Treatment Of Chronic Immune Thrombocytopenia Research Articles

Real-world clinical outcomes with fostamatinib for the treatment of refractory chronic immune thrombocytopenia: a single-center experience.

Fostamatinib is a spleen tyrosine kinase inhibitor indicated for the treatment of chronic immune thrombocytopenia (ITP) unresponsive to a previous treatment. Real-world studies evaluating the utilization and effectiveness of fostamatinib outside the context of a clinical trial are lacking. The objective of this analysis was to evaluate the effectiveness of fostamatinib for the treatment of ITP in a real-world cohort. We conducted a single-center, retrospective, observational study to evaluate the effectiveness of fostamatinib for the treatment of ITP. The primary endpoint was durable response as defined by the American Society of Hematology ITP response criteria. Secondary endpoints included overall response rate, time to response, and safety. Subgroup analysis was performed to assess frequency of durable response in key subgroups of patients based on prior therapies. Thirty-one patients treated with fostamatinib for ITP were included in our analysis. Patients had received a median of four prior lines of therapy. Ten patients (32%) achieved a durable response. Most durable responders maintained their response at 24 months ( n = 7; 70%). The median time to response was 9 days. Four patients (13%) discontinued fostamatinib due to an adverse event. Subgroups who had higher rates of durable responses included those who had received two to three prior lines of therapy (40%), splenectomized patients (50%), and those who had not received prior rituximab (55%). Fostamatinib therapy in a real-world population of patients with heavily pretreated ITP led to a durable response in a third of patients, which was maintained for most responders.

Avatrombopag Plus Fostamatinib Combination Efficacy and Safety in Patients with Immune Thrombocytopenia

INTRODUCTION Avatrombopag (AVA) is a thrombopoietin receptor agonist (TPO-RA), approved for the treatment of immune thrombocytopenia (ITP), as second line in subjects with chronic ITP unresponsive to other treatments. Global response rate of AVA is 69% with a mean duration of 12.4 weeks in its pivotal study 1. The combination of TPO-RA plus immunosuppressive/immunomodulatory drugs could optimize treatment results in ITP, addressing different pathophysiological pathways 2. Among the most widely used immunomodulatory drugs in these circumstances are steroids, azathioprine and mycophenolate. Fostamatinib (FOS) is a splenic tyrosine kinase (SYK) inhibitor. FOS blocks the cascade of signals mediated by SYK after the activation of FcγRs, reducing macrophage activity, proliferation of B lymphocytes and production of antibodies 3. We present the experience in the combined use of AVA with fostamatinib in non-responders to said TPO-RA, an experience not reported to date. METHODS Retrospective, multicenter, international, observational, non-interventional study in patients diagnosed of primary ITP who have received treatment with AVA and FOS in combination between August 2022 and June 2023. We included patients who have not reached platelets >30x10e9/L after at least two weeks of treatment with daily 40mg of AVA, and FOS was prescribed in combination in these circumstances. Epidemiological characteristics, type of ITP, previous treatments received, starting dose, response, concomitant ITP treatment and toxicity are collected. ITP definition and response criteria are based on Provan et al 4: Response (R) as platelets 30-100x10e9/L and complete response (CR) as platelets > 100x10e9/L. Data are described in percentages for the categorical variables and in medians and ranges for the quantitative ones. RESULTS In the period of time evaluated, a total of 55 patients received treatment with AVA in Spain and Norway. The Norwegian data was acquired from the Norwegian ITP registry. In 16 of 55 patients (29%), there was no response after 2 or more weeks with AVA 280 mg weekly. In 6 of these patients, FOS was combined with AVA at a dose of 280mg weekly. Table 1 describes the characteristics of the 6 patients treated with the combination. Median time from initiation of AVA to combination with FOS was 14 days (Range: 14-21 days). The overall response of the combination was 100% (1 R, 5 CR). Median time to R was 25 days and to CR 31 days. Table 2 describes the characteristics of each patient's response. With a median follow-up from the start to last follow up of treatment in combination was 212 days (Range: 45-313 days), there was no relapse. Tapering of AVA and/or FOS was attempted in 5 patients by reducing the dose of FOS in 1 patient and the dose of AVA in 4. In patients 1 and 4, AVA was stopped, but this resulted in drop in the platelets counts. CR was achieved after reintroduction AVA in combination. With regard to toxicity, in the 6 patients treated with the combination AVA plus FOS, only two adverse events were described, both non-serious. One case of headache encountered with the use of AVA, before the initiation of FOS. The other event, was WHO grade 2 liver toxicity attributed to AVA. Hypertransaminasaemia was resolved after the interruption of avatrombopag for 6 days and reduction of AVA from 140mg to 60mg weekly. CONCLUSIONS In subjects with a lack of response to thrombopoietin analogues, the combination with immunosuppressants is an alternative to consider. The combination of avatrombopag and fostamatinib has been shown to be effective and safe, although longer series are needed to support these data. Bibliography 1. Jurczak W, Chojnowski K, Mayer J, et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018;183(3):479-490. 2. Arai Y, Jo T, Matsui H, et al. Comparison of up-front treatments for newly diagnosed immune thrombocytopenia -a systematic review and network meta-analysis. Haematologica. 2018;103(1):163-171. 3. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921-930. 4. Provan D, Arnold DM, Bussel JB, et al Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817

