Immunogenetic, Molecular and Clinical Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Despite therapeutic successes, AA patients (pts) exhibit a much higher risk of leukemic evolution than the general population. Secondary myeloid neoplasia (sMN) remains the most serious AA complication with major therapeutic and prognostic implications. Historically, multiple theories have been proposed as to the origin of leukemic evolution. For instance, sMN may be the consequence of a relentless autoimmune attack producing a maladaptive response to immunosuppression (IST). Alternatively, occurrence of leukemogenic drivers may be an event setting in motion initially successful and overshooting tumor surveillance reactions. Finally, sMN pathogenesis may be related to either CHIP evolution or acceleration of its progression. Each of these theories is supported by clinical-molecular features (e.g. HLA mutations, secondary PNH evolution, somatic mutations at presentation etc.). Here, we took advantage of a multicentric cohort of pts with AA (n=1010; to our knowledge the largest yet explored) and primary MN (n=3599) to define immunogenetic, iatrogenic and molecular determinants of MN progression.