Avatrombopag treatment response in patients with immune thrombocytopenia: the REAL-AVA 1.0 study.

Background: Thrombopoietin-receptor agonists (TPO-RAs) are used to treat immune thrombocytopenia (ITP), a disorder characterized by prolonged low platelet counts (PCs) that pose a risk of serious bleeding episodes. Avatrombopag (AVA) is the most recently approved TPO-RA for the treatment of chronic ITP. A high proportion of patients responded to AVA in clinical trials, and treatment was well-tolerated; however, limited real-world effectiveness data have been reported to date. Objectives: To describe demographic and clinical characteristics, treatment patterns, and outcomes following the initiation of AVA in patients with ITP in the United States. Design: This is a retrospective study using administrative claims data from the Komodo Healthcare Map (1 February 2017 to 28 February 2022) linked with PC laboratory data. Methods: Patients with ⩾1 diagnosis of ITP, ⩾1 paid prescription for AVA (index date), and ⩾1 month of pharmacy coverage after AVA initiation were selected. Baseline characteristics and follow-up steroid, immunosuppressant, and rescue medication use were described. The percentage of patients achieving clinically meaningful PC thresholds (⩾30 × 109/l) were assessed among patients with ⩾1 PC following AVA initiation and prior to AVA discontinuation/switch (effectiveness subgroup). Results: A total of 205 patients met eligibility criteria and 49% reported TPO-RA use in the prior 6 months. Approximately 70% and 93% of patients did not require use of steroid or immunoglobulin rescue medication during follow-up, respectively. Among patients with concomitant steroid (n = 75) or immunosuppressant (n = 7) use at AVA initiation, 35% and 57% discontinued those treatments, respectively. Of the 21 patients in the effectiveness subgroup, 81% achieved clinically meaningful PC thresholds. Conclusion: A high proportion of evaluable patients with ITP in this real-world study achieved clinically meaningful PCs, without requiring rescue medication during AVA treatment, with many able to discontinue baseline concomitant steroid or immunosuppressant utilization. Despite limited availability of PC data, these results are consistent with results from the AVA pivotal clinical trials.

Additional efficacy analysis of avatrombopag phase III data for the treatment of adults with immune thrombocytopenia.

Avatrombopag is an oral thrombopoietin receptor agonist (TPO-RA) that was approved in the US in 2019 for treatment of chronic immune thrombocytopenia (ITP). This post hoc analysis of the pivotal phase III study (NCT01438840) of avatrombopag in adult patients with ITP evaluated platelet count response to avatrombopag during the core study in different subgroups, and durability of response data in patients who responded to avatrombopag treatment both during the core phase (total population) and during the core and extension phase (total population and by subgroup). Loss of response (LOR [platelet count <30 × 109/L]) was defined as LOR over two consecutive scheduled visits. The response was generally similar between subgroups though a few differences were observed. The durability of response analysis showed that avatrombopag-treated patients maintained their response for 84.5% of time on treatment during the core phase and 83.3% during the core and extension phase; 55.2% of patients in the core phase and 52.3% in the core and extension phase never experienced LOR. We conclude that the initial response to avatrombopag is both stable and durable.

What is the context? Avatrombopag is a medicine that helps the body produce platelet cells, which are necessary for blood clotting.Avatrombopag is used to treat people with chronic immune thrombocytopenia (ITP); these patients have low numbers of platelet cells in their blood, so their blood may not clot efficiently, putting them at risk of uncontrolled bleeding.A phase III clinical study in patients with chronic ITP showed that platelet counts increased for most patients who were treated with avatrombopag; patients who had a platelet count ≥50 × 10⁹/L were considered to have a response to avatrombopag treatment.The present study analyzes data from a phase III clinical study to determine whether there are any characteristics that make a patient more or less likely to have a loss of response (LOR) while taking avatrombopag, whether the initial response to avatrombopag is stable, and how long the response lasts.For this analysis, LOR is defined as platelet count <30 × 10⁹/L for either four consecutive weeks or for two consecutive office visits while taking avatrombopag.What is new? In general, patient characteristics did not influence the likelihood of LOR.Patients who responded maintained their response for most of the time they were taking avatrombopag.Most patients did not experience LOR.What is the impact? The initial response to avatrombopag is stable and long-lasting in patients with chronic ITP.These findings indicate that patients with a variety of background characteristics can experience a durable platelet response with avatrombopag treatment.

