Innovative Combinations, Cellular Therapies and Bispecific Antibodies for Chronic Lymphocytic Leukemia: A Narrative Review.

Simple Summary: Chronic Lymphocytic Leukemia (CLL) is one of the most frequent leukemia in the west countries for adult patients. It's typically a slow-growing disease and the majority of patients do not need immediate treatment at diagnosis. Advanced stages or symptomatic disease require therapy. The treatment landscape of CLL has changed considerably in the last decades with the introduction of new targeted agents leading to improved outcome for patients with CLL compared to standard chemo-immunotherapy, especially for those with high-risk features, as del17p13, TP53 mutations and unmutated immunoglobulin heavy chain (IGHV) genes. In this narrative review, we comprehensively summarized and discussed all the new approaches currently investigated in completed and on-going clinical trials, both with single new agents and in combination strategies to pursuing not only a disease control but the eradication of the leukemic clone. In the last few years, several agents targeting molecules that sustain the survival and the proliferation of chronic lymphocytic leukemia (CLL) cells have become clinically available. Most of these drugs target surface proteins, such as CD19 or CD20, via monoclonal or bispecific monoclonal antibodies (BsAbs), CAR T cells, intracellular proteins like BTK by using covalent or non-covalent inhibitors or BCL2 with first or second generation BH3-mimetics. Since the management of CLL is evolving quickly, in this review we highlighted the most important innovative treatments including novel double and triple combination therapies, CAR T cells and BsAbs for CLL. Recently, a large number of studies on novel combinations and newer strategic options for CLL therapy have been published or presented at international conferences, which were summarized and linked together. Although the management of treatment with a single continuous agent is easier, the emergence of protein mutations, long-term toxicities and costs are important concerns that favor the use of a fixed duration therapy. In the future, a measurable residual disease (MRD)-guided treatment cessation and MRD-based re-initiation of targeted therapy seems to be a more feasible approach, allowing identification of the patients who might benefit from continuous therapy or who might need a consolidation with BsAbs or CAR T cells to clear the neoplastic clone. [ABSTRACT FROM AUTHOR]