Combinations or Sequences of Targeted Agents in CLL: Is the whole greater than the sum of its parts (Aristotle, 360 BC)?

Maryam Sarraf Yazdy, Anthony R. Mato and Bruce D. Cheson


The treatment landscape for chronic lymphocytic leukemia (CLL) is rapidly evolving. Targeted agents (TA) have demonstrated impressive single agent activity, and therefore have been replacing chemoimmunotherapy (CIT). Despite their efficacy, the optimal use of the current TAs remains challenging. Perhaps the major dilemma is whether these drugs are best-utilized in sequence, or in combinations. Most patients tolerate TA well, notably early during treatment; however, a substantial number discontinue therapy due to toxicities. Therefore, the reasons for discontinuation and, subsequently, the preferred sequence of these agents become critical issues. While TA monotherapy has revolutionized the treatment of CLL, residual disease, acquired resistance, suboptimal durability of response in patients with high-risk disease, indefinite treatment duration, and decreased compliance over time are issues of concern. To address these challenges, an increasing number of studies are evaluating different combinations of TAs; however, these studies have been mostly small single arm trials in heterogeneous patient populations using different methods for response assessment. A number of questions remain regarding the predictive value of minimal residual disease (MRD) status, durability of response, fixed treatment durations and importantly, criteria for selection of patients for the optimal combinations. Medical comorbidities, performance status, prior therapies and disease risk-profile are fundamental in determining the treatment plan for each individual patient. Furthermore, utilizing prognostic and predictive markers along with monitoring MRD can guide the development of individualized, better-tolerated, time-limited and potentially curative chemo-free treatment regimens.

  • Submitted August 15, 2018.
  • Accepted November 9, 2018.