The role of minimal residual disease (MRD) testing is well defined in curable hematological malignancies like acute lymphoblastic leukemia. However, in chronic lymphocytic leukemia (CLL), which is an incurable low-grade lymphoma, MRD is mostly investigational, especially in the relapsed setting. Newer techniques are trying to get to even deeper levels than before—for instance, 10−6 with sequencing. Here we describe the current techniques of MRD testing in CLL and explore the applications of these modalities in relapsed/refractory CLL in novel targeted therapies, cellular therapy, and other immunotherapies that can lead to deep and durable remissions, especially when used in combinations. More and more prospective interventional trials are now using MRD testing to inform decisions, and the data from these trials will further elucidate the best use of MRD testing in CLL patients. For now, MRD testing is not used for treatment decisions in the real world, although it can be done for monitoring in patients with high-risk genetics.

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