International Paroxysmal Nocturnal Hemoglobinuria Registry Research Articles

Patient-Reported Outcomes: Danicopan As Add-on Therapy to Ravulizumab or Eculizumab Versus Placebo in Patients with Paroxysmal Nocturnal Hemoglobinuria and Clinically Significant Extravascular Hemolysis

Background Treatment with complement C5 inhibitors eculizumab (Ecu) and ravulizumab (Rav) inhibits terminal complement activity, improving hemoglobin (Hgb) levels and clinical outcomes for patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH), including reduced morbidity and mortality by preventing intravascular hemolysis (IVH), thrombotic events, hospitalizations, and death. In an analysis using data from the International PNH Registry (NCT01374360), Ecu improved pt survival through 20 y of real-world follow-up. Rav demonstrated a 98.4% survival rate up to 6 y in an open-label study (NCT03056040). Approximately 10-20% of pts experienced ongoing anemia caused by clinically significant extravascular hemolysis (cs-EVH). The phase 3, international, randomized, double-blind, placebo (Pbo)-controlled ALPHA (NCT04469465) superiority clinical trial assessed the effectiveness and safety of danicopan (Dan) add-on therapy to Rav or Ecu in pts with PNH and cs-EVH. This current analysis examined patient-reported outcomes (PROs) through wk 24. Methods Pts (≥18 y) with PNH and cs-EVH (Hgb ≤9.5 g/dL; absolute reticulocyte count ≥120×10 9/L) on Rav/Ecu >6 mo were randomized 2:1 to Dan or Pbo add-on therapy to Rav/Ecu for 12 wks (treatment period [TP] 1). At wk 12, Pbo arm pts switched to Dan (Pbo-Dan) and Dan arm pts continued treatment (Dan-Dan) for another 12 wks (TP2). The initial Dan dose of 150 mg TID could be escalated to 200 mg TID based on clinical response at investigator's discretion. Endpoints included change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score to wks 12 and 24 (key secondary) and changes in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale (EORTC-QLQ-C30) global health status/QoL and physical functioning subscales and fatigue, nausea/vomiting, appetite loss, constipation, and diarrhea symptom subscales, and EuroQoL-5-Dimensions, 3-level version (EQ-5D-3L) to wk 24 (exploratory). Results As of 20 September 2022, 86 pts were randomized; 60 had completed (n=60) TP2 (Dan n=40; Pbo n=20). Baseline characteristics were similar between arms. The study met its primary endpoint of significant improvement in Hgb and all key secondary endpoints, including FACIT-Fatigue at wk 12 (data previously presented). Clinically meaningful (>5 point) and statistically significant increases from baseline in FACIT-Fatigue score were observed for Dan vs Pbo at wk 12 (least square mean difference [SEM] 7.97 [1.13] vs 1.85 [1.58]; P=0.0021). At wk 24 ( Fig 1), outcomes were maintained in the Dan-Dan arm (40.32) and improved in Pbo-Dan arm (40.55) to levels similar to the general public score of 43.6. Significant improvements from baseline with Dan vs Pbo were demonstrated for EORTC-QLQ-C30 scores (physical function and social function within functional subscales, and fatigue within symptom subscales) at wk 12, maintained at wk 24 for the Dan-Dan arm, and demonstrated at wk 24 in Pbo-Dan arm ( Fig 2). Trends in changes from baseline in other EORTC-QLQ-C30 function subscale scores paralleled that of the physical function subscale. EQ-5D-3L scores (US Health State Index) were similar between arms at baseline (Dan, 0.83; Pbo, 0.80), wk 12 (Dan, 0.90; Pbo, 0.86), and wk 24 (Dan-Dan, 0.90; Pbo-Dan, 0.87); scores at all timepoints are comparable to the general public (0.855-0.958). Dan demonstrated favorable benefit-risk profile with no deaths, meningococcal infections, or discontinuations due to hemolysis; additional safety analyses including adverse events were previously presented. No new safety signals were demonstrated. Conclusions These data suggest that Dan plus Rav or Ecu improves QoL compared to Rav or Ecu alone for pts with PNH and cs-EVH. In this phase 3, randomized, controlled superiority trial, improvements in clinically relevant PROs were observed in the Dan vs Pbo arm in the first double-blind 12 wks of treatment, and FACIT-Fatigue and EORTC-QLQ-C30 scores were maintained during the open-label period to wk 24 in the Dan-Dan arm and improved at wk 24 in Pbo-Dan arm to levels similar to those of the general public. Comparable EQ-5D-3L scores were maintained between arms across the study.

Ravulizumab Provides Durable Control of Intravascular Hemolysis and Improves Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: Long-Term Follow-up of Study 301 and Comparisons with Patients of the International PNH Registry

