SOHO State of the Art Updates and Next Questions | Management of Most Difficult Cases of Chronic Lymphocytic Leukemia: Relapse After Both BTK and BCL2 Inhibition and Richter Transformation

Sequencing and combination of currentsmall‐moleculeinhibitors for chronic lymphocytic leukemia: Where is the evidence?

“…Retreatment with venetoclax (with or without an anti‐CD20 monoclonal antibody) is known to be associated with durable responses with acceptable toxicity profiles in patients who developed either resistance or intolerance to BTK inhibitors 78 . A recent review of three retrospective studies which evaluated the efficacy of venetoclax after BTK inhibition reaffirms the improved PFS conferred by venetoclax in patients who had stopped a prior BTK inhibitor due to toxicity as opposed to disease progression 49 . Venetoclax has activity in both patients who were intolerant of ibrutinib or discontinued ibrutinib because of disease progression 49 …”

“…It must also be noted that clinical trials documenting the efficacy of therapeutic sequencing with small‐molecule inhibitors in patients with relapsed CLL are very limited. Historically, these agents were utilized in patients who had received prior chemoimmunotherapy 49 …”

“…78 A recent review of three retrospective studies which evaluated the efficacy of venetoclax after BTK inhibition reaffirms the improved PFS conferred by venetoclax in patients who had stopped a prior BTK inhibitor due to toxicity as opposed to disease progression. 49 Venetoclax has activity in both patients who were intolerant of ibrutinib or discontinued ibrutinib because of disease progression. 49…”

“…82 Taken together, BTK inhibitor is effective in patients who have received prior venetoclax, especially those who have not received a prior BTK inhibitor. 49…”

“…37,89 Many patients with CLL generally do not require more than one or two agents to keep their disease under control. 49 On the other hand, it is generally hypothesized that combination therapies may produce high response rates and MRD negativity, inferred from the achievement of MRD negativity in the ibrutinib-venetoclax combination for both fit and unfit individuals 90 and obinutuzumab-venetoclax combinations for unfit individuals. 28 Although sequencing of small-molecule inhibitors facilitates optimization based on the patient's comorbidities, performance status, prior therapies, disease risk profile, and guides the development of individualized, better tolerated, time-limited chemotherapy-free treatment options, numerous questions such as acquired resistance (e.g., mutations in BCR signaling), suboptimal durability in patients with high-risk disease, indefinite treatment duration, decreased compliance and controversy of sequential versus combination therapies are yet to be answered.…”