CLL update 2022: A continuing evolution in care

Chronic lymphocytic leukemia (CLL) is diagnosed by the presence of a specific immunophenotype of clonal B cells in the peripheral blood. Prognostic models such as the CLL-International Prognostic Index (CLL-IPI) are now available that evaluate risk and assist in counseling individual patients. High risk CLL is characterized as the presence of del17p13, TP53 mutations and complex karyotype. Multiple phase 3 clinical trials show that continuous therapy with novel agents such as Bruton tyrosine kinase inhibitors (BTKi) and B cell lymphoma 2 (BCL2) inhibitors either alone or in combination is the preferred approach compared to chemoimmunotherapy. Clinical trials testing novel combinations indicate that certain doublet and triplet therapies that are time limited, can achieve higher responses and undetectable minimal residual disease (uMRD). Remaining problems with novel agent approaches are a combination of intolerance and disease progression with the latter occurring more often in high risk CLL. Clinical trials are now testing multiple combinations and sequences along with time limited administration of novel agents to develop refined approaches for both frontline and relapsed/refractory (R/R) CLL cohorts. Further work is needed to accomplish several aspects including: how to deal with intolerance issues, identification of individuals who will relapse from novel combinations, definition of effective time limited approaches and when and if cellular therapies can be utilized to eliminate residual disease.