OBJECTIVES For patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), treatment outcomes are poor and treatment options are limited. Ibrutinib is an oral, once-a-day, first-in-class covalent inhibitor of Bruton’s tyrosine kinase approved by the Food and Drug Administration (FDA) for R/R CLL. In a recent phase III trial (PCYC-1112), ibrutinib was associated with improved progression-free survival (PFS, hazard ratio [HR]=0.215) and overall survival (OS, HR=0.387) versus ofatumumab. The aim of this study is to provide a summary and analysis of results observed with current therapies in high-risk patients with R/R CLL. METHODS A systematic literature review and targeted literature search of clinical trials and international treatment guidelines in PubMed/MEDLINE (January 1, 2001–April 28, 2013) and ASCO/ASH/EHA conference proceedings (2011–2013) were conducted to identify and evaluate current treatment options for R/R CLL, including alemtuzumab, rituximab, bendamustine, chlorambucil, and ofatumumab. RESULTS Study results highlight poor outcomes with existing treatment options and continuously high unmet need in patients. Sixteen trials were identified; the majorities were single-arm with small sample sizes, making comparative effectiveness difficult to establish. Time-to-treatment failure was 5.8 months with alemtuzumab, while median PFS was 5.5 months with rituximab, 5.5–5.7 months with ofatumumab, 8 months with chlorambucil-ritiximab, and 15.2 months in previously-treated patients and 6.8 months in previously-treated patients with del(17p) with bendamustine-rituximab. Ofatumumab has demonstrated activity in patients with difficult-to-treat, high-risk CLL and is the only recognized and approved treatment by health authorities globally in this treatment setting and recommended in treatment guidelines. CONCLUSIONS The lack of standard of care creates challenges for defining comparators in clinical trials and health technology assessments. In R/R CLL with high-risk features, ofatumumab is an appropriate comparator. Interim results from the phase III RESONATE trial showed that ibrutinib achieved significantly improved efficacy versus ofatumumab, even in high-risk disease patients.