Prognostic and predictive impact of small PNH clones in a large cohort of patients with myelodysplastic syndrome and aplastic anemia: a single-center experience

The use of high sensitive FLAER improved the detection of very small PNH clones (<1%) in aplastic anemia (AA)/myelodysplastic syndromes (MDS). Here we aimed to evaluate the prevalence of PNH clones >0.01% in AA/MDS patients tested at a single tertiary center,and to assess their impact on disease prognosis, occurrence of thrombosis, and response to current therapies. We retrospectively collected clinical and laboratory features of 869 MDS and 531 AA patients tested from March 1998 till October 2017. Table 1 shows characteristics of MDS and AA patients, divided according to PNH positivity, which was less frequent in MDS versus AA (20.3% vs 61%). Focusing on MDS, PNH+ cases were significantly more hypoplastic,and showed deeper cytopenias and higher LDH levels. Considering clone size (negative, 0.01-1%, 1.01-10%,10.01-50%, and >50% on granulocytes), we observed a significant worsening of cytopenia and raise of LDH along with clone size increase. As regards therapy, PNH+MDS showed significantly higher response rates to immunosuppressive therapies (ATG and CyA, 84% vs 44.7%, p=0.01) and to HSCT (71% vs 56.6%, p=0.09) compared to PNH-, and the cumulative probability of response to any treatment significantly improved along with clone size increase (from 52 to 100%, p=0.03). PNH+MDS showed lower rate of evolution, and longer OS [mean 11.9+0.7 years (10.5-13.3) vs 7.3+0.3 (6.6-7.9), p<0.0001], confirmed in multivariable analysis. However, PNH+MDS had a higher incidence of thrombotic events (from 5% in PNH- to 50% in PNH+ with clone size >50%, p<0.0001). Similarly to MDS, PNH+AA showed deeper thrombocytopenia and higher LDH, and showed higher response rates to any therapy (97 vs 77% for HSCT, p=0.01; 78 vs 50% for IST, p<0.0001; and88% vs 65% considering any treatment, p<0.0001). They also showed lower rate of MDS progression and death (p=0.01 and p<0.0001), and longer OS [mean 15.8+0.43 years (14.9-16.7) vs 6.5+0.35 (5.8-7.21), p<0.0001], confirmed in multivariable analysis. Prevalence of PNH clones of any size is high in patients with MDS and AA. We firstly show a positive impact of PNH clone positivity on response to IST and HSCT in a large MDS series and confirmed this data in AA. The presence of a PNH clone also correlated with lower disease progression and better OS. Clone size analysis suggests that even small clones (0.01- 1%) have a clinical and prognostic significance.