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Competing Interests: Paolo Ghia received honoraria from AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Janssen, Lilly/LoxoOncology, MSD, and Roche, and research funding from AbbVie, AstraZeneca, BMS, and Janssen, and is an Editor of HemaSphere. Marzia Varettoni received honoraria from AbbVie, AstraZeneca, BeiGene, and Janssen. The remaining authors declare no conflict of interest.

The incidence of pure red cell aplasia (PRCA) in chronic lymphocytic leukemia (CLL) is <1% and treatments include the use of steroids and therapeutic strategies including immunosuppressive therapies. Here we present a case of a CLL-associated PRCA successfully treated with acalabrutinib, a treatment never described before for this specific condition, obtaining a rapid response after failing two lines of therapy. Exploring the treatment rationale, both the immune modulation and the continuous control of the disease, could have played a role in the treatment efficacy. Covalent BTK inhibitors are an effective treatment option for autoimmune complications of CLL, including CLL-associated PRCA., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

As treatments with BTK inhibitors and BCL2 inhibitors have replaced the use of chemoimmunotherapy in CLL in both first-line and relapsed patients, it becomes critical to rationalize their use and exploit the full potential of each drug. Despite their proven, robust, and manifest efficacy, BTKis and BCL2is fail to provide long-term disease control in some categories of patients, and to date this is an unmet clinical need that is critical to recognize and address. Ongoing clinical trials are evaluating new treatment algorithms and new molecules to progressively thin this population. In this review for each category of patients we explicate the different possible patterns of treatment sequencing based on currently available evidence, starting from the frontline to currently ongoing trials, in order to optimize therapies as much as possible.