The treatment landscape of chronic lymphocytic leukemia (CLL) has changed dramatically in the last few years. The role of chemoimmunotherapy has declined significantly for patients with CLL. Fludarabine, cyclophosphamide, rituximab chemotherapy remains the standard frontline therapy for young fit patients with CLL, especially if IGHV mutated. For older adults, ibrutinib has been shown to be superior to chlorambucil. Hence, the role of chlorambucil monotherapy in the current era in the management of CLL is limited. The combination of chlorambucil and obinutuzumab is an alternative option for patients with comorbidities. For patients with del(17p), ibrutinib has become the standard treatment in the frontline setting. Several phase 3 trials with novel targeted agents, either as monotherapy or in combination, are either ongoing or have completed accrual. The results of many of these trials are expected in the next 1 to 2 years, and they will further help refine the frontline treatment strategy.

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