Relapsed/Refractory Chronic Lymphocytic Leukemia: Chemoimmunotherapy, Treatment until Progression with Mechanism-Driven Agents or Finite-Duration Therapy?

Treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) has dramatically improved thanks to the development of mechanism-driven agents including drugs that inhibit kinases in the BCR pathway or BCL2. The treating physician has now the opportunity to decide i) which patient can be still offered chemoimmunotherapy as salvage treatment, ii) which patient at relapse is a candidate to receiving, continuous treatment with ibrutinib, idelalisib and rituximab or venetoclax and iii) which patient may benefit from a fixed-duration treatment using the BCL2 antagonist venetoclax in association with rituximab. Ibrutinib is the most actively investigated drug in R/R CLL and data at a 7-year follow-up were reported, showing durable efficacy and favorable efficacy profile. The patients with cardiac disease, hypertension, and anticoagulant therapy are not ideal candidates for continuous therapy with this agent. Idelalisib and rituximab were tested in patients with unfavorable characteristics including cytopenias. The short follow-up and treatment-emergent adverse events limit its role to patients unlikely to get a benefit with other agents. Venetoclax and rituximab is the only effective chemo-free approach for the treatment of R/R with a fixed duration (up to 24 months) schedule capable of inducing deep responses in the majority of cases with a reassuring safety profile. While a deep knowledge of the growing body of scientific evidence is required to inform and guide the appropriate treatment choice and management, physicians cannot disregard the growing problem of sustainability.