Treatment Of Thrombocytopenia In Patients Research Articles

Impurity assessment, development and validation of an RP-HPLC method for the determination of eleven potential impurities of eltrombopag precursor

Eltrombopag is an oral non-peptide thrombopoietin receptor (TPO-R) agonist indicated for the treatment of thrombocytopenia in patients with persistent or chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura, ITP) or chronic hepatitis C infection and the treatment of severe aplastic anemia. The purpose of this research was to assess the possible impurities that may carry over to eltrombopag from its precursor Eltro-1 (3′-amino-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid) and to develop a specific analytical method for the determination of these impurities. Eltro-1 samples synthesized by two different synthesis routes were investigated during the evaluation and method development studies. Besides the expected process-related impurities (Eltro-1A – Eltro‐1J), e.g., starting materials, intermediates, and/or compounds formed from their further reactions, an unknown impurity detected above 0.10% was identified by LC-MS, synthesized and fully characterized by NMR, MS and FTIR (Eltro‐1K). Accordingly, an HPLC-RP method for the determination of eleven impurities (Eltro-1A – Eltro‐1K) in Eltro-1 was developed and validated according to ICH Q2. The control limits for impurities in Eltro-1 were set at ≤ 0.15% for Eltro-1A – Eltro‐1J and ≤ 1.0% for Eltro‐1K based on fate, spike-purge and carryover studies and in accordance with the ICH M7 classification for impurities in drug substance. Eltro-1 and eleven impurities at the specification limit were separated from each other and the diluent peaks with sufficient resolution without interference. Separation was performed on a Waters XBridge C18 column (150 × 4.6 mm, 3.5 μm) at 40 °C with a 10 µL injection volume at a detection wavelength of 220 nm and 15 °C sample temperature. The gradient elution is performed at a flow rate of 1.0 mL/min for 40 min with mobile phase A (0.1% orthophosphoric acid in water) and B (acetonitrile) according to the following program: Time (min) / Acetonitrile (%): 0/0, 35/70, 36/0, 40/0. Test and standard solutions were prepared at a concentration of 1.0 mg/mL and 1.0 µg/mL, respectively, using a mixture of mobile phase A and acetonitrile (75/25) as diluent. This is the first specific, selective, sensitive, linear, precise, accurate, and robust HPLC method for the determination of Eltro-1A – Eltro‐1K in Eltro-1, which showed no significant degradation under thermal stress, photostability (UV and VIS), and standard accelerated and long-term stability conditions.

Avatrombopag in Combination with Immunosuppressive Therapy for Hepatitis-Associated Aplastic Anemia

Hepatitis-associated aplastic anemia (HAAA) is an uncommon but distinct variant of aplastic anemia (AA), in which an episode of seronegative acute hepatitis precedes the onset of pancytopenia. Previous studies indicated that about only 20% of HAAA patients can get their hematologic partially restored after 3 months treatment with standard immunosuppressive therapy (IST). Recent studies have shown that adding thrombopoietin receptor agonist (TPO-RA) eltrombopag to standard IST can lead to a more, faster, and better hematologic responses. Nevertheless, eltrombopag is often associated with hepatic adverse effects, i.e., elevated transaminases and bilirubin, which maybe limit its use in patients with HAAA who have just experienced severe liver damage. Avatrombopag is also a TPO-RA, which was approved for the treatment of thrombocytopenia in patients with chronic liver disease (CLD) and patients with chronic immune thrombocytopenia (ITP) by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). The pre-clinical studies indicated that avatrombopag can promote the hematopoietic and megakaryocyte progenitor cells proliferation and differentiation by the dose-dependence. These in vitro effects are similar to those of other TPO-RAs, including Eltrombopag. Theoretically, on the basis of adequate IST, avatrombopag can also promote hematopoietic recovery in patients with aplastic anemia just as Eltrombopag works. If this is true, then avatrombopag should be particularly suitable for HAAA due to its favorable hepatic adverse effect profile. Nevertheless, avatrombopag added to standard IST as first-line treatment for aplastic anemia could increase the rapidity and strength of hematologic response is still unknown. Herein, we retrospectively reviewed 8 consecutive cases of patients with hepatitis-associated aplastic anemia who were treated with avatrombopag plus IST regimen. From September 2021 to December 2022, eight patients with hepatitis-associated aplastic anemia treated with avatrombopag in combination with standard IST were enrolled in this study. Among them, seven patients were diagnosed as VSAA and one SAA. The median age was 17 (9-20) years old and the median absolute neutrophil count was 0.09 (0.02-0.39) ×10 9/L. The median time from onset of hepatitis to hematopoietic failure was 2 (0.5-5.5) months, and at the time of beginning of IST all the eight patients had their liver biochemical testing returns to normal. The karyocytes were normal in all patients. One patient presented positive PNH clone at the diagnosis of HAAA, with PNH clone size of 4.7%. Avatrombopag was incorporated into day 1 of standard immunosuppressive therapy with p-ATG and cyclosporine for all the eight HAAA patients. The dose of avatrombopag was 40 mg/d at least 6 months. Dosage adjusting of avatrombopag was according to patient's platelet counts and adverse events. Encouragingly, four of the eight patients (50.0%) achieved hematologic response (HR) with two (20.0%) getting complete response (CR) at 3 months after IST and avatrombopag. Between 3 and 6 months after IST, the other two patient entered their hematologic responded. Then, six of eight (75.0%) patients got HR at 6 months, including 3 CR, 2 good partial hematologic response (GPR), and 1 partial response (PR). Unfortunately, one patient who was diagnosed as very severe HAAA, was without getting hematologic response and died at 118 days after treatment due to gastrointestinal infection. We evaluate the side effects of avatrombopag and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. No hepatic adverse events were observed in all the eight patients, that indicated avatrombopag may not increase the hepatic burden and is safe for HAAA. The median follow-up time was 371(118-665) days. Except for one patient who died within 6 months, six cases achieved hematologic response, with 4 CR and 2 GPR. There is no clonal evolution, i.e., MDS, AML, and PNH, was observed. In conclusion, avatrombopag may be used as a safe and effective TPO-RA, added to IST for the treatment of hepatitis-associated aplastic anemia, which maybe improve the efficacy and the strength of hematologic response in HAAA.

