Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

by Selleckchem | Sep 30 2023

Purpose of review: There have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of treatment remains control of the disease and delay of progression rather than a cure which remains largely elusive. Considering that CLL is mostly seen in older patients, there are multiple factors that play a role in the selection of CLL beyond the frontline treatment. Here, we review the concept of relapsed CLL, factors that predispose to relapse, and therapeutic options available to this patient population. We also review investigational therapies and provide a framework for selection of therapies in this setting.

Recent findings: Please check if the affiliations are presented correctly.Targeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib. However, resistance to the covalent BTK inhibitors may emerge and is commonly associated with mutations in BTK or other downstream enzymes. The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi. Other novel therapies such as chimeric antigen receptor (CAR) T cell therapy have also shown significant activities for relapsed and refractory CLL. Measurable residual disease (MRD) assessment has a growing importance in venetoclax-based limited-duration therapy and there is mounting evidence that MRD negativity improves outcomes. However, it remains to be seen if this will become an established clinically significant endpoint. Further, the optimal sequence of various treatment options remains to be determined. Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents.

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Title: Advances in the Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia: A Review

Abstract: Over the past two decades, significant progress has been made in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). Although a cure for CLL remains elusive, the primary goal of treatment is disease control and delay of progression. This review focuses on the concept of relapsed CLL, factors contributing to relapse, and the available therapeutic options for this patient population. Recent findings highlight the efficacy of targeted therapies, including continuous Bruton tyrosine kinase inhibitors (BTKi) and fixed-duration venetoclax plus anti-CD20 monoclonal antibody therapy, which have demonstrated superiority over chemoimmunotherapy. Second-generation BTK inhibitors, such as acalabrutinib and zanubrutinib, exhibit an improved safety profile compared to ibrutinib. However, resistance to covalent BTK inhibitors may arise, often associated with mutations in BTK or downstream enzymes. Non-covalent BTK inhibitors, such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531), are promising options for relapsed CLL refractory to prior covalent BTKi. Additionally, chimeric antigen receptor (CAR) T cell therapy has shown significant activity in relapsed and refractory CLL. Measurable residual disease (MRD) assessment has gained importance in venetoclax-based limited-duration therapy, with evidence suggesting that MRD negativity improves outcomes. However, the clinical significance of this endpoint is still being determined. Furthermore, the optimal treatment sequence for different therapies remains to be established. The expanding array of treatment options allows for individualized therapy selection, and ongoing research will provide further insights into the optimal use of these agents.

Keywords: chronic lymphocytic leukemia, relapsed/refractory, targeted therapy, BTK inhibitors, venetoclax, chemoimmunotherapy, resistance, measurable residual disease, CAR T cell therapy, treatment sequencing.