88. Fostamatinib for the Treatment of Hospitalized Patients With COVID-19 Who Required Oxygen Supplementation: Results of a Phase 3 Trial

Abstract Background Severe COVID-19 is linked to hyperactivation of the host immune response involving signaling through multiple spleen tyrosine kinase (SYK) pathways. Fostamatinib is an orally administered potent and selective inhibitor of SYK that has been approved in the US, Canada, Japan, and Europe for the treatment of chronic immune thrombocytopenia (ITP). Methods We conducted a double-blind, randomized, placebo-controlled phase 3 trial of fostamatinib in adults hospitalized for COVID-19 who required oxygen supplementation (NCT04629703). Patients (pts) were randomly assigned 1:1 to receive fostamatinib (150 mg BID administered orally) or placebo for 14 days. All pts additionally received standard of care at their hospital. The primary endpoint was days on oxygen (days 1-29). Results A total of 280 pts underwent randomization (with 141 assigned to fostamatinib and 139 to placebo). The primary endpoint was met; those who received fostamatinib had lower mean days on oxygen than those who received placebo (4.8 vs. 7.6 days, P=0.0136; Table 1). Fostamatinib showed significance or trend towards significance in all secondary endpoints of reducing mortality and morbidity compared to placebo. The mean change in the 8-point ordinal score from baseline to the average of Day 5 to 15 was significantly improved in pts who received fostamatinib vs. placebo (P=0.0092,Table 1). Furthermore, 6 pts were enrolled with a baseline ordinal score of 6 (3 in each group). All patients in the fostamatinib group survived, and all in the placebo group died by Day 30. A significantly higher proportion of pts who received fostamatinib were discharged from the hospital by Day 15 compared to placebo (P=0.0029,Table 1). Significantly more patients were alive and oxygen-free by Day 29 and Day 60 with fostamatinib treatment in comparison to placebo (P=0.0213 and P=0.0271, respectively, Table 1). Treatment-emergent adverse events were consistent with previous studies and were similar between the 2 groups. Conclusion The addition of fostamatinib to standard of care treatment resulted in significantly fewer days on oxygen, an improved 8-point ordinal scale score, and significantly more patients alive and oxygen-free by Day 60 compared to placebo in pts with COVID-19 requiring hospitalization and supplemental oxygen. Disclosures Deepa B. Gotur, MD, FCCP, FCCM, GSK: Advisor/Consultant|GSK: Speaker at ATS|Moderna: Advisor/Consultant Vadim Markovtsov, PhD, Rigel Pharmaceuticals, Inc.: Employee|Rigel Pharmaceuticals, Inc.: Stocks/Bonds Lucy Yan, MD, PhD, Rigel Pharmaceuticals, Inc.: Employee|Rigel Pharmaceuticals, Inc.: Stocks/Bonds Wolfgang Dummer, MD, PhD, Rigel Pharmaceuticals, Inc.: Stocks/Bonds.

