Potential clinical trial designs of LSC-directed therapies, administered both at diagnosis and in remission. (A) The optimal approach for use of an LSC-directed therapy at diagnosis, in which the LSC-directed therapy is administered first as a single agent, followed by conventional chemotherapy, usually with continuous concomitant use of the LSC-directed therapy. This scenario allows for the independent study of the impact of the LSC-directed therapy. (B) Concurrent administration of LSC-directed therapy and conventional chemotherapy during induction; this is feasible if the action of the drugs involved is not antagonistic or associated with significant overlapping toxicity. (C) LSC-directed therapies can be used after conventional therapy. The concern with this approach is that instituting conventional chemotherapy first may result in the development of a more complex, heterogeneous LSC population that will be less amenable to treatment with the LSC-directed therapy. During standard consolidation, LSC-directed therapies can be paired with conventional consolidation therapy, with the option of maintaining the LSC-directed therapy for a more extended period (D) or administering in sequence with consolidation chemotherapy (E). (F) LSC-directed therapies may also be administered as maintenance therapy, in the absence of chemotherapy, in some situations in which a patient who has achieved a remission may not be a candidate for consolidation chemotherapy. (G) LSC-directed therapies may be employed in conditioning regimens before allogeneic stem-cell transplantation. (H) LSC-directed therapies can be used in the posttransplantation setting, which is particularly appealing for those patients with risk factors for relapse after transplantation.