Natural history of paroxysmal nocturnal hemoglobinuria clones in patients presenting as aplastic anemia

Abstract

Objective Investigate the natural history of PNH clones in patients with acquired aplastic anemia (AA). Patients and Methods Twenty-seven patients with AA and a detectable PNH clone were monitored for a median of 5.7 years (range1.5 to 11.5 years). Twenty-two patients received high dose cyclophosphamide (HiCy) therapy. The erythrocyte and granulocyte PNH clone sizes were measured using flow cytometry and analyzed via CellQuest software. PE-conjugated anti-glycophorin A, anti-CD15, FITC-conjugated anti-CD59, and FLAER staining were used to define GPI-AP deficient cells. Results We found a linear relationship between PNH clone size and the development of intravascular hemolysis, assessed by LDH values (Pearson Correlation Coefficient=0.80, P<0.001 for erythrocyte PNH clones; and Pearson Correlation Coefficient=0.73, P<0.0001 for granulocyte PNH clones). An erythrocyte PNH size of 3~5% and granulocyte PNH size of 23% were the thresholds to predict hemolysis as measured by an elevated LDH (ROC analyses with AUC=0.96 for erythrocyte PNH clone sizes and AUC=0.88 for granulocyte PNH clone sizes). Patients with small (≤15%) initial PNH clone sizes were less likely to develop an elevated LDH (mean±SD: 236.9±109.9 vs423.1±248.8; P=0.02). Over time, the PNH clone sizes remained stable in 25.9% of patients; 48.1% experienced a rise in the PNH clone size and 25.9% experienced a decrease. Conclusion The risk of developing clinically significant PNH after HiCy therapy appears to be low in AA patients with PNH clones, especially for those with small initial PNH clones and for those who respond to HiCy therapy.

Clonal hematopoiesis in acquired aplastic anemia

“…79,80 PIGA-mutated clones rarely disappear but, more often, persist, even after successful IST, which is in agreement with the theory of natural selection in the population genetics; many functional variants selected against past, but not present, insults are widely observed among the human population. 85 Frequent genetic drifts displayed by PNH-type clones 18,86,87 also seem to favor the explanation.…”

Diagnosis of acquired aplastic anemia

“…21,22 Patients with typical PNH can develop AA in the course of their disease and patients with AA often present a PNH clone. 23 Even the presence of a very small PNH clone is a strong argument for a marrow failure syndrome. Flow cytometry is the Gold Standard method for screening and diagnosis of PNH.…”

“…In such case, the patient may present the typical symptoms and complications of the disease. 23 PNH clone size measurements should be performed at presentation and followed-up on serial monitoring every 6-12 months.…”

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

“…The degree of serum LDH elevation is variable in patients with PNH in the setting of another BM failure syndrome (determined by the size of the PNH clone); however, in a large majority of patients with PNH/BM failure, the clone size is Ͻ 10%, with Ͻ 10% of patients with PNH/BM failure having a clone size of Ͼ 50% (Table 1). 15 By definition, patients with subclinical PNH have neither clinical nor biochemical evidence of hemolysis (Table 1). Patients with classic PNH may be iron deficient due to chronic hemoglobinuria and hemosiderinuria.…”

“…In these patients, BM failure dominates the clinical picture and hemolysis is primarily an incidental finding. 15,16,19 The large majority of patients with PNH/AA and PNH/MDS have relatively small PNH clones (Ͻ 10%) and require no specific PNH therapy; in these cases, treatment should focus on the underlying BM failure syndrome (Table 1 and Figure 3). …”