Past, present and future role of chlorambucil in the treatment of chronic lymphocytic leukemia

For many decades, chlorambucil was the standard of care for chronic lymphocytic leukemia (CLL), but meanwhile has been replaced by purine analog-based chemoimmunotherapy. Monotherapy with the alkylator only retained significance in the treatment of older patients unfit for standard treatment. After successful phase II studies, recent phase III trials established combinations of chlorambucil with anti-CD20 antibodies such as rituximab, ofatumumab and obinutuzumab as a valuable treatment option for these patients. Today, chlorambucil therefore should be used as a chemotherapy backbone for antibody-based chemoimmunotherapy in this patient population rather than as monotherapy. Starting from the past role of chlorambucil in CLL treatment, we here review the most recent efforts to elaborate chlorambucil-based chemoimmunotherapy in CLL and discuss clinically relevant questions that arise from this approach.