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare chronic blood disorder characterized by uncontrolled terminal complement activation, leading to intravascular hemolysis (IVH), major adverse vascular events (MAVEs; including thrombotic events), organ damage and increased morbidity and mortality. Where available, ravulizumab is considered the standard of care for patients with PNH, providing immediate, complete and sustained inhibition of terminal complement activity. In study 301 (NCT02946463), complement component 5 (C5) inhibitor-naïve patients with PNH reported elevated levels of lactate dehydrogenase (LDH) and low hemoglobin (Hb) concentrations at baseline, alongside a history of MAVEs and need for transfusions. In such patients, ravulizumab provides durable control of IVH, reported for up to 2 years. Objectives: To report ravulizumab treatment outcomes for up to 6 years in C5 inhibitor-naïve patients with PNH from study 301 and compare survival with untreated patients of the International PNH Registry (NCT01374360). Methods: C5 inhibitor-naïve patients with PNH and high-disease activity (HDA; LDH level ≥ 1.5 × the upper limit of normal [ULN] and at least one sign or symptom of PNH) (N = 246) were randomized to receive ravulizumab or eculizumab. After the primary evaluation period (26 weeks), patients received ravulizumab for the 5-year open-label extension (OLE) period. LDH level change from baseline, the proportion of patients experiencing MAVEs, and transfusion avoidance were evaluated. Cox-proportional hazards regression analyses compared survival of patients treated with ravulizumab with untreated patients with HDA and clone size ≥ 5% at PNH Registry enrollment. Covariates comprised age at PNH diagnosis, gender, Hb concentration, estimated glomerular filtration rate, PNH clone size, transfusion history and medical history of MAVEs and bone marrow disease at baseline (i.e., date of ravulizumab treatment initiation [study 301] or PNH Registry enrollment). Transfusion history ( p = 0.05), age at PNH diagnosis and gender were included in the final adjusted model. Results: Ravulizumab treatment data were available for 244/246 patients (median [range] follow-up: 46.8 [0.4-69.3] months). At baseline, all 246 patients had LDH levels > 1.5 × ULN; at 26 weeks, 87.1% of patients achieved LDH levels ≤ 1.5 × ULN, which was maintained in 79.3% of patients at last follow-up (day 2045 [n/N = 42/53]; highest proportion reported at day 225 [n/N = 92/97; 94.9%]). At baseline, 17.1% of patients had a history of MAVEs (MAVE rate: 3.4 per 100 patient-years [PYs]). The proportion of ravulizumab-treated patients who experienced MAVEs was low throughout the study (n = 11 [4.5%], 13 events, MAVE rate: 1.4 per 100 PYs), with 9 patients (3.7%) reporting MAVEs during the OLE (11 events, MAVE rate: 1.3 per 100 PYs). Prior to randomization (≤ 6 months of study entry), 24.8% of patients did not need transfusions; at 26 weeks, this increased to 73.6% and was maintained in 53.9% of patients for the entire OLE with the highest proportion not requiring transfusions reported during the final 6 months of the OLE (75.7%). In addition, units transfused reduced from 1019 prior to randomization to 110 during the final 6 months of the OLE. Overall, 33 patients (13.4%) discontinued ravulizumab treatment during the entire study period (30 [12.2%] during the OLE). Reasons for discontinuation were death (n = 8), patient choice (n = 7), physician decision (n = 5), pregnancy (n = 4), adverse event (n = 3), lost to follow-up (n = 1) and other (n = 5). When compared with 413 untreated patients, ravulizumab was associated with an adjusted survival probability (95% confidence interval [CI]) of 84.1% (77.4, 91.3) at 4 years (hazard ratio [95%CI]: 0.14 (0.06, 0.32), p < 0.001; Figure 1) and mortality was 3.5-fold lower than that observed in untreated patients in the PNH Registry. Conclusions: This study reports the longest duration of ravulizumab treatment exposure in C5-inhibitor-naïve patients with PNH (925.7 PYs) to date. For up to 6 years, ravulizumab provided effective long-term control of IVH, evidenced by the maintenance of LDH ≤ 1.5 × ULN and low incidence of MAVEs and death. No new safety signals were identified and ravulizumab improved survival compared with untreated patients in the PNH Registry, further supporting the use of ravulizumab as the first-line treatment of choice for patients with PNH, where available.

Long-term effectiveness of eculizumab: Data from the International PNH Registry.

Data from the International PNH Registry (NCT01374360) were used to estimate the overall survival and first occurrence of thromboembolic events/major adverse vascular events (TEs/MAVEs) for eculizumab-treated patients with paroxysmal nocturnal hemoglobinuria (PNH) compared with a contemporaneous untreated cohort. Patients enrolled in the Registry from March 16, 2007, to February 14, 2022, were included. Treated patients received eculizumab for >35 days; untreated patients did not receive eculizumab at any time. Univariable and multivariable analyses were performed using a Cox proportional hazards regression model comparing eculizumab treatment periods to untreated periods and were adjusted for baseline covariates (e.g., high disease activity [HDA], transfusion dependency, and eculizumab treatment status). The analysis included 4118 patients. The univariable hazard ratio (HR) (95% CI) for mortality in eculizumab-treated time versus untreated time was 0.51 (0.41-0.64; p < 0.0001). Significant baseline covariates included age, sex, history of bone marrow failure, ≥4 erythrocyte transfusions within 12 months before baseline, and an estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 (all p < 0.0001). In the adjusted analysis, patients with baseline HDA had the greatest reduction in mortality risk (HR [95% CI], 0.51 [0.36-0.72]). Treated patients had approximately 60% reduction in TE/MAVE risk during treated versus untreated time (HR [95% CI]: TE: 0.40 [0.26-0.62], MAVE: 0.37 [0.26-0.54]; p < 0.0001). Using data from the largest Registry of patients with PNH, with ≥14 years of overall follow-up, we demonstrate that treatment with eculizumab conferred a 49% relative benefit in survival and an approximately 60% reduction in TE/MAVE risk.

Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case–control study in the International PNH Registry

The objective of this analysis was to identify risk factors for thromboembolic events (TE) in patients with paroxysmal nocturnal hemoglobinuria (PNH) who were not treated with C5 inhibitors. Patients with PNH and a history of ≥ 1 TE at enrollment in the International PNH Registry (NCT01374360; registration date, January 2011) were each matched with up to 5 patients without TE. Multivariable analysis was performed with the following variables: percentage glycosylphosphatidylinositol (GPI)–negative cells, high disease activity (HDA), non-TE major adverse vascular event history, and recent anticoagulation. Of 2541 eligible patients, 57 with TE and 189 matched controls were analyzed. Multivariable analysis (odds ratio [95% CI]) identified the following factors as being associated with increased thrombotic risk: patients with no history of TE (with recent anticoagulation, 9.30 [1.20–72.27]), patients with history of TE (with recent anticoagulation, 8.91 [0.86–92.62]; without recent anticoagulation, 5.33 [0.26–109.57]), patients with ≥ 30% GPI-negative granulocytes (≥ 30% to < 50%, 4.94 [0.54–45.32]; ≥ 50%, 1.97 [0.45–8.55]), or patients with lactate dehydrogenase (LDH) ratio ≥ 1.5 × upper limit of normal (ULN) plus ≥ 2 HDA criteria (2–3 criteria, 3.18 [0.44–23.20]; ≥ 4 criteria, 3.60 [0.38–33.95]). History of TE, ≥ 30% GPI-negative granulocytes, and LDH ratio ≥ 1.5 × ULN with ≥ 2 HDA criteria are TE risk factors for patients with PNH. These findings will aid physicians by providing important clinical and laboratory risk factors that can be used to identify and manage patients with PNH who are at risk of developing TE.