Long-Term Treatment with Fostamatinib in Japanese Patients with Primary Immune Thrombocytopenia: An Open-Label Extension Study Following a Phase 3 Placebo-Controlled, Double-Blind, Parallel-Group Study

Background Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved for the treatment of chronic immune thrombocytopenia (ITP) in adults in the US, Canada, Europe, Israel, and Japan. We evaluated the long-term efficacy and safety of fostamatinib treatment and the off-therapy platelet count in Japanese patients with primary ITP in a phase 3 clinical trial with a 24-week double-blind period, a 28-week open-label extension period, and a pre-defined washout period. Methods The trial enrolled Japanese patients who had failed to respond or did not tolerate ≥1 prior ITP treatment, who had a mean platelet count <30,000/μL (based on 3 screening and baseline platelet measurements), and had a platelet count at each visit <35,000/μL. Dosing was at 100 mg bid for 4 weeks and then 150 mg bid if needed and tolerated. One concomitant treatment was allowed (corticosteroids, azathioprine or danazol). The dosage of the concomitant treatment was to remain the same during the 24-week double-blind period but could be reduced or discontinued during the open-label period. Efficacy endpoints were platelet response rate (i.e., the percentage of patients who achieved a platelet count of ≥ 50 × 10 3/μL at 2 consecutive visits at least 28 days apart). The platelet count of the responders during the study period were evaluated. Results A total of 33 patients who were either treated with fostamatinib in the 24-week double-blind period (Fostamatinib-Fostamatinib group, n=22) or treated with placebo in the double-blind period and then treated with fostamatinib in the 28-week open-label extension period (Placebo-Fostamatinib group, n=11) were analyzed. Of those, 79% (26/33) were women, the median age was 62, the median baseline platelet count was 19 x 10 3/μL, and 58% (19/33) had two or more previous treatments. The platelet response rate was 36% (8/22) in the Fostamatinib-Fostamatinib group and 27% (3/11) in the Placebo-Fostamatinib group. The platelet count of the responders in the Fostamatinib-Fostamatinib group increased to ≥50 × 10 3/μL shortly after initiating fostamatinib and remained around 100 × 10 3/μL between Week 14 and Week 52, whereas the platelet count of the responders in the Placebo-Fostamatinib group remained low while receiving placebo but increased after receiving fostamatinib ( Figure 1). Among 14 patients with concomitant glucocorticoids treatments at the beginning of the open-label period, 43% (6/14) reduced or discontinued glucocorticoids while receiving fostamatinib without disease relapse. In the washout period of up to 4 weeks, all 12 patients experienced a mild decrease in platelet count, but none developed bleeding events ( Figure 2). Three of four patients who completed the 4-week washout period had a slight increase in platelet counts from Week 2 to Week 4. In the double-blind and open-label periods, adverse events were reported in 96% (21/22) of the Fostamatinib-Fostamatinib group and 100% (11/11) of the Placebo-Fostamatinib group, and treatment-related adverse events in 77% (17/22) and 46% (5/11), respectively. In the washout period, adverse events were reported in 50% (6/12) of patients, and treatment-related adverse events in 0% (0/12). We found no new safety risk or late-onset adverse events specific to Japanese patients. Conclusions The long-term efficacy and safety of fostamatinib were observed in Japanese patients with primary ITP, along with the feasibility of glucocorticoid reduction/discontinuation during fostamatinib treatment, and a lack of bleeding events after abrupt discontinuation of fostamatinib. The findings obtained from this study will help position fostamatinib as a second-line treatment in patients with primary ITP.

Real-World Treatment Patterns and Outcomes in Patients with Immune Thrombocytopenia Treated with Avatrombopag in the United States: Real-AVA 2.0 Study Design

