Patients with aplastic anemia (AA) can develop clonal disorders, such as paroxysmal nocturnal hemoglobinuria (PNH) and secondary myelodysplastic syndromes (sMDS). “Distinguishing [patients at risk for developing sMDS following AA] from those with primary hypocellular MDS (hypo-MDS) resembling AA is important for the timely initiation of appropriate therapy,” according to Eiju Negoro, MD, PhD, from the Department of Translational Hematology and Oncology Research at Cleveland Clinic in Ohio, and co-authors, who published a Letter to the Editor in Blood.
To determine potential discriminating features between patients with AA, PNH, sMDS, hypo-MDS, and typical primary hypercellular MDS (hyper-MDS), the researchers analyzed mutational disease evolution patterns within bone marrow and/or blood samples from 258 patients with AA and 59 with PNH, 35 of whom progressed to sMDS. Patients were enrolled from the Cleveland Clinic in Ohio and University Hospital Basel in Switzerland.
For comparison, the authors included another cohort of 853 patients with primary MDS (pMDS), including 28 with hypo-MDS and 825 with hyper-MDS.
They detected somatic mutations via whole-exome sequencing in 69 of 133 (52%) patients with AA (32/71 [45%] at presentation and 42/74 [57%] cases after immunosuppressive therapy [IST]). “In contrast, acquired alterations were detected in 15 of 23 (65%) patients with sMDS and 657 of 853 (77%) patients with pMDS,” the authors noted.
The average number of somatic mutations was:
- 0.8 in patients with PNH
- 1.0 in patients with AA
- 1.5 in patients with sMDS
- 1.5 in patients with hypo-MDS
- 2.0 in patients with hyper-MDS
The spectrum of mutations differed among patients with AA, sMDS, and pMDS, the researchers reported. Compared with patients with AA, patients with sMDS had a higher prevalence of ASXL1, RUNX1, splicing factors, and CBL mutations; however, compared with patients with pMDS, patients with sMDS had a higher prevalence of RUNX1 mutations, but a lower prevalence of SF3B1 mutations.
DNMT3A mutations occurred in two of the 69 patients with AA but did not occur in any of the 15 patients with post-AA MDS, “suggesting that the mutagenic event did not initiate the MDS clonal cascade,” the authors wrote. BCOR/BCORL1 mutations were also present in AA and expanded during treatment with IST; “however, the clonal burden was lower for [these] mutations, … [which] suggests the secondary role of BCOR/BCORL1 mutations in the clonal hierarchy,” they added.
Mutation profiles also differed among patients with –7/del(7q). For example, –7/del(7q) was a characteristic feature of sMDS that evolved from AA (present in 63% of patients), whereas only 14 percent of patients with pMDS had the mutation (p value not provided). TP53 mutations appeared to be more common in pMDS with –7/del(7q), but ASXL1, RUNX1, TET2, and SETBP1 mutations “appeared to be over-represented” in sMDS with –7/del(7q). The difference was only statistically significant for RUNX1 (p=0.003) because of low numbers of events, the authors reported.
The researchers then analyzed a cohort of 21 patients with AA, eight of whom progressed to sMDS, finding that mutations were observed more frequently in progressors than non-progressors (50% vs. 8%; p=0.048). Progressors also had a higher average number of mutations than non-progressors (3.4 vs. 0.7; p=0.005). These data suggest “that certain clonal events seen in MDS stage of the disease are indeed acquired early at presentation of AA and that some early hits may lead to subsequent clonal evolution,” the authors wrote, adding that ASXL1, U2AF1, and JAK2 found at AA presentation were also observed in MDS progressors.
Finally, to assess the potential impact of somatic mutations on treatment outcomes, the researchers analyzed a subset of AA patients (n=37) who received IST. Clonal somatic alterations, which were identified in six of 25 patients who responded and in four of 12 patients who were refractory to IST treatment, did not predict the efficacy of IST, “consistent with the transient nature of most of these events,” the authors wrote. They also found that patients with AA who had any of the mutational hits found both at initial AA presentation and in subsequent MDS (n=4) had a shorter median progression-free survival (2.0 years vs. not reached; p<0.001) and overall survival (2.6 years vs. not reached; p=0.02), compared with patients without somatic alterations (n=67).
“While most of these [clonal somatic] events, found typically in MDS, reflect clonal hematopoiesis and do not occur in or predict sMDS, certain founder mutations can be found at presentation in AA and have potential to initiate progression to sMDS,” the authors concluded.
The study is limited by the small number of patients in certain cohort analyses.
The authors report no financial conflicts.
Negoro E, Nagata Y, Clemente MJ, et al. Origins of myelodysplastic syndromes after aplastic anemia. Blood. 2017 September 11. [Epub ahead of print]