Time-limited, Combined Regimen in Chronic Lymphocytic Leukemia: A Promising Strategy to Achieve a Drug Holiday.

Chemoimmunotherapy (CIT) is defined as standard first line treatment for chronic lymphocytic leukemia (CLL) patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain (UM-IGHV) and TP53 aberration failed to benefit from it. The emergency of the small molecular targeted agents including Bruton's tyrosine kinase (BTK) inhibitor (BTKi) leads to a brand-new era, from a CIT to a chemo-free era in CLL. However, the treatment of target agents is not enough to attain a deep remission and high rate of complete remission (CR), especially in patients with high risks. The long duration brought about problems, such as cost, drug resistance and toxicity. To benefit CLL in progression free survival (PFS) and long-term remission, exploration of time-limited therapies, mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials. The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors, although long term follow-up is required to consolidate the conclusion. In this review, we intend to introduce key results of clinical trials with combination therapy, discuss the achievements and limitations and put forward future direction for clinical trial design in this field.