Background: Thrombopoietin-receptor agonists (TPO-RAs) are used in the treatment of chronic immune thrombocytopenia (ITP), a disorder characterized by prolonged low platelet counts (PCs) that pose a risk of serious bleeding events. The TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have been available for more than 10 years. ELT is an oral medication with food restrictions and carries a boxed warning for hepatoxicity, requiring hepatic laboratory monitoring and a potential need for statin dosing adjustments. ROMI, an injectable, is typically administered in a health care practitioner's office on a weekly basis without food restrictions. Avatrombopag (AVA), an oral medication taken with food, is the most recently approved TPO-RA for the treatment of chronic ITP (2019 by FDA and 2021 by EMA). Hence, the real-world evidence on AVA treatment and its clinical effectiveness in broader and more diverse ITP patient populations have been limited, and additional studies are warranted. REAL-AVA 2.0 is a retrospective chart review which will gather a substantially greater amount of platelet counts per patient than either a claims database review or an electronic medical record review. More granular efficacy data with more patients, more platelet counts per patient, and in a broader population will be used to better assess the clinical effectiveness of AVA in the real-world. This study will also describe the demographic and clinical characteristics of adult patients with primary ITP treated with AVA in the United States (US), and assess treatment patterns and clinical outcomes of these patients. Methods: This retrospective, observational medical chart review study will include patients treated in the US with AVA in a non-clinical trial setting from approximately 20 centers (both academic and community). The study aims to include approximately 200 ITP patients (at least 25 with an ITP disease duration < 12 months) treated with at least one dose of AVA between July 2019 and March 2023. The date the patient initiated treatment with AVA is defined as the index date. The period from the index date through the study end date, end of data availability for the patient or date of death, whichever occurs first, is defined as the post-index period. Results: The primary objective of the study is to describe treatment patterns and response to AVA. Primary outcome measures to be assessed include: achievement of meaningful PC thresholds (PC ≥ 30 X10 9/µL and ≥ 50 X10 9/µL) at any time during AVA treatment, time to achieve an initial platelet response with AVA based on achieving meaningful PC thresholds (PC ≥ 30X10 9/µL and ≥ 50 X10 9/µL) after AVA index date and before AVA discontinuation, durability of platelet response among patients who respond to AVA, and reduction in the use of concomitant steroids or immunosuppressant agents from the index date. The secondary objectives include: assessment of the demographic and clinical characteristics of patients treated with AVA, assessment of changes in PCs following the index date, ITP-related medication use prior to and following the index date, and treatment patterns with AVA (including treatment persistence and changes in dose/frequency). The exploratory objectives include assessment of AVA effectiveness in specific subpopulations (e.g. prior number of ITP treatments, persistent vs chronic ITP, switch from particular ITP treatments, gender, race, age) and, if feasible, to evaluate social determinants of health among ITP patients treated with AVA (including assessment of treatment response among those subpopulations of interest) [ Table 1]. Summary/Conclusions: The study aims to fill current gaps in knowledge by assessing treatment patterns and outcomes, clinical, and demographic characteristics of patients treated with AVA in a real-world clinical setting in the US. We look forward to presenting this data at upcoming scientific meetings.

Fostamatinib or Thrombopoietin for the Treatment of Chronic Immune Thrombocytopenia in Adult Patients: A Real-World Assessment of Safety, Effectiveness and Cost

Introduction: Chronic immune thrombocytopenia purpura (ITP) in adults is a serious autoimmune disease in which platelets are prematurely destroyed, leaving the patient vulnerable to bruising and bleeding. Initial treatment starts with corticosteroids. In patients who become resistant or intolerant to corticosteroids, the thrombopoietic agents (TPOs), consisting of romiplostim (ROM), eltrombopag (ELT), and avatrombopag (AVA), or the spleen tyrosine kinase inhibitor fostamatinib (FOS), are appropriate next lines of therapy. In this study, the comparative safety, effectiveness, and cost of care between fostamatinib and the TPOs were evaluated in a real-world setting. Methods: A retrospective analysis of 17 community hematology practices across the USA was conducted to identify adult ITP patients who received one of the four agents. Data collection consisted of patient demographics, disease characteristics, as well as number and type of prior treatments. From the first day until the end of treatment, data were also collected on platelet (PLT) counts, adverse events, the use of rescue IVIG, platelet transfusions, and corticosteroids. Multivariable logistic regression analysis was used to compare PLT-related endpoints between agents. Results: A sample of 179 ITP patients who had received at least one of the four agents was identified. This resulted in a final sample of 51, 87, 127, and 44 patients who received FOS, ELT, ROM, or AVA, respectively. At month six, there were no significant differences between FOS and the TPOs in terms of the proportion of patients with the PLT count being ≥30 × 103/μL, ≥50 × 103/μL as well as the proportion of patients whose PLT levels doubled relative to baseline. The frequency of thromboembolic events (TEs) was 3.9% in FOS patients compared to 9.2%, 4.7%, and 11.4% in the ELT, ROM, and AVA groups. The mean cost per patient with FOS was $99,209 (95% CI: $59,595–$115,074), compared to $92,426 (95% CI: $68,331–$115,519), $108,482 (95% CI: $84,782–$132,182), and $131,050 (95% CI: $83,327–$179,897) for ELT, ROM, or AVA, respectively. Conclusions: In this real-world analysis, FOS was comparable to the TPOs in maintaining PLTs at clinically beneficial levels. Given these findings, the choice of therapy should be based on overall patient safety, preexisting risk factors for TEs, and cost effectiveness.