A Single Institutional Experience Using Avatrombopag to Manage Severe and Refractory Treatment Related Thrombocytopenia in Solid Tumor and Hematologic Malignancy Patients

Background:Cancer therapy induced thrombocytopenia (CTIT) is a common complication of systemic treatment for cancer, both in solid tumors and hematologic malignancies. Some patients had persistent severe thrombocytopenia that failed to respond to thrombopoietin receptor (TPO-R) agonists such as eltrombopag, hetrombopag or recombinant human thrombopoietin (rhTPO). Avatrombopag, a second generation TPO-R agonist, has been approved for the treatment of thrombocytopenia in patients with chronic liver disease scheduled to undergo invasive procedures and primary chronic immune thrombocytopenia (ITP). Recent studies testified the effect of avatrombopag in ITP patients not responding to romiplostim and/or eltrombopag. In this study, we share the experience of the off-label use of avatrombopag in the management of CTIT with grade 4 thrombocytopenia, and assessed the efficacy as well as safety of the drug. Methods: This study retrospectively evaluated patients with severe and refractoryCTIT treated at Qilu Hospital of Shandong University between 2021-2023 who received avatrombopag. Severe and refractoryCTIT met all of the following conditions: platelet count <25 × 10 9/L as grade 4 thrombocytopenia; previously unresponsive to rhTPO or TPO-R agonists other than avatrombopag. Patients' baseline characteristics were summarized in Table 1, including tumor types, dosing and duration of avatrombopag administration, and response at 4 weeks. The primary outcome was achievement of a response measured through (1) the proportion of patients with platelet count ≥50×10 9/L and increased by ≥ 100% above baseline at 4 weeks after medication and throughout the medication, (2) the time from avatrombopag initiation to first achievement of platelet count ≥50 × 10 9/L and increased by ≥ 100%, (3) the median maximum platelet count throughout avatrombopag administration. Safety was assessed by monitoring treatment emergent adverse events such as venous thromboembolism (VTE) development during treatment. Results: A total of 28 patients were included with mean age 59 years (range 27 to 78). The median duration of severe CTIT pre-avatrombopag was 4.5 weeks (range 2 to 96). The overall median time on avatrombopag support was 13 weeks (range 0.7 to 148). The median maximum dose was 50 mg QD (range 20 mg QD to 60 mg QD). Treatment with avatrombopag led to significantly higher median platelet count compared with baseline (137.5 × 10 9/L vs. 12 × 10 9/L; p < 0.0001) (Figure 1), and the response rate was 86%. The median time to response was 3.5 weeks (range 1 to 19). Of the total 24 solid tumor patients, 22 (92%) achieved a platelet response. Fifteen of the 28 patients (54%) met the response criteria at 4 weeks. With respect to disease subgroup, patients with breast cancer on avatrombopag had higher platelet count compared to ovarian cancer subgroup (p = 0.048), while the duration of severe CTIT pre-avatrombopag in the two groups was similar. At 4 weeks, the response group showed an increased tendency in the median number of bone marrow megakaryocytes in smear at baseline than the non-response group (9.5 vs. 2; p = 0.069). In assessing incidence of adverse events, 1 patient were noted to be on anticoagulation for a documented VTE at six days post-avatrombopag discontinuation. Conclusions: Avatrombopag was effective and safe in patients with severe and refractory CTIT. Future, prospective study is needed to investigate the efficacy of TPO-R agonists in patients with severe and refractory CTIT.

Safety and effectiveness of lusutrombopag in patients who have chronic liver disease with thrombocytopenia and undergoing invasive procedures: Real-world post-marketing surveillance in Japan.

