Three hypothetical models of operational cure of CML. The models are not mutually exclusive. Different models may pertain in different individuals. (A) Stem-cell depletion. The progressive depletion of immature CML cells over years of continued therapy is shown. The risk of relapse on TKI cessation is related to the duration of therapy and the intrinsic sensitivity of CML stem and early precursor cells. (B) Stem-cell exhaustion. The CML stem-cell pool is relatively small and, due to stochastic events that direct self-renewal or proliferation, this pool of cells may become extinct before diagnosis or early in therapy. The risk of relapse upon TKI cessation is related to the depletion of committed CML progenitors and progeny. (C) Immunological control. A reduction in the level of MRD by TKI therapy is sufficient to overcome T-cell anergy and enables the emergence of an autologous immunological response that suppresses, but may not eradicate, the CML clone. The risk of relapse on TKI cessation is dependent on the functional immune response and the intrinsic immunogenicity of the CML cells.