S865 CHANGE IN CLONE SIZE DOES NOT PREDICT RISK OF MAJOR ADVERSE VASCULAR EVENTS: RESULTS FROM THE INTERNATIONAL PNH REGISTRY
Authors: R. Peffault de Latour, A. Kulasekararaj, L. Larratt, R.S. Go, D. David, B. Höchsmann, A. Wilson, P. Gustovic, A. Kulagin
Journal: HemaSphere (2019)

Background: In paroxysmal nocturnal hemoglobinuria (PNH), the granulocyte clone size is often used as an indicator of disease severity. However, the prognostic value of changing clone size on clinical outcomes in PNH is not well understood. Aims: To assess the prognostic value of change in PNH granulocyte clone size on the risk of developing major adverse vascular events (MAVE) or high disease activity (HDA: elevated hemolysis [lactate dehydrogenase {LDH} ≥1.5 x upper limit of normal] and one or more PNH‐related symptom[s]) in patients with PNH. Methods: The International PNH Registry is the largest worldwide observational study of patients with a diagnosis of PNH or a detected PNH clone as low as 0.01%. This study assessed patients with a baseline value for PNH clone size (defined as the closest value to disease onset) and at least one additional clone size value, who were untreated with complement inhibitor therapy at enrollment, and had ≥12 months of untreated follow‐up. Patients were stratified by clone size at baseline and change in clone size was estimated using regression models of clone size vs duration from disease start, adjusted for baseline clone size. Patients were categorized as having stable, increasing, or decreasing clone size depending on the slope, where a change in clone size &gt;10% per year was considered increasing/decreasing. Prognostic value of change in clone size was assessed using Poisson regression to estimate rate ratios of MAVE and logistic regression to estimate odds ratios of HDA during follow‐up, with stable clone size as the reference. Adjusted models included baseline LDH ratio category, history of bone marrow disease at baseline, baseline clone size, and duration. Results: As of April 3, 2018, a total of 1894 patients were available for analysis: cohort (COH) 1 (clone size &gt;0.01% to ≤1%, n = 381); COH 2 (clone size &gt;1% to ≤5%, n = 318); COH 3 (clone size &gt;5% to ≤10%, n = 159); COH 4 (clone size &gt;10% to ≤50%, n = 480); COH 5 (clone size &gt;50% to ≤100%, n = 556). Median duration was 3.5 years. Clone size was stable in only 16.2% of patients, as compared with 45.3% increasing and 38.5% decreasing; stable clone size was primarily seen in patients with a clone size ≤1% at baseline (58% of patients in COH 1 with a stable clone), with less than 10% of patients with a stable clone in the other cohorts. Clone size change over time was highly prognostic of HDA; patients with increasing and decreasing clone size had an increased risk of HDA, compared to patients with stable clone size, although this may be due to patients with a stable clone largely in COH 1 with a low risk of HDA; after adjusting, we see no increased risk of HDA in patients with decreasing clone size, but the increased risk of HDA in patients with increasing clone size is maintained (Table). Due to limited data on covariates at baseline, only 156 patients were available for this adjusted analysis. There was no difference in the MAVE rate in patients with increasing or decreasing clone size as compared with those with a stable clone size. The lack of effect was maintained even after adjusting for covariates (Table). Summary/Conclusion: This is the first analysis of the prognostic value of PNH clone size changes on clinical outcomes over time in patients with PNH. Increasing clone size over time was predictive of patients experiencing HDA during their disease course. Interestingly, no difference in the MAVE rate was seen in patients with increasing or decreasing clone size, suggesting that change in clone size does not change the increased risk of MAVE in patients with PNH. image