Lustrombopag has been approved for the treatment of thrombocytopenia in patients with chronic liver diseases (CLD) who are scheduled to undergo an invasive procedure. Here we report the final results of a post-marketing surveillance assessing the safety and effectiveness of lusutrombopag in Japan. This multicenter, prospective, real-world surveillance collected data from case report forms between October 2016 and May 2021. The observation period was 2 months after the first day of lusutrombopag treatment. Safety and effectiveness (proportion of patients avoiding preoperative platelet transfusion and responders who achieved platelet count increase from baseline) were assessed. The safety analysis set included 1033 (100.0%), 130 (12.6%), and 14 (1.4%) patients received ≥1, ≥2, and ≥3 treatment cycle(s), and 482 (48.9%), 457 (46.3%), and 43 (4.4%) patients were Child-Pugh (CP) class A, B, and C, respectively. The most common serious adverse drug reactions (ADRs) were portal vein thrombosis (PVT), pancytopenia, and white blood cell count decreased, reported in 14 (1.36%), 3 (0.29%), and 2 (0.19%) patients, respectively. The incidence of ADRs was not higher in patients with CP class C or those undergoing retreatment cycles compared with other CP classes or the first treatment cycle, respectively. During the observation period of the first treatment cycle, 94.7% (889/939) of patients avoided preoperative platelet transfusion and 82.8% (741/895) of the patients met the responder criteria. This surveillance further supports the safety and effectiveness of lusutrombopag in a broad range of patients with CLD undergoing planned invasive procedures. This article is protected by copyright. All rights reserved.

Avatrombopag for the Treatment of Adult Patients with Chronic Immune Thrombocytopenia (cITP): Focus on Patient Selection and Perspectives.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a reduced number of circulating platelets due to immune-mediated destruction and decreased platelet production in the bone marrow. Thrombopoietin receptor agonists (TPO-RAs) are highly effective and widely used in the treatment of patients with steroid treatment failure or dependency. Avatrombopag represents a new supplement to the TPO-RAs family. It was originally approved for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo an invasive procedure. However, labeled indications for avatrombopag have been relatively recently expanded to include treatment of chronic ITP in adults with insufficient response to the previous treatments. In this article, we provide an overview of pharmacodynamics and pharmacokinetics of avatrombopag as well as results of the clinical trials related to safety and efficacy of avatrombopag with a perspective on current clinical use. Available data so far suggests that avatrombopag can be effectively used in ITP patients and has a favorable safety profile. Though further studies are needed to affirm the efficacy and safety, avatrombopag has the potential to become a TPO agonist of choice for many patients with ITP.

Prevention and treatment of thrombocytopenia in dengue patients: a narrative review

Background and Aims: Dengue fever is a major health concern, especially in developed countries, because it often leads to undifferentiated febrile illness such as dengue haemorrhagic fever and dengue shock syndrome or expanded dengue syndrome, which are often reported with thrombocytopenia (TCP) and turn out to be hazardous to life. The WHO reported 23 million dengue cases and 82,000 deaths between 1955-2012. 2019 was a hallmark for the dengue epidemic from Latin America to South Asia. Due to unavailability of a dengue vaccine and antiviral therapies, additional medical attention and effort are required to treat thrombocytopenia (TCP). These approaches include thrombopoietin receptor agonists such as Oprelvekin, Eltrombopag, Romiplostim and corticosteroids, and platelet transfusion and intravenous immunoglobulin transfusions. The outcomes might not be achievable unless the proper assessment is carried out to evaluate these approaches to treat TCP in dengue patients. This narrative review aims to summarize the findings regarding the treatment of TCP in patients affected by the dengue virus. Methods: A total of 55 published articles, including clinical trials, descriptive studies and case studies were reviewed regarding treatment of TCP in the context of dengue infection. The electronic databases PubMed, Cochrane Library, Google Scholar and Science Direct were searched for articles published from January 1990 to June 2020. Conclusions: We concluded that dengue fever is becoming a global health concern. Premedical attention like the use of corticosteroids, Thrombopoietin receptor agonist (TPO-R) agonists and transfusions like (PT & IVIG) are not fully assessed by double-blind randomized clinical trials and cost-effectiveness analysis. However, as compared to other treatment approaches, the use of TPO-R agonists seems to be more suitable in TCP management due to its easy access and compliance.

Treatment algorithm for thrombocytopenia in patients with chronic liver disease undergoing planned invasive procedures.

Thrombocytopenia is highly prevalent in patients with chronic liver disease (CLD) and these patients often require invasive procedures that carry a risk of bleeding. To prevent bleeding, guidelines recommend increasing platelet counts in patients with CLD who have thrombocytopenia and are planned to undergo invasive procedures. There are currently two options to increase platelet counts in patients in this setting: platelet transfusion or thrombopoietin receptor agonists (TPORAs). Several treatment algorithms have been developed in the US to help physicians choose the best course of treatment for each patient; however, to date, no such algorithm has been proposed in other countries, where the choice of treatment has been based on each physician's judgment and experience. Here, we discuss the pathogenesis and treatment of thrombocytopenia in patients with CLD, we review and present current evidence of the efficacy of TPORAs for the treatment of thrombocytopenia in patients with CLD, and we present our expert opinion on a Japanese treatment algorithm for thrombocytopenia in patients with CLD who are planned to undergo invasive procedures. This algorithm aims to provide guidance for optimal decision making in the selection of TPORA therapy or platelet transfusion based on the latest evidence and according to actual clinical practice.

Implementing pre-procedural thrombopoietin receptor agonists in cirrhotic patients with severe thrombocytopenia: Indiscriminate, selective or unneeded?