Clinically important change for the FACIT-Fatigue scale in paroxysmal nocturnal hemoglobinuria: a derivation from international PNH registry patient data

BackgroundFatigue is the most common symptom associated with paroxysmal nocturnal hemoglobinuria (PNH). The objective of this analysis was to estimate values that would suggest a clinically important change (CIC) for the functional assessment of chronic illness therapy-fatigue scale (FACIT-Fatigue) in patients with PNH.MethodsAdults with PNH who initiated eculizumab within 28 days of enrollment in the International PNH Registry as of January 2021 with baseline FACIT-Fatigue scores were included in the analysis. Distribution-based estimates of likely difference were calculated using 0.5 × SD and SEM. Anchor-based estimates of CIC considered the European Organization for Research and Treatment of Cancer (EORTC) global health status/quality of life summary score and the EORTC Fatigue Scale score. Changes in anchors and high disease activity (HDA) shift from start of eculizumab treatment to each follow-up visit were then assessed by FACIT-Fatigue score change (≤ 1 CIC, no change, or ≥ 1 CIC).ResultsAt baseline, 93% of 423 patients had fatigue documented in their medical history. The distribution-based estimates for FACIT-Fatigue were 6.5 using 0.5 × SD and 4.6 using SEM; internal consistency was high (α = 0.87). For anchor-based estimates, the FACIT-Fatigue CIC ranged from 2.5 to 15.5, and generally supported 5 points as a reasonable lower end of the value for meaningful individual change. The percentage of patients who changed from having HDA at baseline to no HDA at eculizumab-treated follow-up visits increased over time.ConclusionThese results support the use of 5 points as the CIC for FACIT-Fatigue in patients with PNH, which is within range of the CICs reported in other diseases (3–5 points).

Concomitant Immunosuppressive Therapy and Eculizumab Use in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Analysis

Introduction: Complement C5 inhibitor eculizumab is the first approved treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder caused by uncontrolled terminal complement activation. Approximately 50% of patients with aplastic anemia (AA) have PNH cells. Limited data are available for patients with AA-PNH taking concomitant immunosuppressive therapy (IST) and eculizumab. Methods: Data from the International PNH Registry (NCT01374360) were used to evaluate the safety and effectiveness of eculizumab and IST in patients taking IST followed by concomitant eculizumab (IST + c-Ecu) or eculizumab followed by concomitant IST (Ecu + c-IST). Results: As of January 1, 2018, 181 Registry-enrolled patients were included in the eculizumab effectiveness analyses (n = 138, IST + c-Ecu; n = 43, Ecu + c-IST); 87 additional patients received IST alone. Reductions from baseline with eculizumab were observed in the least squares mean lactate dehydrogenase ratio (IST + c-Ecu, −3.4; Ecu + c-IST, −3.5); thrombotic event incidence rates were similar between groups (IST + c-Ecu, 1.3; Ecu + c-IST, 0.7). Red blood cell transfusion rate ratios decreased from baseline for IST + c-Ecu (0.7) and increased for Ecu + c-IST (1.2); there were none for IST alone. Hematological parameters generally improved for IST + c-Ecu and IST alone, and changed minimally or worsened for Ecu + c-IST. Safety signals were generally consistent with those previously described for the respective therapies. Discussion/conclusion: Although some intergroup differences were seen, concomitant eculizumab and IST were safe and effective regardless of treatment sequence.

Effect of eculizumab treatment in patients with paroxysmal nocturnal hemoglobinuria with or without high disease activity: Real-world findings from the International Paroxysmal Nocturnal Hemoglobinuria Registry.

The effects of eculizumab treatment in paroxysmal nocturnal hemoglobinuria (PNH) patients with or without high-disease activity (HDA), defined by LDH ≥ 1.5 × ULN and history of major adverse vascular events (MAVEs; including thrombotic events [TEs]); anemia; and/or physician-reported abdominal pain, dyspnea, dysphagia, erectile dysfunction, fatigue, and/or hemoglobinuria, in the International PNH Registry were evaluated. Registry patients were stratified by baseline HDA and eculizumab-treatment status. Longitudinal changes in laboratory and clinical PNH-related endpoints were evaluated using linear mixed models (continuous variables) or Poisson regression (incidence rates). As of May 1, 2017, 3009 patients (HDA/eculizumab-treated, n=913; HDA/never-treated, n=651; no-HDA/eculizumab-treated, n=173; no-HDA/never-treated, n=1272) were analyzed. Higher proportions of eculizumab-treated patients had HDA and history of MAVEs. In patients with and without HDA, respectively, eculizumab treatment resulted in reductions from baseline for (1) LDH ratio (mean [SD]: -5.3 [4.0] and -2.3 [3.8]); (2) incidence rate ratio (IRR) for MAVEs (-80% and -70%); (3) IRR for TEs (-80% for both); and (4) units of red blood cell transfusions per year (from 6.8 to 2.8 and 3.6 to 2.5units). Eculizumab treatment in a real-world setting improved outcomes, including substantial decreases in hemolysis, MAVE rates, TEs, and transfusions in PNH patients regardless of HDA.