Evaluation of safety, efficacy and pharmacokinetics of Eltrombopag in patients with chronic immune thrombocytopenia: Meta-analysis of randomized controlled trials

Introduction: Immune thrombocytopenia (ITP) is a complex autoimmune syndrome associated with low platelet count. Eltrombopag is an oral thrombopoietin receptor agonist that used in the treatment of chronic ITP. The aim of the study: The present meta-analysis is to evaluate the safety and efficiency of Eltrombopag in theprevention and therapy of ITP. Materials and Methods: The analysis was performed according to the PRISMA guideline with use of Excerpta MedicaDatabase (EMBASE) as well as Web of Science and the Cochrane (CENTAL) databases. Results: Seven randomized controlled trials (N=766 patients) were included in the final analysis. Overall platelet response was significantly higher in the Eltrombopag group than in placebo (RR=3.90; 95%CI [2.89-5.25];P<0.00001) showing mild heterogeneity (I2=45%). Incidences of significant bleeding events in Eltrombopaggroup (World Health Organization [WHO] grades II-IV) (RR=0.63; 95% CI: [0.47-0.85]; P=0.003) showed lowerheterogeneity (I2=18%) in comparison to placebo group. Cases of use of rescue medications in Eltrombopag group compared to placebo group (RR=0.40; 95% CI: [0.29- 0.55]; P<0.00001) in all considered studies showed low heterogeneity (I2=41 %; P=0.16). Incidences of any bleeding in Eltrombopag group compared to placebo group(RR=0.77; 95% CI: [0.70-0.86]; P<0.00001; I2=65%) showed substantial heterogeneity. Finally, subgroup analysis of Eltrombopag efficiency revealed significant difference in frequency of bleeding cases between adults (RR=0.84)and children (RR=0.51); (P=0.005). Conclusion: This systematic review presents class one evidence suggesting Eltrombopag as safe and effective drug for therapy of both children and adult patients with ITP.

RWD137 A Real-World Comparative Effectiveness Analysis of Fostamatinib Vs. Thrombopoietic Receptor Agonists (TPOS) for the Treatment of Chronic Immune Thrombocytopenia in Adult Patients

Chronic immune thrombocytopenia purpura (ITP) is an acquired autoimmune disease characterized by antibody-induced platelet (PLT) destruction, leading to a reduction in the number of circulating PLTs. Initial treatment is with corticosteroids. In patients who become resistant to corticosteroids, the TPOs, consisting of romiplostim (ROM), eltrombopag (ELT) and avatrombopag (AVA) or the spleen tyrosine kinase inhibitor fostamatinib (FOS), are appropriate next lines of therapy. In this study, the comparative safety and effectiveness between fostamatinib vs. the TPOs was evaluated in a real-world setting.

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.

Evaluation of the effect of eltrombopag therapy on the platelet collagen receptor glycoprotein VI (GPVI) expression and soluble GPVI levels in young patients with immune thrombocytopenia

