Lusutrombopag for the Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Invasive Procedures (L‐PLUS 2)

Abstract

Thrombocytopenia may be associated with increased bleeding risk impacting timing and outcome of invasive procedures in patients with chronic liver disease (CLD). Lusutrombopag, a small‐molecule, thrombopoietin (TPO) receptor agonist, was evaluated as a treatment to raise platelet counts (PCs) in patients with thrombocytopenia and CLD undergoing invasive procedures. L‐PLUS 2 was a global, phase 3, randomized, double‐blind, placebo‐controlled study. Adults with CLD and baseline PCs < 50 × 109/L were randomized to receive once‐daily lusutrombopag 3 mg or placebo ≤ 7 days before an invasive procedure scheduled 2‐7 days after the last dose. The primary endpoint was avoidance of preprocedure platelet transfusion and avoidance of rescue therapy for bleeding. A key secondary endpoint was number of days PCs were ≥ 50 × 109/L throughout the study. Safety analysis was performed on patients who received at least one dose of study drug. This study occurred between June 15, 2015, and April 19, 2017, with a total of 215 randomized patients (lusutrombopag, 108; placebo, 107); 64.8% (70/108) of patients in the lusutrombopag group versus 29.0% (31/107) in the placebo group met the primary endpoint (P < 0.0001; difference of proportion 95% confidence interval [CI], 36.7 [24.9, 48.5]). The median duration of PCs ≥ 50 × 109/L was 19.2 days with lusutrombopag (without platelet transfusion) compared with 0.0 in the placebo group (with platelet transfusion) (P = 0.0001). Most adverse events were mild or moderate in severity, and rates were similar in the lusutrombopag and placebo groups (47.7% and 48.6%, respectively). Conclusion: Lusutrombopag was superior to placebo for reducing the need for platelet transfusions and achieved durable PC response in patients with thrombocytopenia and CLD undergoing invasive procedures, with a safety profile similar to placebo.

Safety and effectiveness of lusutrombopag in Japanese chronic liver disease patients with thrombocytopenia undergoing invasive procedures: Interim results of a postmarketing surveillance

“…All 21 patients who received a second or third round of treatment with lusutrombopag avoided platelet transfusion before their invasive procedure. Contrary to the protocols of the clinical trials of lusutrombopag, 26 patients did not receive platelet transfusion, despite having a platelet count <50 × 10 9 /L before the procedure. This was based on a decision by their physician, as per routine clinical practice.…”

“…In the lusutrombopag treatment group of the phase 3 L‐PLUS 1 trial, the median platelet count increased to ≥50 × 10 9 /L after 5 days, and the mean time to reach maximum platelet count was 13.4 days . The follow‐up L‐PLUS 2 study confirmed the efficacy of lusutrombopag, with the median platelet count increasing to ≥50 × 10 9 /L after 6 days, and maximum platelet count being reached around day 12 …”

“…In this surveillance, only one patient with a baseline platelet count ≥50 × 10 9 /L experienced a thrombus‐related AE. Furthermore, 10.9% of patients in our surveillance population had a current thrombosis/thromboembolism or a history of thrombosis/thromboembolism, although such patients were excluded in the prior clinical trials . Of patients who had a current thrombosis/thromboembolism or a history of thrombosis/thromboembolism, only one developed portal vein thrombosis (aggravation of portal vein thrombosis).…”

“…Data from multicenter, randomized, double‐blind, placebo‐controlled, clinical trials showed that lusutrombopag significantly reduced the proportion of patients with CLD who required platelet transfusion before invasive procedures ( P < 0.01 vs. placebo) . In the lusutrombopag treatment group of the phase 3 L‐PLUS 1 trial, the median platelet count increased to ≥50 × 10 9 /L after 5 days, and the mean time to reach maximum platelet count was 13.4 days .…”

“…Lusutrombopag was approved in Japan (2015) and the USA (2018) for the treatment of thrombocytopenia in adult patients with CLD who are scheduled to undergo a procedure . In the European Union, the approved indication (2019) is the treatment of severe thrombocytopenia in adult patients with CLD undergoing invasive procedures …”