Clinically Important Difference for the FACIT-Fatigue Scale in Paroxysmal Nocturnal Hemoglobinuria: A Derivation from International PNH Registry Patient Data

Background: Fatigue is a common symptom associated with paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab, a C5 inhibitor approved for treatment of PNH, has been shown to significantly alleviate fatigue, as indicated by reduced scores on the Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-Fatigue). FACIT-Fatigue scores range from 0-52 (higher scores indicate less fatigue); this assessment is validated for use in patients with PNH and has been used extensively both in clinical trials and in the International PNH Registry. In patients with cancer, the FACIT-Fatigue clinically important difference (CID) is estimated to be improvement of 3-5 points. This CID is commonly applied in PNH studies; however, no disease-specific CID for FACIT-Fatigue has been estimated in patients with PNH. A PNH-specific CID would be informative in evaluating changes in fatigue impact and could serve as a more robust criterion for evaluating treatment efficacy. The objective of this analysis was to determine the FACIT-Fatigue CID for patients with PNH using distribution- and anchor-based approaches and real-world data from the International PNH Registry.Methods: Adults with PNH who initiated eculizumab within 28 days of enrollment in the PNH Registry as of January 2021 with non-missing baseline FACIT-Fatigue scores were included in the analysis. FACIT-Fatigue scores were assessed at baseline and 6, 12, 24, and 36 months. Two distribution-based CID estimates were calculated using: 1) 0.5 × SD and 2) standard error of measurement (SEM). The SEM was calculated as SD−sqrt(1-α), where α represents the internal consistency measurement Cronbach's alpha. Cronbach's alpha was calculated from the 13 FACIT-Fatigue subscales. Anchor-based estimates considered 2 continuous patient-reported outcome variables: 1) European Organization for Research and Treatment of Cancer (EORTC) Global Health Status Quality of Life (QoL) summary score (quartiles; higher scores indicate better quality of life), and 2) EORTC Global Health Status Fatigue Subscale score (quartiles; lower scores indicate less fatigue). The baseline FACIT-Fatigue score was calculated for each predefined categorization of the anchors; the mean of differences in FACIT-Fatigue between adjacent categories was calculated and referenced as the anchor-based CID. Changes in anchors and high disease activity (HDA) shift from baseline to each follow-up visit were then assessed by FACIT-Fatigue score change (≤1 CID, no change, or ≥1 CID). HDA was defined as lactate dehydrogenase ratio ≥1.5 × upper limit of normal and ≥1 of the following: history of a major adverse vascular event (including a thrombotic event); anemia; or physician-reported abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, or erectile dysfunction.Results: 423 patients were included in the analysis (Table). The majority of patients were white or of Caucasian descent (84%); 3% were of Hispanic or Latino ethnicity. At baseline, 93% of patients had physician documentation of fatigue in their medical history (mean FACIT-Fatigue score, 29.4). The 2 distribution-based CIDs were 7 using 0.5 × SD and 5 using SEM; internal consistency was high (α=0.87). For anchor-based measurements, the CID was 8 using the EORTC QoL score and 10 using the EORTC fatigue subscale score. The percentage of patients who changed from having HDA at baseline to no HDA at eculizumab-treated follow-up visits increased over time. Using the SEM as the referent CID (owing to the high α value), the majority of these patients experienced >1 CID in FACIT-Fatigue that was sustained through 36 months (Figure). Results were similar when 0.5 × SD was used.Conclusion: Collectively, these results support the use of 5 points as the CID for FACIT-Fatigue in individual patients with PNH, which, although not necessarily the minimal value, is close to the range of CIDs reported in other diseases (3-5 points). This finding, obtained from a real-world dataset with a large number of patients, helps establish an important metric for assessment of the meaningful treatment response of patients with PNH. Of note, this CID is markedly smaller than the group average FACIT-Fatigue improvement of 10 points achieved with long-term eculizumab treatment in the pivotal blinded Phase 3 TRIUMPH study. [Display omitted] DisclosuresCella: FACIT: Membership on an entity's Board of Directors or advisory committees. Ueda: Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Chugai Pharmaceutical: Consultancy, Honoraria, Research Funding; Alexion Pharma: Consultancy, Honoraria. Tomazos: Alexion, AstraZeneca Rare Disease: Current Employment. Gustovic: Alexion, AstraZeneca Rare Disease: Current Employment. Wang: Alexion, AstraZeneca Rare Disease: Current Employment. Patel: Alexion, AstraZeneca Rare Disease: Current Employment. Schrezenmeier: Novartis: Honoraria; Alexion, AstraZeneca Rare Disease: Honoraria, Other: Travel support, Research Funding; Roche: Honoraria; Apellis: Honoraria; Sanofi: Honoraria.

Long-Term Survival Benefit of Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from the International PNH Registry

Long-Term Survival Benefit of Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from the International PNH Registry

Comparison of Baseline Clinical Characteristics between Asian Vs. Non-Asian Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) from International PNH Registry