BackgroundPlatelet glycoprotein VI (GPVI) receptor is essential for platelet adhesion and aggregation. Eltrombopag is as an effective treatment for chronic immune thrombocytopenia (ITP); yet, its effect on platelet function is not fully characterized.AimThis prospective study investigated the effect of eltrombopag therapy on platelet function through assessment of GPVI receptor expression and soluble GPVI levels among pediatric patients with persistent or chronic ITP.MethodsThirty-six children and adolescents with persistent or chronic ITP were divided equally into two groups either to receive eltrombopag therapy or the standard of care. All patients were followed-up for 12 months with assessment of bleeding score and complete blood count (CBC). Evaluation of GPVI expression using flow cytometry and measurement of its soluble form by ELISA was done at baseline and at 6 months.ResultsITP patients on eltrombopag had significantly lower bleeding score after 6 months of therapy while the quality of life has significantly improved. Platelet count was significantly increased throughout the study. GPVI expression by flow cytometry and soluble GPVI levels were significantly increased after eltrombopag therapy. After 12 months, ITP patients on eltrombopag were able to maintain a good quality of life and low bleeding score.ConclusionOur data suggest that eltrombopag, through its effect on the GPVI receptor expression and its soluble form, might reduce bleeding manifestations and improve the quality of life of chronic and persistent ITP children independent of its effect on the platelet count.

Avatrombopag Treatment Response in Patients with Immune Thrombocytopenia: A Real-World Evidence Study

Introduction: Thrombopoietin-receptor agonists (TPO-RAs) are used in the treatment of chronic immune thrombocytopenia (ITP), a disorder characterized by prolonged low platelet counts (PCs) that pose a risk of serious bleeding episodes. The TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have been available for over 10 years. ELT is an oral medication with food restrictions and carries a boxed warning for hepatoxicity; additionally, ELT requires hepatic monitoring and has a potential need for statin dosing adjustment. ROMI, an injectable, is typically administered in a health care practitioner's office on a weekly basis without food restrictions. Avatrombopag (AVA), an oral medication taken with food, is the most recently approved TPO-RA for the treatment of chronic ITP (2019 by FDA and 2021 by EMA). AVA does not require hepatic monitoring or potential statin dose adjustment. A high proportion of patients (~90%) responded to AVA in clinical trials, and treatment was well-tolerated; however, limited real-world effectiveness data have been reported to date. This study is the first to use administrative claims linked to lab data to evaluate treatment response following the initiation of AVA in patients with ITP in the US. Methods: This retrospective study used administrative claims data from the Komodo Healthcare Map (02/01/2017-02/28/2022) linked with platelet count (PC) laboratory data from Quest Diagnostics. Patients with >1 diagnosis of ITP (ICD-9-CM: 287.31; ICD-10-CM: D69.3) followed by ≥1 paid prescription for AVA (first such prescription was defined as the index date) and ≥1 PC during the twelve-month period following the index date (study observation period) were selected. The percentages of patients achieving clinically meaningful PC thresholds (≥30 x 109/L, ≥50 x 109/L, ≥75 x 109/L, and ≥100 x 109/L) were assessed at any time within 1 year of AVA initiation. Additionally, median and mean PCs were assessed at baseline (PC closest to and within 3 months before the index date), and within each 3-month period after AVA initiation, among the subgroups of patients with available PC data in each subsequent 3-month period. Results: A total of 46 patients met all eligibility criteria. On average, patients were 56.1 (±16.7) years of age, and 52.2% were female. Of the 46 patients, 32 (69.6%) had a baseline PC; among them, median baseline PC was 40.5 x 109/L. Across the full sample of 46 patients, 89.1%, 78.3%, 67.4%, and 50.0% of patients achieved thresholds of ≥30 x 109/L, ≥50 x 109/L, ≥75 x 109/L, and ≥100 x 109/L, respectively, during the 12-month period following AVA initiation (Table 1). Median PCs were 68.0 x 109/L during months 1-3 post initiation, 67.7 x 109/L between months 4-6, 80.5 x 109/L between months 7-9, and 58.0 x 109/L between months 10-12 (Table 2). Mean PCs were notably higher, reflecting the wide variability in the platelet counts data. Conclusions: The majority of patients with ITP in this real-world study achieved clinically meaningful platelet counts following AVA initiation. Throughout the 12-month study observation period, mean and median PC values obtained were above a clinically meaningful threshold of 50 x 109/L. While this study was limited by the availability of PC data, the results are consistent with those from the pivotal clinical trials of AVA. Additional real-world studies are warranted to confirm these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Herombopag for Enhancement of Platelet Engraftment in Patients Undergoing Hematopoietic Stem Cell Transplantation

