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Background: Tremendous developments in the field of chronic lymphocytic leukemia （CLL） in recent years have led to a revolutionary change in the treatment approach, which today is based on targeted treatments with a good response and optimal prognosis. Nevertheless, CLL can present or progress to “accelerated CLL” （A-CLL） or to “Richter transformation” （RT） and these two entities have a more aggressive course and are still characterized by challenges in the fields of diagnosis and therapy. In the current review, we summarized the latest knowledge in terms of diagnostic approaches to A-CLL, available treatments and clinical trials, for both A-CLL and RT which still pose an unmet need and require additional basic and clinical investigations. Summary: A-CLL is a rare and underdiagnosed entity that probably stands in the “gray zone” between CLL and RT, generally holding an intermediate prognosis. Its diagnosis is mainly based on histological findings including expanded proliferation centers, increased mitotic activity, and/or high Ki-67 index. Due to its rarity, its treatment approach has still not been defined, but it seems that novel agents, especially Bruton tyrosine kinase inhibitors （BTKi）, are effective. As for RT, the standard therapy still consists of chemo-immunotherapy followed by stem-cell transplantation for fit responders with a dismal prognosis. New approaches are recently adopted including B-cell inhibition via novel agents （BTKi, venetoclax）, T-cell engagers （checkpoint inhibitors, bispecific antibodies [BiTe] or the chimeric antigen receptor [CAR] technology）, antibody-drug conjugates, or drug combinations. Although both CAR-T and BiTe seem promising, especially when combined with BTKi, evidence is still insufficient, and patients should generally be recruited in clinical trials. Key Messages: The field of CLL has been a subject of major advances in recent years, but A-CLL and RT remain topics of “unmet need” and require further studies to identify the best diagnostic approach and a more effective treatment.
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