Background: PNH is clinically characterized by intravascular haemolysis, bone marrow failure and thrombosis. Thrombosis and bleeding/serious infections have been reported as major causes of death in PNH. The difference in clinical manifestations of PNH among different races has also been suggested; however, it has not been clearly demonstrated due to rarity of the disease. Objectives: The aim of this study was to clarify whether the racial background of patients with PNH affects their clinical characteristics. Methods: As of June 5, 2017, 4,928 patients were enrolled in the International PNH Registry. After excluding patients with missing data for race, birth date, sex, enrollment date, and/or treatment status with eculizumab, 1,793 patients, who were eculizumab naïve at enrollment and had ≥1% GPI-deficient granulocytes or erythrocytes, were selected for analysis. The study population was divided into two cohorts according to their racial background. The “Asian cohort” consisted of patients with Asian or mixed Asian race (N=246), and the non-Asian cohort consisted of patients with White/Caucasian, Black/African descent and other racial background (N=1547). “Asian cohort” was further divided into “Asians in Asia cohort” (N=202) where the patients were enrolled in the registry from Japan (N=22), South Korea (N=122), Taiwan (N=25), and other Asian countries (N=33), and “Asians in non-Asia cohort” where Asian patients were enrolled from countries outside Asia (N=44). Baseline was defined as enrollment in the registry for all patients. Results: Median (Q1, Q3) disease duration (time from disease start to enrollment) was 1.6 years (0.3, 6.1) for Asian cohort and 1.2 years (0.4, 5.0) for non-Asian cohort. There was no significant difference in sex ratio, median age, and the proportion of patients with a history of bone marrow disorder, aplastic anemia, or myelodysplastic syndrome between the two cohorts. The mean platelet counts at baseline also did not differ significantly between two cohorts. However, Asian cohort had higher LDH value (Median LDH Ratio (Q1, Q3), 2.0 (1.1, 5.6) in the Asian cohort and 1.6 (1.0, 3.8) in the non-Asian cohort; p<0.0001) and mean percent GPI-deficient granulocyte clone (50% vs 43%; p=0.0041) compared with non-Asian cohort. In comparison between Asian in Asia cohort and Asian in non-Asia cohort, the difference in mean percent GPI-deficient granulocyte clone remained significant (53% vs 39%; p=0.036). The proportion of patients with a history of major adverse vascular events (MAVE) at baseline was significantly higher in non-Asian cohort than in Asian-cohort (p=0.0005). The significant differences were also observed in all thrombotic events (TE), venous TE, and non-TE MAVE (Fig. 1). However, the proportion of patients with a history of arterial TE was not significantly different between two cohorts, or in comparison between Asians in Asia cohort and Asians in non-Asia cohort (Fig. 2). The proportion of patients with a history of MAVE/TE at baseline did not differ significantly among Japan, Taiwan, and Korea. Regarding the treatment, Asian cohort had more patients with a history of RBC transfusion (67% vs 52%; p=<0.0001) and corticosteroid therapy (47% vs 34%; p=0.0003) than non-Asian cohort, but less patients with a history of anticoagulant therapy such as heparin or warfarin (9% vs 16%; p=0.002) and cyclosporine/ATG (29% vs 42%; p<0.0001). The difference remained significant in the comparison between Asians in Asia and Asians in non-Asia except for the history of cyclosporine/ATG. Regarding the history of physician-reported symptoms, the proportion of patients with easy bruise/bleeding was higher in non-Asian cohort than Asian cohort (38% vs 20%; p<0.0001). The same difference was also observed between Asians in Asia cohort and Asians in non-Asia cohort (15% vs 41%; p=0.0004). Conclusions: This study with large-scale data base strongly suggested that history of MAVE/TE is higher in non-Asian patients with PNH compared with Asian patients. The comparison between Asians in non-Asia and Asians in Asia cohorts suggested that genetic factors rather than life style and diet play a role in developing MAVE/TE in PNH patients. This study also highlighted that the registry data serve as a valuable resources to understand the clinical course of PNH and thus contribute to establish optimal therapeutic approaches according to patient's racial background. [Display omitted] DisclosuresOkamoto:Chugai Pharmaceutical Co.: Research Funding; Novartis: Research Funding; Bristol-Myers K.K: Research Funding; Pfizer: Research Funding; Bristol-Myers K.K: Honoraria; Astellas: Honoraria; Pfizer Japan: Speakers Bureau; Alexion Pharma G.K.: Honoraria. Sakurai:Alexion: Honoraria. Wilson:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Nishimura:Alexion Pharma GK: Honoraria, Research Funding. Kanakura:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding; Nippon Shinyaku: Research Funding; Pfizer: Research Funding; Kyowa Hakko Kirin: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Shionogi: Research Funding; Bristol Myers: Research Funding; Toyama Chemical: Research Funding; Chugai Pharmaceutical: Research Funding; Fujimotoseiyaku: Research Funding.

Efficacy of Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) and High Disease Activity with or without History of Aplastic Anemia in the International PNH Registry

Background/Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive, potentially life-threatening, hematologic disorder characterized by uncontrolled activation of the terminal complement pathway; it often occurs in patients with underlying bone marrow failure (BMF), most commonly aplastic anemia (AA). The presence of both diseases may present challenges to clinicians regarding optimal patient management. The International PNH Registry is a prospective, observational study of patients with PNH regardless of treatment with eculizumab, a humanized monoclonal antibody that blocks terminal complement activation at C5. The objective of this analysis was to evaluate clinical and laboratory outcomeswith eculizumab in patients with PNH, with or without history of AA. The analysis was restricted to the subpopulation of patients with high disease activity (HDA) to allow for an appropriate assessment of eculizumab-related treatment effects in the presence or absence of a history of AA in the setting of PNH.Methods: Eculizumab-treated patients with HDA at initiation of therapy in the Registry were stratified by history of AA as reported by their treating physicians. HDA was defined as evidence of hemolysis (elevated lactate dehydrogenase [LDH] ratio ≥1.5 x upper limit of normal) and presence of any PNH-related symptoms, including fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia (hemoglobin <100 g/L), major adverse vascular event (MAVE; including thrombotic event [TE]), dysphagia, or erectile dysfunction. Patients were assessed at baseline (defined as the date of eculizumab initiation) and at last follow-up. Outcomes were assessed in patients with at least 6 months of follow-up time after initiation of eculizumab and included rates of MAVE, TE, and red blood cell (RBC) transfusions received before and after baseline, and changes from baseline to last follow-up in laboratory values.Results: As of June 5, 2017, 4928 patients were enrolled in the Registry. Of these, 769 patients with HDA, treated with eculizumab, with non-missing data on demographics, enrollment date, and BMF status, and with ≥6 months of follow-up were included in these analyses. Of these, 286 (37%) had a history of AA at initiation of eculizumab (including 223 [78%] reported as ongoing AA), and 483 patients (63%) had no history of any BMF. Median (min, max) follow-up on treatment was 3.6 (0.5, 12.0) and 4.0 (0.5, 12.0) years in patients with history of AA and without any history of BMF, respectively. The majority of patients in both the history of AA group and the group without any history of BMF had >50% glycosylphosphatidylinositol-deficient granulocytes at baseline (82% and 93%, respectively); median (Q1, Q3) LDH ratio at baseline was 4.9 (3.0, 7.5) and 6.2 (3.7, 9.0), respectively. Treatment with eculizumab was associated with substantial improvement in the rates of MAVE, TE, and RBC transfusion as well as a significant reduction from baseline in mean LDH ratio, regardless of whether patients had history of AA at initiation of eculizumab (Table).Conclusions: Eculizumab treatment was associated with significant improvement in clinical and laboratory outcomes related to PNH, regardless of AA history. Findings from this analysis suggest that history of AA does not adversely impact the effectiveness of eculizumab in patients with PNH. Our findings are consistent with the notion that patients with PNH who have HDA, including those with history of AA, should be treated with eculizumab. [Display omitted] DisclosuresPeffault De Latour:Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Brodsky:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding. Hill:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Roeth:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Schrezenmeier:Alexion Pharmaceuticals, Inc.: Honoraria, Other: Research Funding to University of Ulm . Wilson:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Marantz:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Ra Pharma: Consultancy; Apellis Pharmaceuticals: Consultancy.

