Pb2040: lactate dehydrogenase is a predictor of thromboembolism, and thromboembolism is a predictor of death, in patients with paroxysmal nocturnal hemoglobinuria (pnh): results from a korean pnh registry

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and severe hematologic disorder caused by uncontrolled terminal complement activation, which leads to intravascular hemolysis, thromboembolism (TE), and renal failure, the most common causes of death and morbidity in untreated patients. Although intravascular hemolysis is an important contributor to anemia in PNH, there are limited real-world data on the relationship between hemolysis, hemoglobin (Hb) levels, and clinical outcomes in PNH. Aims: To describe the relative importance of risk factors, specifically lactate dehydrogenase (LDH) and Hb, in predicting the incidence of TE, impaired renal function (IRF), and death in patients with PNH not treated with complement C5 inhibitors using multivariate regression modeling and standardized mortality ratios (SMRs). Methods: We performed a secondary analysis of registry data collected from complement inhibitor-naïve patients with PNH enrolled from July 2009 to November 2010 in the Korean PNH Registry. Patients were stratified by LDH status (LDH level at diagnosis) and Hb (lowest level within 2 months of diagnosis). Elevated hemolysis was defined as LDH ≥1.5 × upper limit of normal (ULN), severe anemia as Hb <8 g/dL, and non-severe anemia as Hb ≥8 g/dL. Multivariate regression modeling tested the extent to which risk factors, including LDH ≥1.5 × ULN and severe anemia, may predict TE incidence, IRF, and death. SMRs were calculated as a ratio of observed deaths in the PNH population to expected deaths of age- and sex-matched individuals in the general Korean population for the follow-up period studied. Results: For the 301 patients included in the study, mean (standard deviation; SD) age at diagnosis was 39.3 (15.4) years, 49.8% were male, 41.5% had a history of aplastic anemia, and 6.3% a history of myelodysplastic syndrome; mean (SD) follow-up was 7.8 (6.0) years. When stratified by LDH status, incidence of TE (p<0.001), death (p=0.019), hemoglobinuria (p=0.046), abdominal pain (p=0.006), and pain (p=0.020) were higher in patients with LDH ≥1.5 × ULN than those with LDH <1.5 × ULN. When stratified by Hb status, no significant differences in clinical outcomes were observed in patients with severe anemia compared with non-severe anemia. Multivariate regression modeling indicated that LDH ≥1.5 × ULN, male sex, and pain were associated with increased incidence of TE (p=0.016, 0.045, and 0.033, respectively), hemoglobinuria and pain were associated with an increased incidence of IRF (p=0.034 and 0.022, respectively), and TE was associated with an increased incidence of death (p<0.001; Table). Severe anemia was not a predictor of TE, IRF, or death in patients with PNH in multivariate regression analyses. SMR analysis indicated that LDH ≥1.5 × ULN (p<0.001), severe anemia (p<0.001), and non-severe anemia (p=0.004) were risk factors for death; patients with LDH <1.5 × ULN had similar mortality to the general population. Summary/Conclusion: In complement inhibitor-naïve patients with PNH, LDH ≥1.5 × ULN was a significant predictor of TE, and TE was a significant predictor of death. Severe anemia was not predictive of TE, IRF, or death. SMR analysis indicated that LDH ≥1.5 × ULN and anemia, irrespective of severity, were risk factors for death. In contrast, patients with LDH <1.5 × ULN had a life expectancy similar to that of the general population. These findings suggest that primary treatment goals in PNH should focus on controlling terminal complement activation and intravascular hemolysis (aim for LDH <1.5 × ULN) to prevent TE and death.Keywords: Hemolysis, Paroxysmal nocturnal hemoglobinuria (PNH), Mortality, Anemia