Recent studies promote thrombopoietin-receptor agonists (TRAs), instead of platelet transfusions, before elective invasive procedures in patients with cirrhosis and platelet count below 50 × 109/L [ 1 Afdhal N.H. Giannini E.G. Tayyab G. et al. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med. 2012; 367: 716-724 Crossref PubMed Scopus (214) Google Scholar , 2 Hidaka H. Kurosaki M. Tanaka H. et al. Lusutrombopag reduces need for platelet transfusion in patients with thrombocytopenia undergoing invasive procedures. Clin Gastroenterol Hepatol. 2019; 17: 1192-1200 Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar , 3 Tateishi R. Seike M. Kudo M. et al. A randomized controlled trial of lusutrombopag in Japanese patients with chronic liver disease undergoing radiofrequency ablation. Jpn J Gastroenterol. 2019; 54: 171-181 Crossref Scopus (53) Google Scholar , 4 Peck-Radosavljevic M. Simon K. Iacobellis A. et al. Lusutrombopag for the treatment of thrombocytopenia in patients with chronic liver disease undergoing invasive procedures (L-PLUS 2). Hepatology. 2019; 70: 1336-1348 Crossref PubMed Scopus (75) Google Scholar , 5 Terrault N. Chen Y.C. Izumi N. et al. Avatrombopag before procedures reduces need for platelet transfusion in patients with chronic liver disease and thrombocytopenia. Gastroenterology. 2018; 155: 705-718 Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar – [6] Terrault N.A. Hassanein T. Howell C.D. et al. Phase II study of avatrombopag in thrombocytopenic patients with cirrhosis undergoing an elective procedure. J Hepatol. 2014; 61: 1253-1259 Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar to prevent procedure-related bleeding. In the current issue of Digestive and Liver Disease the systematic review and meta-analysis by Rose and colleagues [ [7] Rose P.D. Au M. Woodman R.J. et al. Pre-procedural use of thrombopoietin-receptor agonists in cirrhosis and severe thrombocytopenia: a systematic review and meta-analysis. Dig Liver Dis. 2021; 53: 1396-1403 Abstract Full Text Full Text PDF Scopus (2) Google Scholar ] confirms that TRAs significantly decrease the amount of the supposed required platelet transfusions. At variance with platelet transfusions, which have a slight and short-term effect on the platelet count, second generation TRAs more often achieve a predictable and persistent increase of the platelet count above the conventional threshold of 50 × 109/L, thus allegedly providing higher protection against peri‑procedural and delayed bleeding. This benefit appears to occur without increasing the thrombotic risk as compared to placebo, and the risks related to platelet transfusion, as plasma volume expansion, transfusion reactions, infection, alloimmunization and refractoriness after repeated transfusions, are avoided. Pre-procedural use of thrombopoietin-receptor agonists in cirrhosis and severe thrombocytopenia: A systematic review and meta-analysisDigestive and Liver DiseaseVol. 53Issue 11PreviewSevere thrombocytopenia in cirrhosis can preclude invasive procedures. Platelet transfusion is recommended if platelet count pre-procedure is potential alternative to platelet transfusion is thrombopoietin-receptor (TPO) agonists. Full-Text PDF

Development and validation of a novel reporter gene assay for determination of recombinant human thrombopoietin

Recombinant human thrombopoietin (rhTPO) was approved by the National Medical Products Administration in 2010 for the treatment of thrombocytopenia in patients with immune thrombocytopenic purpura and chemotherapy-induced thrombocytopenia. Nevertheless, no method for determining rhTPO bioactivity has been recorded in different national/regional pharmacopoeia. Novel methods for lot release and stability testing are needed that are simpler, quicker, and more accurate. Here, we developed a novel reporter gene assay (RGA) for rhTPO bioassay with Ba/F3 cell lines that stably expressed human TPO receptor and luciferase reporter driven by sis-inducible element, gamma response region, and gamma-interferon activated sequence. During careful optimization, the RGA method demonstrated high performance characteristics. According to the International Council for Harmonization Q2 (R1) guidelines and the Chinese Pharmacopoeia 2020 edition, the validation results demonstrated that this method is highly time-saving, sensitive, and robust for research, development, manufacture, and quality control of rhTPO.

Platelet Response to Lusutrombopag, a Thrombopoietin Receptor Agonist, in Patients with Chronic Liver Disease and Thrombocytopenia Undergoing Non-Emergency Invasive Procedures: Results from a Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