Interim Analysis of Safety Outcomes during Treatment with Eculizumab: Results from the International Paroxysmal Nocturnal Hemoglobinuria Registry

Background/Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive, life-threatening disorder characterized by complement-mediated intravascular hemolysis and a prothrombotic state. Eculizumab, a terminal complement inhibitor inhibits intravascular hemolysis and thrombosis, and decreases mortality risk in patients with PNH. More information is needed regarding outcomes associated with long-term treatment. The International PNH Registry (NCT01374360) is an ongoing prospective, multinational, observational study established to record the natural history of patients with PNH and collect data on long-term efficacy and safety of eculizumab treatment. The objective of this analysis was to assess safety outcomes in patients in the PNH Registry by treatment status with eculizumab.Methods: Patients enrolled in the Registry as of July 5, 2016, were eligible for the current analyses. Patient-time was classified as ever-treated with eculizumab or untreated with eculizumab. The patient-time in the eculizumab-treated group was assessed starting at initiation of eculizumab and followed through last Registry follow-up. The untreated-with-eculizumab group included those who never received eculizumab treatment prior to enrollment in the Registry; these patients contributed untreated patient-time starting at enrollment and followed through last untreated follow-up (initiation of eculizumab or last Registry follow-up). For the eculizumab-treated group, baseline was defined as the date of eculizumab initiation; for the untreated-with-eculizumab group, baseline was defined as the date of Registry enrollment. Patients who were enrolled while untreated and later initiated treatment with eculizumab contributed patient-time to both groups. Incidence rates were calculated for outcomes of interest reported on case report forms, except for subtypes of infections and malignancies where write-in text describing the infection or malignancy was coded by the authors to be one of the subtypes of interest.Results: Of the 4448 patients enrolled in the Registry, 4013 had non-missing data on demographics, enrollment date, and eculizumab status and were included in the current analyses (eculizumab-treated, n=1587; untreated-with-eculizumab at enrollment, n=3058); 632 patients contributed patient-time to both groups. The mean (standard deviation) follow-up time for the eculizumab-treated and untreated-with-eculizumab groups was 50.0 (30.9) and 32.1 (25.0) months, respectively. Mean age at baseline was similar in the eculizumab-treated and untreated-with-eculizumab groups (43.4 vs 44.8 years, respectively). At baseline, 91% in the eculizumab-treated group had LDH ≥1.5x upper limit of normal prior to treatment, compared with 50% of untreated-with-eculizumab patients. More patients in the eculizumab-treated group had a history of thrombotic events (TE; 23% vs 9%) or other major adverse vascular events (MAVE; 12% vs 9%) compared with untreated-with-eculizumab patients. Rates of TE, other MAVE, solid tumors, impaired renal function (IRF), impaired hepatic function (IHF), pulmonary hypertension, and mortality were substantially lower in the eculizumab-treated group during follow-up compared with the untreated-with-eculizumab group, while estimated rates of overall infections and hematologic malignancies were similar in the 2 treatment groups (Table). In the subset of 632 patients enrolled while untreated with eculizumab but later started eculizumab after enrollment, rates of TE, other MAVE, solid tumors, IRF, IHF, and pulmonary hypertension were lower following initiation of eculizumab. Of the 18 cases of Neisseria infection in 16 patients in the eculizumab-treated group (Table), 13 were confirmed meningococcal infections (12 resolved, 1 ongoing at time of data cut-off). One patient in the untreated-with-eculizumab group had a Neisseria infection. No fatal outcomes due to meningococcal infection or other encapsulated organisms were reported in any group in this analysis.Conclusions: With 6399 patient-years of eculizumab exposure in the largest global Registry of patients with PNH, eculizumab appears to be safe with no new safety findings identified. Rates of complications of PNH are lower in patients treated with eculizumab compared with those who are untreated. The benefit-risk ratio for patients treated with eculizumab remains favorable. [Display omitted] DisclosuresHill:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Roeth:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Socié:Alexion Pharmaceuticals, Inc.: Consultancy. Caby-Tosi:Alexion Europe SAS: Employment, Equity Ownership. Wilson:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Gustovic:Alexion Pharma GmbH: Employment, Equity Ownership. Bedrosian:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Brodsky:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding.

Analysis of Baseline Clinical Characteristics and Disease Burden in Patients Enrolled in the International Paroxysmal Nocturnal Hemoglobinuria Registry

