Eliminating minimal residual disease as a therapeutic end point: Working toward cure for patients with CLL

Deep remission and prolonged diseasefree survival can be achieved with first-line chemoimmunotherapy (CIT), such as combined fludarabine, cyclophosphamide, and rituximab, in the majority of patients with chronic lymphocytic leukemia (CLL). More modest results are reported with less intense regimens like obinutuzumab plus chlorambucil. Clinical assessment has limited sensitivity indetecting residualdisease responsible for subsequent relapse, even including morphologic bone marrow (BM) evaluation. Multicolor flow cytometry and polymerase chain reaction (PCR)-based methods can detect minimal residual disease (MRD) to a sensitivity of 1:10 000 (1024). Achieving BM MRD-negative complete remission (CR) is associated with superior progression-free survival (PFS) and overall survival; MRD status is the single best posttreatment predictor of long-term outcomes after CIT. Newer oral B-cell receptor signaling pathway inhibitors are highly effective at controlling disease, but best monotherapy responses are typically partial remission, and patientsmust remain on treatment tomaintaindisease control.Therapeutic progress is still needed for CLL.We propose that targeting MRD provides opportunity torealize thisprogress.Achieving BM MRD-negative CR is a prerequisite for long-term unmaintained disease-free survival and potential for cure. We review available methodologies for detecting MRD and correlations with posttreatment outcomes. We discuss the potential utility of MRD to direct individualized therapy. Finally,we discuss the importance ofMRDnegative status as a surrogate marker for longer PFS in clinical studies to allow more rapid determination of clinical benefit.