Relationship of paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size to disease burden and risk of major vascular events in untreated patients: results from the International PNH Registry.

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by acquired gene mutations resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins on the surface of blood cells, leading to terminal complement-mediated intravascular hemolysis and increased risk of major adverse vascular events (MAVEs). Using data from the International PNH Registry, this study investigated the relationship between the proportion of GPI-deficient granulocytes at PNH onset and (1) the risk for MAVEs (including thrombotic events [TEs]) and (2) the following parameters at last follow-up: high disease activity (HDA); lactate dehydrogenase (LDH) ratio; fatigue; abdominal pain; and rates of overall MAVEs and TEs. A total of 2813 patients untreated at enrollment were included and stratified by clone size at PNH disease onset (baseline). At last follow-up, higher proportion of GPI-deficient granulocytes (≤ 5% vs. > 30% clone size) at baseline was associated with significantly increased HDA incidence (14% vs. 77%), mean LDH ratio (1.3 vs. 4.7 × upper limit of normal), and rates of MAVEs 1.5 vs. 2.9 per 100 person-years) and TEs (0.9 vs. 2.0 per 100 person-years). Fatigue was evident in 71 to 76% of patients regardless of clone size. Abdominal pain was more frequently reported with clone size > 30%. A larger clone size at baseline appears to indicate a greater disease burden and risk of TEs and MAVEs and may inform decision making among physicians managing PNH patients at risk of experiencing TEs or other MAVEs. ClinicalTrials.gov ID: NCT01374360.

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

OBJECTIVES: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.

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.

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

OBJECTIVES: 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. METHODS: Registry patients enrolled on or before January 1, 2018, initiated on eculizumab no more than 12 months prior to enrollment, having known transfusion status for the 12 months before eculizumab initiation, and ≥12 months of Registry follow-up after eculizumab initiation, were included. RESULTS: 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. CONCLUSIONS: The benefit of eculizumab therapy does not appear to be limited to any group defined by transfusion history or bone marrow disease history.

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

BACKGROUND: Fatigue 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. METHODS: Adults 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). RESULTS: At 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. CONCLUSION: These 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).

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disease that leads to breakdown of the body's red blood cells in the blood vessels (intravascular hemolysis). Many people with PNH have fatigue, which consists of tiredness and weakness. A self-report questionnaire called the FACIT-Fatigue scale that objectively measures how fatigued a patient feels has been validated in clinical trials. Changes in the FACIT-Fatigue score help determine if a treatment is helping patients. The clinically important difference (difference between groups of people) or clinically important change (change within an individual) on the FACIT-Fatigue scale is a value that helps patients and clinicians find out if a drug helps or worsens patient fatigue. There is currently no defined clinically important difference and clinically important change on the FACIT-Fatigue scale for people with PNH. The International PNH Registry is a noninterventional, observational study collecting safety, treatment outcomes, and quality of life data from adults with PNH. This study used data from the International PNH Registry to find a clinically important difference and clinically important change in terms of improvement on the FACIT-Fatigue scale for adults with PNH who started eculizumab treatment. Different approaches were used to determine the amount of change in FACIT-Fatigue that would show that eculizumab has meaningful benefits, meaning patients are less fatigued. The authors demonstrated that a 5-point change on the FACIT-Fatigue is meaningful for people with PNH. This number is similar to the clinically important difference and clinically important change values of 3­5 points determined in other diseases.