Distinctive and common features of moderate aplastic anaemia

Abstract

Summary 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.

Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells

“…The differences between patients with severe and nonsevere AA in genomic features were recently reported by Patel J et al [4]. Although at least one mutation was identified in 19% of patients with AA at the time of diagnosis, independently of the severity of the AA, these mutations included DNMT3A, PIGA, SRSF2 and CEBPA and there were no differences in the average number of mutations.…”

“…Although at least one mutation was identified in 19% of patients with AA at the time of diagnosis, independently of the severity of the AA, these mutations included DNMT3A, PIGA, SRSF2 and CEBPA and there were no differences in the average number of mutations. Patients with AA had a higher mutation rate/more pronounced mutational burden in comparison to moderate AA (56% vs 19%) which corresponds to the unstable hematopoietic clones and higher risk of evolution [4].…”

“…Acquired aplastic anemia is a rare disorder presenting with bone marrow failure syndrome due to autoimmune destruction of early hematopoietic stem cells and stem cell progenitors [1,2]. It has been shown that acquired AA may predispose to myelodysplastic syndrome and leukemia in approximately 15-16% of cases as a consequence of clonal hematopoiesis and evolution [3,4]. In Europe, the incidence is about two cases per million per year, while in Asia there are about three times as many cases when compared to Europe [5][6][7].…”

Interleukin‐10 promoter variability is associated with the susceptibility, severity, and clinical outcomes of aplasitc anemia in Han‐Chinese population

“…This might be partly explained by the different pathogenesis of SAA and NSAA. In a recent study, 31 NSAA was concluded to contain a mix of patients with diverse etiologies which is different from the autoimmune pathogenesis in SAA. They also found the distinctive gene mutation burden between NSAA and SAA which might reflected the different gene background and gave this another explanation.…”

The impact of clonal hematopoiesis on outcomes in patients with aplastic anemia

“…However, other somatic mutations such as DNMT3A and ASXL1 are associated with worse outcomes. Recently, a study into mutation status and the differences between severe and non-severe AA by Patel et al [47] detected at least one mutation in 19% of patients with AA at the time of diagnosis, independent of the severity of the AA. However, patients with severe AA had a higher mutation rate compared to moderate AA (56% vs. 19%), which corresponds to the unstable hematopoietic clones and higher risk of clonal evolution [47].…”