Thrombocytopenia is a common complication of chronic liver disease (CLD), which may be caused by multiple factors including decreased production of thrombopoietin (TPO). The presence of thrombocytopenia may complicate the conduct of routine invasive procedures that are commonly performed in CLD patients, leading to delayed or cancelled procedures. Lusutrombopag (formerly S-888711) is an orally available, small molecule agonist of human TPO receptor. Here we report the platelet response data from a confirmatory global phase 3, randomized, double-blind, placebo-controlled study (L-PLUS 2 study) evaluating lusutrombopag for the treatment of thrombocytopenia in patients with CLD who were undergoing non-emergency invasive procedures.Key eligibility criteria included 18 years of age or older, platelet count < 50 × 109/L at baseline, Child-Pugh Class A or Class B, and expecting to undergo a non-emergency invasive procedure. Patients with existing or history of portal vein thrombosis (PVT), or with past or present thrombosis or prothrombotic conditions were excluded. Patients were randomized 1:1 to receive oral lusutrombopag 3 mg once daily or placebo for up to 7 days. Stopping criteria based upon platelet count measurement on days 5, 6 and 7 were used to prevent platelet overshoot. Invasive procedures were performed between Day 9 and Day 14. Platelet transfusion was mandated by the study protocol if a patient's platelet count prior to the invasive procedure was < 50×109/L. The primary efficacy endpoint was proportion of patients who require no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding from randomization to 7 days after the primary procedure. Safety assessment included adverse events, physical exams, laboratory tests and imaging for detection of PVT.A total of 215 patients were randomized, constituting the ITT population (lusutrombopag 108, placebo 107). Baseline patient characteristics were similar between the two treatment groups. The most common invasive procedures included endoscopic variceal ligation (28%), endoscopy with or without polypectomy/biopsy (27%), dental extraction (11%), and transarterial chemoembolization (9%). The study met its primary efficacy endpoint: 64.8% of patients in lusutrombopag group required no platelet transfusion prior to their procedures and no rescue therapy for bleeding up to 7 day after the procedure, compared to 29.0% of patients in the placebo group (p<0.0001). The proportion of patients who met the definition of platelet responder (platelet count ≥ 50×109/L and an increase from baseline of ≥ 20×109/L at least once during the study) was 64.8% in lusutrombopag group and 13.1% in placebo group (p<0.0001). Figure 1 shows the median platelet count over the study period for both treatment groups. Among patients in the lusutrombopag group who did not receive platelet transfusion, the mean peak platelet count was 86.9×109/L (mean increase from baseline 47.1×109/L) which occurred on average around Day 12, and the median duration of platelet count maintained at ≥ 50×109/L was 19 days. Treatment-emergent adverse events (TEAEs) were reported for 47.7% of patients in lusutrombopag group and 48.6% in placebo group, with serious TEAEs at 6.5% in each treatment group. Three PVT events were observed, 1 in lusutrombopag group and 2 in placebo group; all were incomplete occlusion considered not clinically significant and all events resolved with therapy. Bleeding-related TEAEs occurred in 3 patients of lusutrombopag group and 6 patients in placebo group.In conclusion, oral lusutrombopag 3 mg once daily demonstrated superiority over placebo as treatment for thrombocytopenia in patients with CLD undergoing invasive procedures in this global phase 3 study, meeting all pre-specified primary and secondary endpoints. Lusutrombopag was well tolerated, with a safety profile similar to that of placebo. [Display omitted] DisclosuresAfdhal:Shionogi: Consultancy; Merck: Consultancy; Ligand: Consultancy; Jansen: Consultancy; Gilead: Consultancy; Echosens: Consultancy; Spring Bank Pharmaceuticals: Employment, Equity Ownership; Allurion: Equity Ownership; TRIO Healthcare: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Duggal:Shionogi: Consultancy. Ochiai:Shionogi: Employment. Motomiya:Shionogi: Employment. Kano:Shionogi: Employment. Nagata:Shionogi: Employment. Peck-Radosavljevic:Shionogi: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Jansen: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Takeda: Research Funding.

Thrombocytopenia and Hemostatic Changes in Acute and Chronic Liver Disease: Pathophysiology, Clinical and Laboratory Features, and Management.

Thrombocytopenia, defined as a platelet count <150,000/μL, is the most common complication of advanced liver disease or cirrhosis with an incidence of up to 75%. A decrease in platelet count can be the first presenting sign and tends to be proportionally related to the severity of hepatic failure. The pathophysiology of thrombocytopenia in liver disease is multifactorial, including (i) splenomegaly and subsequently increased splenic sequestration of circulating platelets, (ii) reduced hepatic synthesis of thrombopoietin with missing stimulation both of megakaryocytopoiesis and thrombocytopoiesis, resulting in diminished platelet production and release from the bone marrow, and (iii) increased platelet destruction or consumption. Among these pathologies, the decrease in thrombopoietin synthesis has been identified as a central mechanism. Two newly licensed oral thrombopoietin mimetics/receptor agonists, avatrombopag and lusutrombopag, are now available for targeted treatment of thrombocytopenia in patients with advanced liver disease, who are undergoing invasive procedures. This review summarizes recent advances in the understanding of defective but at low level rebalanced hemostasis in stable cirrhosis, discusses clinical consequences and persistent controversial issues related to the inherent bleeding risk, and is focused on a risk-adapted management of thrombocytopenia in patients with chronic liver disease, including a restrictive transfusion regimen.

