Contributions
Abstract: S301
Type: Oral Presentation
Session title: Dilemmas in coagulation and thrombosis
Background
Patients with paroxysmal nocturnal hemoglobinuria (PNH) are at an increased risk of thromboembolism (TE) which may be fatal. Results of a univariate retrospective analysis from the International PNH Registry showed that patients with intravascular hemolysis, defined as lactate dehydrogenase (LDH) ≥ 1.5 × upper limit of normal (ULN; 246 U/L), and ≥ 2 × ULN, high disease activity (HDA) symptoms, and history of TEs and major adverse vascular events (MAVEs) are at significantly greater risk of experiencing TE. Where available, ravulizumab is the current standard of care for PNH, however, its long-term effectiveness in preventing TEs and MAVEs in patients with HDA is unknown.
Aims
To evaluate the long-term effectiveness of ravulizumab at preventing TEs and MAVES in patients with PNH and HDA in a phase 3 study stratified by baseline LDH levels.
Methods
This ongoing phase 3, multicenter, randomized, open-label study (NCT02946463) enrolled adult patients (aged ≥ 18 years) with PNH and HDA (LDH levels ≥ 1.5 × ULN and presence of 1 or more PNH-related symptoms within 3 months of screening) who were complement-inhibitor-naïve. Patients received weight-based dosing of ravulizumab every 8 weeks or eculizumab (900mg every 2 weeks) during the randomized treatment period and continued or switched to ravulizumab during the extension period (5 years). In this post-hoc analysis, patients who received ravulizumab were stratified by baseline LDH levels into two groups: 1.5 – < 3 × ULN (Group A) or ≥ 3 × ULN (Group B). Proportion of patients experiencing MAVE or TE in 2 years prior to enrollment and after receiving ravulizumab during 2 years of the study were compared for each group. TEs included thrombophlebitis/deep vein thrombosis (DVT), renal vein thrombosis, renal arterial thrombosis, mesenteric/visceral vein thrombosis, mesenteric/visceral arterial thrombosis, hepatic/portal vein thrombosis, dermal thrombosis, acute peripheral vascular disease occlusion, cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, and pulmonary embolus. MAVEs include both TEs and non-TEs (amputation [nontraumatic, nondiabetic], myocardial infarction, transient ischemic attack, unstable angina, gangrene [nontraumatic, nondiabetic], and specified if other).
Results
Patients were stratified to Group A (n = 33) or Group B (n = 211), respectively. Patient demographics were comparable between the two groups, with mean (SD) age at first infusion of 48.2 (15.5) years for Group A and 44.9 (15.6) years for Group B. However, more patients in Group A were white compared with Group B (51.5% and 36.5%, respectively). Over the 2 years of study, patients in Group A and Group B underwent 56.7 and 361.2 patient-years of exposure to ravulizumab, respectively. Treatment with ravulizumab resulted in fewer reported MAVEs and TEs compared with the 2 years prior to enrollment in both groups (Figure 1). MAVEs reported during the 2 years of treatment with ravulizumab were all TEs. Only 1 patient (3.0%) in Group A experienced TE, which was classified as a pulmonary embolism event. In Group B, 5 patients (2.4%) experienced TE, including 2 DVT events, and 1 event each of thrombosis, jugular vein thrombosis and peripheral artery thrombosis. Ravulizumab was well-tolerated in all patients for up to 2 years with no new safety signals.
Conclusion
Ravulizumab reduces the risk of thrombosis in patients with PNH and HDA, who are at an increased risk of TE.
Keyword(s): Complement, Paroxysmal nocturnal hemoglobinuria (PNH), Safety, Thrombosis
Abstract: S301
Type: Oral Presentation
Session title: Dilemmas in coagulation and thrombosis
Background
Patients with paroxysmal nocturnal hemoglobinuria (PNH) are at an increased risk of thromboembolism (TE) which may be fatal. Results of a univariate retrospective analysis from the International PNH Registry showed that patients with intravascular hemolysis, defined as lactate dehydrogenase (LDH) ≥ 1.5 × upper limit of normal (ULN; 246 U/L), and ≥ 2 × ULN, high disease activity (HDA) symptoms, and history of TEs and major adverse vascular events (MAVEs) are at significantly greater risk of experiencing TE. Where available, ravulizumab is the current standard of care for PNH, however, its long-term effectiveness in preventing TEs and MAVEs in patients with HDA is unknown.
Aims
To evaluate the long-term effectiveness of ravulizumab at preventing TEs and MAVES in patients with PNH and HDA in a phase 3 study stratified by baseline LDH levels.
Methods
This ongoing phase 3, multicenter, randomized, open-label study (NCT02946463) enrolled adult patients (aged ≥ 18 years) with PNH and HDA (LDH levels ≥ 1.5 × ULN and presence of 1 or more PNH-related symptoms within 3 months of screening) who were complement-inhibitor-naïve. Patients received weight-based dosing of ravulizumab every 8 weeks or eculizumab (900mg every 2 weeks) during the randomized treatment period and continued or switched to ravulizumab during the extension period (5 years). In this post-hoc analysis, patients who received ravulizumab were stratified by baseline LDH levels into two groups: 1.5 – < 3 × ULN (Group A) or ≥ 3 × ULN (Group B). Proportion of patients experiencing MAVE or TE in 2 years prior to enrollment and after receiving ravulizumab during 2 years of the study were compared for each group. TEs included thrombophlebitis/deep vein thrombosis (DVT), renal vein thrombosis, renal arterial thrombosis, mesenteric/visceral vein thrombosis, mesenteric/visceral arterial thrombosis, hepatic/portal vein thrombosis, dermal thrombosis, acute peripheral vascular disease occlusion, cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, and pulmonary embolus. MAVEs include both TEs and non-TEs (amputation [nontraumatic, nondiabetic], myocardial infarction, transient ischemic attack, unstable angina, gangrene [nontraumatic, nondiabetic], and specified if other).
Results
Patients were stratified to Group A (n = 33) or Group B (n = 211), respectively. Patient demographics were comparable between the two groups, with mean (SD) age at first infusion of 48.2 (15.5) years for Group A and 44.9 (15.6) years for Group B. However, more patients in Group A were white compared with Group B (51.5% and 36.5%, respectively). Over the 2 years of study, patients in Group A and Group B underwent 56.7 and 361.2 patient-years of exposure to ravulizumab, respectively. Treatment with ravulizumab resulted in fewer reported MAVEs and TEs compared with the 2 years prior to enrollment in both groups (Figure 1). MAVEs reported during the 2 years of treatment with ravulizumab were all TEs. Only 1 patient (3.0%) in Group A experienced TE, which was classified as a pulmonary embolism event. In Group B, 5 patients (2.4%) experienced TE, including 2 DVT events, and 1 event each of thrombosis, jugular vein thrombosis and peripheral artery thrombosis. Ravulizumab was well-tolerated in all patients for up to 2 years with no new safety signals.
Conclusion
Ravulizumab reduces the risk of thrombosis in patients with PNH and HDA, who are at an increased risk of TE.
Keyword(s): Complement, Paroxysmal nocturnal hemoglobinuria (PNH), Safety, Thrombosis