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

Abstract

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.

One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study

“…15 Elevated levels of LDH (⩾1.5× ULN), are associated with increased prevalence of PNH-related symptoms compared with LDH levels <1.5× ULN, as well as with an increased risk of complications associated with thromboembolism, mortality, and reduced QoL. 3,16 Transfusion is typically used as a supportive measure to manage hemolytic anemia, 2 or the underlying bone marrow failure, and 61.3% of patients enrolled in the International PNH Registry reported history of red blood cell transfustion. 16 Treatment with eculizumab has been shown to reduce transfusion dependence and rapidly decrease LDH levels.…”

“…3,16 Transfusion is typically used as a supportive measure to manage hemolytic anemia, 2 or the underlying bone marrow failure, and 61.3% of patients enrolled in the International PNH Registry reported history of red blood cell transfustion. 16 Treatment with eculizumab has been shown to reduce transfusion dependence and rapidly decrease LDH levels. 6,7,17 During the primary evaluation period, ravulizumab demonstrated non-inferiority to eculizumab with respect to LDH normalization and transfusion avoidance, 13 and these benefits were maintained during the extension period for the majority of patients in both treatment arms.…”

Thrombotic Complications in Patients with Immune-Mediated Hemolysis

“…AIHA is a group of rare (1–3 cases per 100,000 person-years) [ 3 ] and heterogeneous diseases characterized by the presence of autoantibodies that react against red blood cell self-antigens and could lead to a variety of life-threatening complications including thrombosis. After the first evidence in the 1960’s of the occurrence of pulmonary embolism in 11% of patients with AIHA [ 4 ], a hypercoagulable state has been demonstrated in these patients [ 5 ] and more and more reports have been published making thrombotic manifestations a hallmark of AIHA, as 10–20% of patients experience a thrombotic event, either arterial or venous ( Table 1 ) [ 1 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Moreover, one fatal pulmonary embolism has been reported among 21 AIHA patients who received antithrombotic prophylaxis with low-molecular-weight heparin [ 6 ].…”

Even mild hemolysis in paroxysmal nocturnal hemoglobinuria could severely compromise the quality of life due to long-term sustained intolerant fatigue

“…As a result, patients with PNH often suffer from an impaired health-related QOL [6] . Since the degree of hemolysis is strongly related to the disease severity and GPI-deficiency clone size [5] , a physician can easily decide if an anti-human C5 monoclonal antibody should be used in patients showing severe hemolysis and/or progressive anemia. Two anti-human C5 monoclonal antibody therapies, eculizumab, and ravulizumab were approved for PNH in 2010 and 2019, respectively.…”

“… [3] While fatigue is one of the most common symptoms associated with PNH and directly impairs lifestyle leading to a poor QOL[3], it is not well recognized in previous studies that the fatigue could not depend on the disease activity (lactic acid dehydrogenase (LDH) over or under 1.5 x upper limit of normal) or percentage of glycosylphosphatidylinositol (GPI) -deficient granulocyte. [ 4 , 5 ] Eculizumab is expensive and must be used indefinitely to maintain a sustained effect. Hence, it is not prescribed in cases of severe fatigue with only a mild LDH elevation or anemia; instead these patients undergo ongoing follow-up examinations.…”