Distinctive and common features of moderate aplastic anaemia

The therapy algorithm for severe aplastic anaemia (sAA) is established but moderate AA (mAA), which likely reflects a more diverse pathogenic mechanism, often represents a treatment/management conundrum. A cohort of AA patients (n = 325) was queried for those with non-severe disease using stringent criteria including bone marrow hypocellularity and chronic persistence of moderately depressed blood counts. As a result, we have identified and analyzed pathological and clinical features in 85 mAA patients. Progression to sAA and direct clonal evolution (paroxysmal nocturnal haemoglobinuria/acute myeloid leukaemia; PNH/AML) occurred in 16%, 11% and 1% of mAA cases respectively. Of the mAA patients who received immunosuppressive therapy, 67% responded irrespective of time of initiation of therapy while conservatively managed patients showed no spontaneous remissions. Genomic analysis of mAA identified evidence of clonal haematopoiesis with both persisting and remitting patterns at low allelic frequencies; with more pronounced mutational burden in sAA. Most of the mAA patients have autoimmune pathogenesis similar to those with sAA, but mAA contains a mix of patients with diverse aetiologies. Although progression rates differed between mAA and sAA (P = 0·003), cumulative incidences of mortalities were only marginally different (P = 0·095). Our results provide guidance for diagnosis/management of mAA, a condition for which no current standard of care is established.