Idiopathic aplastic anemia vs hypocellular myelodysplastic syndrome

Abstract

Proper diagnostic distinction of bone marrow failure syndromes can often be challenging. In particular, for older patients with idiopathic aplastic anemia (AA), differential diagnosis includes myelodysplastic syndrome (MDS), which can atypically present in a hypocellular form. In addition to blasts and overt dysplasia, the presence of chromosomal abnormalities and a spectrum of somatic mutations may be revealing. Both clonal cytogenetic aberrations and somatic mutations most typically correspond to a clonal myelodysplasia, but clonal somatic mutations have also recently been found in AA. True driver myeloid mutations are uncommon in AA. Marrow hypocellularity in AA and occasionally in MDS patients points toward a similar immune mechanism responsible for deficient blood cell production and indicates that cytopenias in early hypocellular MDS might be treated with immunosuppressive modalities. Primary hypocellular MDS has to be distinguished from post-AA secondary MDS, most commonly associated with del7/7q. Post-AA MDS evolves at the rate of about 10% in 10 years, but recent observations suggest that widespread use of eltrombopag may influence the risk of progression to MDS. This complication likely represents a clonal escape, with founder hits occurring early on in the course of AA. A similar mechanism operates in the evolution of paroxysmal nocturnal hemoglobinuria (PNH) in AA patients, but PNH clones are rarely encountered in primary MDS.

Figure 1.

Hypothetical fates of aberrant myeloid clones in AA, typical MDS, and hypocellular MDS. HSC, hematopoietic stem cells.

Figure 2.

Differential distribution of somatic mutations in AA, MDS (hypoplastic [Hypo] and hyperplastic [hyper]), and PNH. The red bars depict the percentage of patients affected by a given somatic mutation. Proportion of patients with PNH clones (PIGA mutation) is indicated in blue. Adapted from Negoro et al. IST, immunosuppressive therapy; Normo, normocellular; sMDS, secondary myelodysplastic syndrome: sMDS refers to MDS after AA.

Figure 3.

Clonal evolutionary chart of bone marrow failure syndromes over time for AA and primary MDS. Normal hematopoiesis would, if not influenced by a disease pathology, be expected to remain relatively stable with only a slow age-related decline. (A) CHIP, random or pathogenic aberrant myeloid clones, or idiopathic triggers can induce an immune reaction against the hematopoietic stem and progenitor cell (HSPC) compartment leading to AA with contraction of the HSCP pool. Transient or persistent benign clonality may result from CHIP. Either CHIP or another de novo aberrant clone may be an origin of clonal progression (eg, by the acquisition of additional genetic hits resulting in post-AA secondary MDS). (B) Similarly, primary MDS including its classic (hypercellular or normocellular) or atypical (hypocellular) forms can evolve from a slow-driving preexisting CHIP clone or an aberrant de novo somatic hit. Hypocellularity may be a result of immune attack stemming from a tumor surveillance reaction similar to idiopathic AA.

Figure 4.

Pathogenetic theories of bone marrow failure as a result of interaction of the HSC compartment with the immune system. (A) Various triggers of a cytotoxic T-lymphocyte reaction in AA. (B) Immune attack against a hypothetical initiating event results in endogenous carcinogenesis and de novo acquisition of clonal events. Immune selection pressure can lead to further clonal evolution of secondary MDS after AA. (C) Theoretically, the aberrant clone itself may be a trigger leading to a similar pathogenic escape reaction and a similar outcome. It is also possible that either a nonspecific or an overshooting immune reaction leads to a contraction of the HSPC compartment as seen in AA or hypocellular MDS. Finally, ineffective tumor surveillance reaction fails to prevent clonal evolution analogous to classic or typical MDS. (D) Recent data demonstrate the presence of somatic mutant clones, consistent with CHIP, in patients with otherwise typical AA. In this scenario, immune response may further augment the oligoclonality by the removal of normal HSCs. Depending on the penetrance of somatic CHIP hits, they expand whereas normal cells are eliminated thus leading to hypocellular MDS. Alternatively, upon successful immunosuppression and recovery of the normal HSCs, the mutant clones are diluted out by expanded normal HSCs.