A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Avatrombopag for the Treatment of Chemotherapy-Induced Thrombocytopenia in Patients with Solid Tumors

Background: Chemotherapy-induced thrombocytopenia (CIT) is a common complication in cancer patients receiving myelosuppressive chemotherapy. Not only can it increase the risk of bleeding, but it also complicates cancer treatment due to chemotherapy delays, dose reductions, and discontinuation, potentially resulting in sub-optimal treatment outcomes. There are currently no FDA approved medications available to manage CIT in the US and Europe. While platelet transfusions are used to rescue patients with very low platelet levels, they are associated with risks of viral and bacterial infections. Avatrombopag is an orally administered thrombopoietin (TPO) receptor agonist that mimics the biologic effects of TPO, resulting in increased platelet production. Avatrombopag is approved for the treatment of thrombocytopenia in patients with chronic liver disease (CLD) scheduled to undergo a procedure, and in adults with chronic immune thrombocytopenia (ITP) that have had an insufficient response to a prior therapy. Pre-clinical data as well as clinical data in patients with CLD and ITP suggest that Avatrombopag is a promising candidate for treatment of thrombocytopenia of diverse etiologies, including CIT. Study design and method: This is a phase 3 randomized, double-blind, placebo-controlled, multi-national (United States, Russia, Ukraine, Poland, China, Serbia, Hungary), study evaluating the efficacy and safety of oral Avatrombopag for the treatment of CIT in 120 adult patients with NSCLC, SCLC, bladder, or ovarian cancer (NCT03471078). To be eligible for the study, patients must have experienced severe thrombocytopenia (platelet counts (PC) &amp;lt;50x109/L) during their current chemotherapy regimen (the qualifying cycle defined as "cycle X"), , and receiving a 21- or 28-day chemotherapy regimen including one or more of the following agents/class of agents: gemcitabine, 5-FU, carbo- or cisplatin, anthracyclines, or alkylating agents. Main exclusion criteria include history of chronic platelet or bleeding disorders, thrombocytopenia due to an etiology other than CIT, &amp;gt;2 prior lines of myelosuppressive chemotherapy, prior history of CIT (PC &amp;lt;75 x109/L) in the previous 6 mo , history of hematologic malignancies, known clinically significant acute or active bleeding within 7 days of screening andrecent history of significant cardiovascular disease. Eligible patients will be randomized in a 2:1 ratio to receive either 60 mg Avatrombopag or placebo once daily for 5 days prior to and for 5 days immediately after the subsequent chemotherapy dose (cycle X+1). Cycle X+2 is an observational period with no study drug administered. The primary endpoint is the proportion of patients not requiring a platelet transfusion, a chemotherapy dose reduction by ≥15% ordelay by ≥4 days due to thrombocytopenia. Secondary endpoints include duration of platelet count &amp;lt;50x109/L after Avatrombopag treatment and through chemotherapy treatment cycle X+2, change in platelet count from baseline (nadir) to cycle X+1 (nadir), proportion of patients who do not have clinically relevant bleeding after Avatrombopag treatment and through chemotherapy treatment cycle X+2, proportion of patients who do not receive a platelet transfusion after treatment with Avatrombopag and through chemotherapy treatment cycle X+2 and incidence of adverse events. The treatment effect will be tested between Avatrombopag and placebo using the Cochran-Mantel-Haenszel test, adjusting for number of eligible chemotherapy agents (1, or ≥2). The study will consist of three periods: the double-blind treatment period and observational period of appr 8 to 9 weeks, an optional open label extension period for cycle X+3 (which may continue until the patients' current chemotherapy regimen ends), and a long-term follow-up period of up to 5 years. Summary: The study aims to evaluate the efficacy of Avatrombopag, an orally administered thrombopoietic agent, in increasing platelet counts to avoid platelet transfusions, chemotherapy dose delays and dose reductions in patients with solid tumors and severe CIT. This study has recently concluded enrollment as of June 2020. Disclosures Tian: Dova Pharmaceuticals: Current Employment. Jamieson:Dova Pharmaceuticals: Current Employment.

A Molecular-Based Response Prediction Model to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndrome and Severe Thrombocytopenia

A Molecular-Based Response Prediction Model to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndrome and Severe Thrombocytopenia

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

Background and AimThrombocytopenia 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.MethodsA 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.ResultsIn 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).ConclusionThe use of avatrombopag is expected to be cost-saving while reducing the need for prophylactic platelet transfusions compared with platelet transfusion and lusutrombopag.

Lusutrombopag Is Safe and Efficacious for Treatment of Thrombocytopenia in Patients With and Without Hepatocellular Carcinoma

Patients with hepatocellular carcinoma (HCC) secondary to chronic liver disease often require invasive procedures but frequently have thrombocytopenia. Lusutrombopag is an agonist of the thrombopoietin receptor that activates platelet production. We performed an integrated analysis of data from 2 phase 3 trials (L-PLUS 1, Japan, October 2013 to May 2014, and L-PLUS 2, global, June 2015 to April 2017) that compared the efficacy and safety of lusutrombopag with placebo in patients with chronic liver disease, with and without HCC. Our analysis included patients with Eastern Cooperative Oncology Group grades of 0 or 1, Child-Pugh classes A or B, and a platelet count less than 50× 109/L who were scheduled to undergo invasive procedures in 9 to 14 days. Patients received lusutrombopag (3 mg) or placebo daily for 7 days or fewer before an invasive procedure. Imaging studies assessed treatment-emergent adverse events, including asymptomatic portal vein thrombosis. The primary end point was no requirement for platelet transfusion before the invasive procedure and rescue therapies for bleeding 7 days or fewer after the invasive procedure. The per-protocol population included 270 patients (95 with HCC). A significantly higher proportion of patients with HCC who received lusutrombopag achieved the primary end point (68.0%) vs patients who received placebo (8.9%) (P < .0001); in patients without HCC, these proportions were 77.0% vs 21.6% (P < .0001). Lusutrombopag reduced the need for platelet transfusions, increased platelet counts for 3 weeks, and reduced the number of bleeding events in patients with and without HCC compared with placebo. Risk of thrombosis was similar to that of placebo. Patients with and without HCC receiving lusutrombopag had a reduction in the number of platelet transfusions before invasive procedures compared with patients receiving placebo, with no increase in thrombosis or bleeding. L-PLUS 1: JapicCTI-132323; L-PLUS 2: ClinicalTrials.gov number no: NCT02389621.