Background/Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, potentially life-threatening hematologic disorder characterized by chronic uncontrolled intravascular hemolysis, thrombosis, end organ damage, and impaired quality of life (QoL) and survival. The International PNH Registry (NCT01374360) is an ongoing, global observational study to evaluate the safety profile of eculizumab and to characterize the burden and progression of PNH including clinical outcomes, morbidity, and mortality irrespective of treatment. The objective of this analysis was to characterize the demographic and clinical characteristics, disease-associated morbidities, PNH symptoms, and health-related QoL of the largest cohort of PNH patients enrolled in the Registry.Methods: Registry patients who had data available as of May 1, 2017, were eligible for the current analysis. All patients were untreated at baseline, defined as the date of eculizumab initiation for patients ever treated with eculizumab and the date of Registry enrollment for patients never treated with eculizumab. Proportions of patients with high disease activity (HDA), history of major adverse vascular events (MAVE; including thrombotic events [TE]) and bone marrow disorders (BMD) including aplastic anemia, red blood cell (RBC) transfusions, concomitant medication use, and physician-reported symptoms were based on the number of patients with non-missing responses at baseline. Laboratory values and QoL scores assessed with the European Organisation for Research and Treatment of Cancer [EORTC] Global Health and Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue questionnaires within 6 months prior to baseline were summarized using medians and quartiles or proportions for the patients with non-missing responses. Patients with percent glycosylphosphatidylinositol (GPI)-deficient granulocyte values available prior to baseline were stratified based on the most recent value prior to baseline and statistical analysis (i.e., P values) was used to assess potential trends related to clone size.Results: A total of 4903 patients were enrolled. Of these, 4398 had non-missing data on demographics, enrollment date, and eculizumab status, and were eligible for the analysis. Median (Q1, Q3) age at disease onset was 35.3 (23.9, 53.1) years; 53% of the patients were female. Median (Q1, Q3) percent GPI-deficient granulocyte clone size was 33% (3%, 85%) in the 2654 patients with clone size reported prior to baseline. Clinical characteristics at baseline for the overall population and stratified by percent GPI-deficient clone size are summarized in the Table. Overall, patients had a high burden of disease at baseline, as reflected by the proportion with HDA (52%), history of MAVE (19%), BMD (63%), RBC transfusions (61%), and impaired renal function defined as estimated glomerular filtration rate <90 mL/min (42%). Patients frequently experienced symptoms such as fatigue (81%), dyspnea (45%), hemoglobinuria (45%), abdominal pain (35%), and impaired QoL with median (Q1, Q3) FACIT-Fatigue and EORTC Global Health scores of 34.0 (27.0, 40.0) and 58.3 (41.7, 75.0), respectively. All measures of disease burden except for history of RBC transfusions were significantly correlated with clone size (P <0.05); specifically, higher disease burden correlated with larger clone size. However, a substantial number of patients with clone size <10% had hemolysis (LDH ≥1.5 x ULN; 10%), MAVE (10%), HDA (9%), and/or experienced symptoms such as fatigue (82%), dyspnea (46%), abdominal pain (19%), or hemoglobinuria (13%). History of RBC transfusion and immunosuppressive therapy were reported in 60% and 59% of patients with clone size <10%, potentially due to patients with history of BMD. Interestingly, median LDH ratio and the proportion of patients with history of MAVE and TE were modestly higher in the cohort with clone size 10-<50% vs <10%, while the proportion of those patients was substantially higher in the cohort with clone size ≥50% vs 10-<50%.Conclusions: PNH is associated with high burden of disease, particularly in patients with larger GPI-deficient clone sizes; however, even patients with smaller clone sizes had significant disease burden and symptoms. Improved characterization of clinical measures and of relationships between these measures may help inform patient management. [Display omitted] DisclosuresSchrezenmeier:Alexion Pharmaceuticals, Inc.: Honoraria, Other: Research Funding to University of Ulm . Maciejewski:Ra Pharma: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Apellis Pharmaceuticals: Consultancy. Roeth:Roche: Consultancy, Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Araten:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Kanakura:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding; Astellas: Research Funding; Bristol Myers: Research Funding; Toyama Chemical: Research Funding; Kyowa Hakko Kirin: Research Funding; Eisai: Research Funding; Shionogi: Research Funding; Fujimotoseiyaku: Research Funding; Pfizer: Research Funding; Nippon Shinyaku: Research Funding; Chugai Pharmaceutical: Research Funding. Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Other: Research Funding to the laboratory at University of Alberta, for ADAMTS13 testing. Shammo:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Wilson:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Shayan:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Hillmen:Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Celgene: Research Funding; Roche: Consultancy, Honoraria, Research Funding.

Risk Factors for Thrombotic Events in Patients with PNH: A Nested Case-Control Study in the International PNH Registry

Risk Factors for Thrombotic Events in Patients with PNH: A Nested Case-Control Study in the International PNH Registry

Pregnancy in Classical Paroxysmal Nocturnal Hemoglobinuria and Aplastic Anemia-Paroxysmal Nocturnal Hemoglobinuria: A High-Risk Constellation.

Pregnancies in paroxysmal nocturnal hemoglobinuria (PNH) are associated with increased morbidity and mortality. Retrospective studies suggest that outcome has improved with the advent of the complement inhibitor eculizumab. To substantiate this assumption we analyzed the data from patients treated in our department since 2009. All patients were included in the International PNH registry and followed prospectively. We identified 16 pregnancies in 9 patients with classical PNH, and two pregnancies in two patients with aplastic anemia (AA)-PNH. In classical PNH, 13 pregnancies were supported by eculizumab. Breakthrough hemolysis occurred in six pregnancies, necessitating an increase in the biweekly eculizumab dose from 900 mg to 1,200–1,800 mg. Red blood cell transfusions were given in six and platelet transfusions in two pregnancies. A Budd-Chiari syndrome and cholecystitis complicated the course of two pregnancies. Four of 13 pregnancies supported by eculizumab ended in spontaneous abortion or stillbirth, and one was prematurely terminated because of fetal trisomy 21. None of the three pregnancies not supported by eculizumab had a successful outcome. Half the deliveries were preterm. None of the patients died, and, in all but one patient, the post-partum period was uneventful. Both pregnancies in patients with AA-PNH took a favorable course. Our results confirm low maternal mortality and frequent breakthrough hemolysis in pregnant PNH patients receiving eculizumab. Fetal mortality and the rate of preterm delivery were higher than reported previously, possibly related to the use of registry data that are likely to reduce the risk of publication and recall biases.

Beneficial effects of eculizumab regardless of prior transfusions or bone marrow disease: Results of the International Paroxysmal Nocturnal Hemoglobinuria Registry.

To evaluate the effects of eculizumab on transfusions and thrombotic events (TEs) in patients with and without prior history of transfusion in the International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry. Registry patients enrolled on or before January 1, 2018, initiated on eculizumab no more than 12months prior to enrollment, having known transfusion status for the 12months before eculizumab initiation, and ≥12months of Registry follow-up after eculizumab initiation, were included. Eculizumab treatment was associated with a 50% reduction in transfusions in patients with a transfusion history (10.6 units/patient-year before eculizumab vs 5.4 after; P<.0001), with greater reduction observed in those with no history of bone marrow disease vs those with bone marrow disease. Mean lactate dehydrogenase levels decreased from a mean of 6.7 to 1.4 times the upper limit of normal (ULN) in patients with transfusion history and from 5.1 to 1.2 times ULN in those with no transfusion history. TE and major adverse vascular event rates also decreased by 70% in patients with and without history of transfusion. The benefit of eculizumab therapy does not appear to be limited to any group defined by transfusion history or bone marrow disease history.

Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry

The International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry (NCT01374360) was initiated to optimize patient management by collecting data regarding disease burden, progression, and clinical outcomes. Herein, we report updated baseline demographics, clinical characteristics, disease burden data, and observed trends regarding clone size in the largest cohort of Registry patients. Patients with available data as of July 2017 were stratified by glycosylphosphatidylinositol (GPI)-deficient granulocyte clone size (< 10%, ≥ 10%–< 50%, and ≥ 50%). All patients were untreated with eculizumab at baseline, defined as date of eculizumab initiation or date of Registry enrollment (if never treated with eculizumab). Outcomes assessed in the current analysis included proportions of patients with high disease activity (HDA), history of major adverse vascular events (MAVEs; including thrombotic events [TEs]), bone marrow failure (BMF), red blood cell (RBC) transfusions, and PNH-related symptoms. A total of 4439 patients were included, of whom 2701 (60.8%) had available GPI-deficient granulocyte clone size data. Among these, median clone size was 31.8% (1002 had < 10%; 526 had ≥ 10%–< 50%; 1173 had ≥ 50%). There were high proportions of patients with HDA (51.6%), history of MAVEs (18.8%), BMF (62.6%), RBC transfusion (61.3%), and impaired renal function (42.8%). All measures except RBC transfusion history significantly correlated with GPI-deficient granulocyte clone size. A large proportion of patients with GPI-deficient granulocyte clone size < 10% had hemolysis (9.7%), MAVEs (10.2%), HDA (9.1%), and/or PNH-related symptoms. Although larger GPI-deficient granulocyte clone sizes were associated with higher disease burden, a substantial proportion of patients with smaller clone sizes had history of MAVEs/TEs.

Prophylactic Antibiotic Use and Risk of Meningococcal Infections in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Eculizumab Who Received Meningococcal Vaccination: Results from the International PNH Registry

Prophylactic Antibiotic Use and Risk of Meningococcal Infections in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Eculizumab Who Received Meningococcal Vaccination: Results from the International PNH Registry

Epidemiology of PNH and Real-World Treatment Patterns Following an Incident PNH Diagnosis in the US

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life-threatening blood disease. While PNH is known to be a rare disease, the incidence and prevalence of the condition has been described only in a few small studies. In addition, while the International PNH registry is a rich source of data on real-world PNH patients globally, it is not possible to estimate the incidence and prevalence of PNH directly from the registry. As complement inhibitors are becoming the standard of care for PNH treatment, we also sought to explore how patients are managed following an incident PNH diagnosis. The objective of this study was to estimate the incidence and prevalence of PNH and to describe real-world treatment patterns among patients newly diagnosed with PNH in the United States (US). Methods: We conducted a retrospective cohort study using Truven US MarketScan Commercial/Medicare data (1 Jan 2015 to 30 June 2018), an employer-sponsored insurance claims database including annually approximately 30 million insured patients and their dependents' complete longitudinal records of inpatient services, outpatient services, and prescription drug claims covered under a variety of fee-for-service and capitated health plans. While these data are considered nationally representative of Americans with employer-provided health insurance, data come mainly from large employers. To estimate prevalence, we identified patients with ≥ 1 PNH diagnosis (ICD10: D59.5) among persons continually enrolled in the databases in 2017. To estimate incidence, we required ≥1-year of baseline enrolment and no PNH diagnosis or eculizumab exposure, identified using national drug codes [NDC] or procedure codes for drug administration, during the baseline period. Person-time accrued post-baseline until PNH diagnosis, end of study period, or disenrollment. We stratified incidence and prevalence estimates by age and sex and described patients with incident PNH in terms of demographics, comorbidities, and past-year healthcare resource utilization. Using Kaplan-Meier estimators, we estimated incidence of eculizumab initiation, timing of initiation, treatment duration, and risk of discontinuation/treatment holiday (&amp;gt;42 days between eculizumab exposures [i.e. 14-day exposure period + 28-day grace period between infusions], the equivalent of missing 2 infusions assuming a bi-weekly infusion schedule for eculizumab) following the incident PNH diagnosis. While accounting for censoring, we also investigated patterns of red blood cell (RBC) transfusions, identified using procedure codes, in terms of incidence and timing of first transfusion following an incident PNH diagnosis. Results: The prevalence of PNH varied little between 2016 and 2017, from 12 to 13 per 1,000,000. The incidence rate over the study period was 5.7 per 1,000,000 person-years, representing 257 incident PNH cases. The incidence rate of PNH increased with age and was similar across sex. At diagnosis, mean age was 50.0 years (standard deviation [SD]: 18.6), 3.1% (8/257) were less than 18 years, 52.1% were women, 19.5% had a past-year diagnosis of aplastic anemia, 8.2% had a past-year diagnosis of myelodysplastic syndrome, 14.0% had a past-year RBC transfusion, and 31.5% had been hospitalized in the past-year. Over a mean follow-up time of 385.6 days (SD: 253.2), 10.3% (95% confidence interval [CI]: 6.3-14.1%) of patients initiated eculizumab on average 60.5 days (SD: 55.9) from PNH diagnosis. At 1 year, about one third of patients discontinued eculizumab or had taken a treatment holiday; average treatment duration was 328.2 days (SD:245.4). Cumulative incidence of RBC transfusions at 6 months and 1 year was 14.6% (10.1-18.9%) and 17.4% (12.2-22.3%), respectively. On average, the first RBC transfusion occurred within 63.6 days (SD: 114.4) of an incident PNH diagnosis. Conclusions: In routine clinical practice, only a minority of patients recently diagnosed with PNH are initiated on eculizumab. Among PNH patients treated with eculizumab, less than 70% remain on treatment after 1 year. Findings must be interpreted in the context of limitations including lack of information on clone size, symptom burden, measures of disease activity, or bone marrow failure state which may affect treatment course. Future studies should explore factors affecting eculizumab initiation and persistence on treatment. Disclosures Jalbert: Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Chaudhari:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Weyne:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Shammo:Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onconova: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Speakers Bureau; Astex Pharma: Research Funding; Novartis: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; CTI Pharma: Research Funding.

S865 CHANGE IN CLONE SIZE DOES NOT PREDICT RISK OF MAJOR ADVERSE VASCULAR EVENTS: RESULTS FROM THE INTERNATIONAL PNH REGISTRY

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