Adults with immune thrombocytopenia who switched to avatrombopag following prior treatment with eltrombopag or romiplostim: A multicentre US study.

Patients with immune thrombocytopenia (ITP) may respond to one thrombopoietin receptor agonist (TPO-RA) but not another. Limited data are available describing outcomes in patients who switched from romiplostim or eltrombopag to avatrombopag, a newer oral TPO-RA. We performed a retrospective observational study of adults with ITP who switched from eltrombopag or romiplostim to avatrombopag at four US tertiary ITP referral centres. Forty-four patients were included, with a mean ITP duration of 8.3 years and a median (range) of four prior ITP treatments. On avatrombopag, 41/44 patients (93%) achieved a platelet response (≥50 × 109 /l) and 38/44 patients (86%) achieved a complete response (≥100 × 109 /l). In all patients, the median platelet count on eltrombopag or romiplostim was 45 × 109 /l vs 114 × 109 /l on avatrombopag (p < 0.0001); in patients switched for ineffectiveness of romiplostim/eltrombopag, it was 28 × 109 /l on romiplostim/eltrombopag vs 88 × 109 /l on avatrombopag (p = 0.025). Fifty-seven percent of patients receiving concomitant ITP medications before switching discontinued them after switching, including 63% of patients receiving chronic corticosteroids. In a heavily pretreated chronic ITP population, avatrombopag was effective following therapy with romiplostim or eltrombopag, with high response rates even in patients with inadequate response to a prior TPO-RA.

Efficacy and Safety of Avatrombopag in Patients with Chronic Immune Thrombocytopenia: A Systematic Literature Review and Network Meta-Analysis.

INTRODUCTION: A network meta-analysis (NMA) was performed to assess the efficacy and safety of avatrombopag, relative to eltrombopag, romiplostim, and fostamatinib, for patients with chronic immune thrombocytopenia (ITP) not responding adequately to corticosteroids. METHODS: A systematic search of publication and clinical trial databases was conducted to identify relevant randomized controlled trials (RCTs) and observational studies. Data from eligible studies were extracted and analyzed in a Bayesian framework using relative effect sizes vs placebo. Outcomes included durable platelet response; need for rescue therapy; reduction in use of concomitant ITP medication; incidence of any or World Health Organization (WHO) grade 2-4 bleeding events, and any adverse events. Results were reported as odds ratios or incidence rate ratios (IRR) with 95% credible intervals (CrIs). RESULTS: The NMA included seven phase 3 RCTs. Compared with placebo, avatrombopag was associated with statistically significant improvements in durable platelet response, reduction in use of concomitant ITP medication, and incidence of any bleeding events. Statistically significant differences vs placebo were also observed for durable platelet response and need for rescue therapy (eltrombopag, romiplostim, and fostamatinib); reduction in use of concomitant ITP medication (eltrombopag and romiplostim); incidence of any bleeding events (fostamatinib); and incidence of WHO grade 2-4 bleeding events (romiplostim and fostamatinib). No statistically significant differences were observed for any adverse events. Avatrombopag was associated with a statistically significant lower incidence of any bleeding events vs eltrombopag (IRR 0.38 [95% CrI 0.19, 0.75]) and romiplostim (IRR 0.38 [95% Crl 0.17, 0.86]); no other between-treatment differences were observed. CONCLUSION: In this NMA, avatrombopag significantly increased the chance of achieving durable platelet response and reducing the use of concomitant ITP medication vs placebo, and significantly reduced the incidence of any bleeding events compared with placebo, eltrombopag, and romiplostim. The study aims to help guide clinicians managing patients with chronic ITP and insufficient response to previous treatment.

Cost- Effectiveness of Avatrombopag for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease.