Avatrombopag for the management of thrombocytopenia in patients with chronic liver disease.

Severe thrombocytopenia (platelet count < 50 x 109/l) is the most frequent hematological disorder in patients with chronic liver disease, affecting 64-84 % of individuals with cirrhosis. The pathophysiological mechanisms that underlie thrombocytopenia are complex, but the reduction of thrombopoietin levels is considered to play a key role. Until recently, there was a continuous debate about the optimal management of patients with chronic liver disease and whether low platelet counts require a scheduled invasive procedure. Transfusion of platelet concentrates is considered to be the standard treatment, but has major limitations such as its short lifespan, limited efficacy and relevant adverse effects. Avatrombopag is an oral thrombopoietin receptor agonist that induces megakaryocytic proliferation and differentiation and platelet production. It has been approved by the Spanish Agency of Medicines and Health Products for the treatment of severe thrombocytopenia in adult patients with chronic liver disease before scheduled procedures, to decrease the risk of bleeding. Randomized trials have demonstrated that this agent is effective in maintaining platelet counts above 50 × 109/l over a period of more than two weeks, with a similar safety profile to the placebo. In this article, we review avatrombopag in the treatment of thrombocytopenia in patients with chronic liver disease. Furthermore, the main differences of this intervention in comparison to the previous standard of care therapy are discussed.

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

Background: Patients with chronic liver disease (CLD) often have severe thrombocytopenia (platelet counts &amp;lt;50,000/mL) that can complicate the invasive diagnostic and therapeutic procedures these patients require as part of their clinical management, due to the increased bleeding risk. Avatrombopag is a thrombopoietin receptor agonist (TPO-RA) that is approved for the treatment of thrombocytopenia in patients with CLD as an alternative to platelet transfusions for patients undergoing a procedure. The aim of this study was to evaluate the relative cost-effectiveness of avatrombopag compared with platelet transfusion or treatment with lusutrombopag, another TPO-RA also approved for the treatment of thrombocytopenia in adult patients with CLD. Methods: A decision-tree model was developed from a US payer perspective to capture the clinical events observed in registration trials, and to project potential longer-term complications resulting from a major bleed or thromboembolic event in the scenario analyses. Treatment costs were taken from publicly available data sources; avatrombopag and lusutrombopag estimates were calculated from the US prescribing information and Phase 3 study data. The interventions were evaluated in the overall trial population, patients with platelet counts &amp;lt;50,000/mL, and in subpopulations with higher (&amp;gt;40,000/mL to &amp;lt;50,000/mL) and lower (&amp;lt;40,000/mL) Baseline platelet counts. The primary metric for this economic analysis was the per-person total cost, the cost of prophylactic platelet transfusions required, and the incremental cost per prophylactic platelet transfusion avoided. Results: In the overall population, avatrombopag reduced the need for platelet transfusions and produced cost-savings per person compared to Intended Platelet Transfusion (80% fewer prophylactic platelet transfusions), resulting in a relative cost savings of $4,250. The cost for lusutrombopag (15% more platelet transfusions) relative to avatrombopag was $5,819 higher than the cost of avatrombopag. Similar results were seen in both the higher and lower platelet count subgroups. The one-way and probabilistic sensitivity analyses showed that the use of avatrombopag remained cost-saving over a wide range of changes in input variables, with the incremental cost-effectiveness ratio falling into quadrant IV (decreased costs while prophylactic platelet transfusions were avoided). Conclusions: From the cost-effectiveness standpoint, the use of avatrombopag is a practical strategy compared with the cost of both platelet transfusion and lusutrombopag, as it saves costs and reduces the need for prophylactic platelet transfusions. Table Disclosures Allen: Dova Pharmaceuticals: Equity Ownership, Other: Chief Medical Officer . Aggarwal:Dova Pharmaceuticals: Employment. Vredenburg:Dova Pharmaceuticals: Employment, Other: Shareholder.

Pre-clinical development of a cryopreservable megakaryocytic cell product capable of sustained platelet production in mice.

Platelet (PLT) transfusions are the most effective treatments for patients with thrombocytopenia. The growing demand for PLT transfusion products is compounded by a limited supply due to dependency on volunteer donors, a short shelf-life, risk of contaminating pathogens, and alloimmunization. This study provides preclinical evidence that a third-party, cryopreservable source of PLT-generating cells has the potential to complement presently available PLT transfusion products. CD34+ hematopoietic stem/progenitor cells derived from umbilical cord blood (UCB) units were used in a simple and efficient culture system to generate a cell product consisting of megakaryocytes (MKs) at different stages of development. The cultures thus generated were evaluated ex vivo and in vivo before and after cryopreservation. We generated a megakaryocytic cell product that can be cryopreserved without altering its phenotypical and functional capabilities. The infusion of such a product, either fresh or cryopreserved, into immune-deficient mice led to production of functional human PLTs which were observed within a week after infusion and persisted for 8 weeks, orders of magnitude longer than that observed after the infusion of traditional PLT transfusion products. The sustained human PLT engraftment was accompanied by a robust presence of human cells in the bone marrow (BM), spleen, and lungs of recipient mice. This is a proof-of-principle study demonstrating the creation of a cryopreservable megakaryocytic cell product which releases functional PLTs in vivo. Clinical development of such a product is currently being pursued for the treatment of thrombocytopenia in patients with hematological malignancies.

