Patterns of clonal evolution during the progression of MDS to secondary AML. Multiple patterns of subclone expansion are associated with progression from MDS to secondary AML. Subclones (red, green) can be acquired from the founding clone (blue) in a sequential (ie, linear) order (A) or in parallel (ie, branching) (B). Clonal evolution can also be influenced by treatment, including transplant and chemotherapy. (C) Although chemotherapy can suppress the founding clone [eg, lenalidomide in del(5q)-associated MDS], the acquisition of additional mutations (eg, TP53) or cytogenetic abnormalities can occur during disease progression and contribute to subclone expansion. Similar patterns of progression can occur following progression after a transplant. (D) Treatment may also cause subclone clearance while sparing the founding clone (eg, MEK inhibitor repressing a RAS-mutated subclone). Progression can occur when a new subclone emerges carrying additional mutations (green) that drive progression to secondary AML. allo-HSCT, allogeneic hematopoietic stem call transplant; CR, complete remission. Adapted from Nangalia et al.¹⁰⁸