BACKGROUND AND AIM: Thrombocytopenia is common in people with chronic liver disease, who frequently undergo invasive procedures. To minimize the risk of bleeding, prophylactic platelet transfusions have traditionally been used but carry many risks. The aim of this study was to evaluate the cost-effectiveness of avatrombopag compared with platelet transfusion and lusutrombopag as a treatment for thrombocytopenia in adult patients with chronic liver disease scheduled to undergo a medical procedure. METHODS: A decision-tree model was developed from a US payer perspective to capture acute events observed in phase 3 global randomized controlled clinical trials and, to support exploratory analyses, potential longer-term complications resulting from a major bleed or thromboembolic event. Treatment costs were taken from publicly available data sources. The interventions were evaluated in the overall trial populations and in subpopulations with higher and lower baseline platelet counts. Results were presented as incremental cost per platelet transfusion avoided. One-way and probabilistic sensitivity analyses were conducted. RESULTS: In the overall population, avatrombopag reduced the need for platelet transfusions and produced cost-savings compared with platelet transfusion (80% fewer prophylactic platelet transfusions, $4250 lower costs) and lusutrombopag (42% fewer prophylactic platelet transfusions, $5819 lower costs). Similar results were seen in both the higher and lower platelet count subpopulations. The one-way and probabilistic sensitivity analyses found that the use of avatrombopag is cost-saving with the incremental cost-effectiveness ratio in quadrant IV (decreased costs, prophylactic platelet transfusions avoided). CONCLUSION: The use of avatrombopag is expected to be cost-saving while reducing the need for prophylactic platelet transfusions compared with platelet transfusion and lusutrombopag.

Cost estimate of platelet transfusion in the United States for patients with chronic liver disease and associated thrombocytopenia undergoing elective procedures.

AIMS: This study aimed to estimate the cost of platelet transfusion in patients with chronic liver disease (CLD)-associated thrombocytopenia undergoing an elective procedure in the United States. MATERIALS AND METHODS: The study was conducted in two parts: development of a conceptual framework identifying direct, indirect and intangible costs of platelet transfusion, followed by the estimation of the total cost of platelet transfusion in patients with CLD-associated thrombocytopenia before an elective procedure in the United States using the conceptual framework and cost data obtained from a literature search. The cost of the entire care required to raise a patient's platelet count before the procedure was considered. RESULTS: The final conceptual framework included the costs of generating the supply of platelets, the platelet transfusion itself, adverse events associated with platelet transfusion and refractoriness to platelet transfusion. When costs were accounted for in all the framework cost categories, the total direct cost of a platelet transfusion in a patient with CLD and associated thrombocytopenia was estimated to be in the range of $5258 to $13,117 (2017 US dollars) in the United States. The largest portion of costs was incurred by the transfusion event itself ($3723 to $4436) and the cost of refractoriness ($874 to $7578), which included the opportunity cost of a delayed procedure and subsequent platelet transfusions with human leukocyte antigen-matched platelets. LIMITATIONS AND CONCLUSIONS: Although we were unable to include all cost components identified in the conceptual framework in our total cost estimate, thus likely underestimating the true total cost, and despite the data gaps and challenges limiting our estimate of the full cost of a platelet transfusion in patients with CLD-associated thrombocytopenia undergoing an elective procedure in the United States, this study outlines a comprehensive conceptual framework for estimating the cost elements of a platelet transfusion in these patients.

The 4'-O-benzylated doxorubicin analog WP744 overcomes resistance mediated by P-glycoprotein, multidrug resistance protein and breast cancer resistance protein in cell lines and acute myeloid leukemia cells.

BACKGROUND: The synthetic 4'-O-benzylated doxorubicin analog WP744 was designed to abrogate transport by the multidrug resistance (MDR)-associated ATP-binding cassette (ABC) proteins P-glycoprotein (Pgp) and multidrug resistance protein (MRP-1). We compared its uptake and cytotoxicity with those of doxorubicin and daunorubicin in cell lines overexpressing Pgp, MRP-1 or breast cancer resistance protein (BCRP) and in acute myeloid leukemia (AML) cells. METHODS: Cellular uptake was studied by flow cytometry and cytotoxicity in 96-h 96-well cultures in cell lines overexpressing Pgp, MRP-1 or wild type (BCRP(R482)) or mutant (BCRP(R482T), BCRP(R482G)) BCRP and in pre-treatment AML marrow cells. RESULTS: Uptake and cytotoxicity of WP744 were consistently greater than those of doxorubicin and daunorubicin at equimolar concentrations in all cell lines studied and in AML cells. CONCLUSION: WP744 overcomes transport by Pgp, MRP-1 and BCRP in cell lines and AML cells and is a promising agent for clinical development in AML and other malignancies with broad-spectrum multidrug resistance.