PSU1 LUSUTROMBOPAG CAN SAFELY INCREASE PLATELET COUNT IN PATIENTS WITH CHRONIC LIVER DISEASE PRIOR TO AN INVASIVE PROCEDURE, REDUCING THE NEED FOR PLATELET TRANSFUSIONS AND LOWERING THE RISK OF BLEEDING

Thrombocytopenia complicates management of chronic liver disease (CLD), and may interfere with the performance of invasive procedures. Lusutrombopag (LUSU), an oral, small molecule thrombopoietin receptor agonist, has been studied for the treatment of thrombocytopenia in patients with CLD who are scheduled for invasive procedures. Aiming to further assess its efficacy and safety, a meta-analysis of LUSU randomised controlled trial (RCT) data is presented. A direct random-effects meta-analysis was conducted in Stata 14.2MP, using the method of DerSimonian and Laird, with data from three RCTs enrolling pre-procedure CLD patients with a platelet count (PC) < 50 × 10ˆ9/L. Patients were randomised to receive LUSU 3 mg once daily or placebo (PBO) for up to seven days prior to their invasive procedure, with the procedure performed between day 9 and 14. LUSU is statistically significantly better than PBO in reducing the need for platelet transfusions (PT) prior to and after an invasive procedure (No PT during study: Odds ratio 11.24 (95% CI: 2.83, 44.64); p = 0.001). During the procedure window, patients who received LUSU and no PT had a statistically significant higher increase in PC than patients who received PBO and a PT (mean difference between LUSU and no PT versus PBO with PT at day 12: 34.18 × 10ˆ9/L (95% CI: 30.31, 38.06; p < 0.001)). LUSU significantly reduced the rate of any bleeding (irrespective of severity) during the study compared to PBO (OR 0.45 (95% CI: 0.22, 0.93; p = 0.03)). Overall, there was no significant difference between LUSU and PBO in the rate of treatment emergent adverse events (TEAEs), including splanchnic thrombosis. LUSU can safely increase PC in thrombocytopenic CLD patients prior to an invasive procedure, reducing the need for platelet transfusions and lowering the risk of bleeding.

947 Lusutrombopag for Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Who Are Undergoing Planned Invasive Procedures: Pooled Safety Analysis of Bleeding-Related Adverse Events

INTRODUCTION: Thrombocytopenia is a common complication in patients with chronic liver disease. A low platelet count in chronic liver disease patients who require an invasive procedure is a serious condition that may be associated with an increased risk of bleeding during or after the procedure. Lusutrombopag is a thrombopoietin receptor agonist approved in Japan (2015) and the US (2018) for treatment of thrombocytopenia, and in the EU (2019) for severe thrombocytopenia, associated with chronic liver disease in patients undergoing a planned invasive procedure. A pooled safety analysis was performed to assess differences in bleeding events following treatment with lusutrombopag without platelet transfusion or placebo with platelet transfusion. METHODS: Safety data were pooled from 3 double-blind, placebo-controlled studies, in patients with thrombocytopenia associated with chronic liver disease undergoing a planned invasive procedure (Phase 2b: M0626 [Japan; JapicCTI-121944]; Phase 3: L-PLUS 1 [Japan; JapicCTI-132323], L-PLUS 2 [global; NCT02389621]). Patients enrolled in these studies were randomized to lusutrombopag 3 mg or placebo for up to 7 days prior to procedure. Platelet transfusion was administered if platelet count was &lt; 50 × 109/L no more than 2 days prior to procedure. Patients were classified into 1 of 4 subgroups: lusutrombopag alone or +platelet transfusion or placebo alone or +platelet transfusion. This analysis focused on patients in the lusutrombopag alone and placebo + platelet transfusion subgroups. Bleeding events were summarized pre-, during, and post-procedure. RESULTS: Lower bleeding event rates, regardless of severity and timing of onset, were observed for lusutrombopag alone vs placebo + platelet transfusion (Table 1). Percent of patients with bleeding events was numerically higher with placebo + platelet transfusion vs lusutrombopag alone, both during (4.8% vs 3.2%) and post-procedure (7.1% vs 4.0%). Percent of patients with procedural and post-procedural bleeding events in liver-related procedures was greater in the placebo + platelet transfusion (16.1%) vs lusutrombopag alone (11.1%) arm, and a larger difference was seen with gastrointestinal-related procedures in the placebo + platelet transfusion (8.9%) vs lusutrombopag alone (2.0%) arm. CONCLUSION: In this pooled analysis, a trend toward lower bleeding event rates was observed with lusutrombopag alone vs placebo + platelet transfusion, regardless of type of invasive procedure.