated with chlorambucil-obinutuzumab as compare to close to 4 years for venetoclax + obinutuzumab (VEN-O). 62 Long-term follow-up from a Phase 2 study of ibrutinib in treatment-naïve CLL/SLL showed that 27 patients with TP53 mutated disease treated upfront with ibrutinib had a 5-year PFS of 66%.…”

“…The use of BTK inhibitors is also approved in the R/R setting following prior treatment with CIT or venetoclax-based therapy. 60 Should a BTK inhibitor treatment be discontinued due to adverse events, and alternative BTK inhibitor may be used. However, progressive CLL/SLL while being treated on a covalent BTK inhibitor would indicate likely resistance.…”

CAR-T after Stem Cell Transplantation in B-Cell Lymphoproliferative Disorders: Are They Really Autologous or Allogenic Cell Therapies?

“…B-cell malignancies are a diverse group of neoplasms that emerge from the malignant proliferation of B cells during their different stages of development [1], and they include lymphomas and leukemias [2]. The first line of treatment includes chemotherapy, but proposals of chemotherapy vary depending on the subtype of disorder and multiple patient factors [3], new chemoimmunotherapy drugs, such as ibrutinib and imatinib, as well as hematopoietic stem cell transplant (HSCT) [4][5][6][7].…”

STL1, a New AKT Inhibitor, Synergizes with Flavonoid Quercetin in Enhancing Cell Death in A Chronic Lymphocytic Leukemia Cell Line

“…These findings may be relevant in terms of the potential clinical application considering that CLL remains the most common form of leukemia in Western countries. The overall survival (OS) at 5 years of high-risk patients, those resistant to therapy, is of about 20% [ 12 ]. Moreover, considering that, a significant group of patients with CLL survive for many years or decades in the absence of treatments (Rai stage 0 or Binet classification A) due to the relatively slow progression rate of the disease, a chemopreventive intervention with low doses of quercetin may result as beneficial [ 13 ].…”

“…Duvelisib, approved in 2018 for the treatment of patients with relapsed or refractory CLL, is a dual inhibitor of PI3Kδ and PI3Kγ [ 23 ]. Other PI3Kδ are currently under development [ 12 ]. More intriguing is the synthesis and clinical efficacy of inhibitors that directly target AKT.…”