Abstract Background Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for many patients suffering from hematological malignancies. However, thrombocytopenia is a common and potentially severe complication of HSCT. A recent study found that the median time to platelet engraftment, defined as the first of 7 consecutive days of an unsupported platelet count of at least 20,000/μl, was more than 54 days. It was also reported that the incidence of mortality was significantly higher in patients with post-HSCT thrombocytopenia. We developed a clinical trial to facilitate platelet engraftment after HSCT using herombopag, an oral nonpeptide thrombopoietin receptor agonist. Herombopag is CFDA-approved for the treatment of chronic immune thrombocytopenia, and patients with severe aplastic anemia who do not respond well to immunosuppressive therapy in June 2021. From the pharmacological point of view, it functions by phosphorylating multiple downstream signaling proteins and has stronger effects than eltrombopag when used at the same dosages. Here we present the results of this prospective clinical trial. Methods: This is a phase I/II clinical trial. Eligible patients had: a platelet count before conditioning regimen≥ 50,000/μl, >18 years of age, ECOG ≤ 2, ALT ≤ 3 ULN (upper limit of normal), AST ≤ 3 ULN, total bilirubin ⩽ 1.5 ULN, creatinine ⩽ 1.5 ULN, the first HSCT and an expected survival period ≥ 3 months. The primary objective was to evaluate the safety and efficacy of herombopag for platelet engraftment after HSCT. After transplantation, oral herombopag (7.5 mg) was administered until platelet counts reached 50,000/μL for 7 consecutive days without platelet transfusions. The primary endpoints of this trial were the 21-day incidence of partial platelet engraftment (A platelet count exceeding 20,000/μl for 7 consecutive days without transfusion), and 50-day cumulative incidence of complete platelet engraftment (A platelet count exceeding 50,000/μl for 7 consecutive days without transfusion) after HSCT. We used Propensity Score Matching (PSM) to select matching subjects among other eligible subjects. Differences between groups were analyzed using Chi-squared tests. Results: Between February 2022 and June 2022, 17 patients with acute leukemia were enrolled (Table1). For partial and complete engraftment, the median time was 13 (range, 8-24) days, and 20 (range, 14-61) days. The median time to neutrophil engraftment was 11 (range, 9-19) days. We performed a comparison of engraftment data between our study cohort and a historical cohort comprised of 17 individuals. The 2 cohorts were matched in sex, age, ABO match, and transplantation type using the propensity score matching method (PSM). The incidence of partial and complete platelet engraftment was significantly higher in the study group (partial, 89% versus 59%, p=0.05; complete, 94% versus 65%, p=0.03). The median follow-up duration was 3 (range, 1-5) months. The median number of platelet transfusions required within 30 days after HSCT was 3 (range 1-9) U. The overall survival (OS) was 94%, and 1（6%）patient suffered from molecular recurrence. 1（6%）patient developed grade III aGVHD and died 3.4 months after transplantation. 5 (29%) developed grade I-II aGVHD and no grade IV aGVHD occurred. 3（18%）patients suffered cytomegalovirus (CMV) viremia. According to acute WHO side effects, 7 (41%) patients suffered grade I-II AEs of the digestive tract, and 1 (6%) patient suffered grade III. 3 (18%) patients suffered grade I-II AEs of fever, and no grade IV adverse events occurred. The AEs of the digestive tract included nausea (3/17, 18%), vomiting (2/17, 12%), oral ulcer (7/17, 41%), and diarrhea (3/17, 18%). Conclusions: Herombopag has a significant contribution to platelet engraftment in patients undergoing HSCT and the drug is very well-characterized and safe. While Further investigations for a longer period and more cases would be necessary next. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Fostamatinib for the Treatment of Japanese Patients with Primary Immune Thrombocytopenia: A Phase 3, Placebo-Controlled, Double-Blind, Parallel-Group Study

Background Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved for the treatment of chronic immune thrombocytopenia (ITP) in the US, Canada, and Europe. We conducted a phase 3, multi-center study to evaluate the efficacy and safety of fostamatinib in Japanese patients with ITP. The study was composed of 3 treatment periods and 1 non-dosing period: a placebo-controlled, double-blind study of fostamatinib for 24 weeks, an open-label study of fostamatinib for 28 weeks, a non-dosing period of up to 4 weeks, and the voluntary open-label study of fostamatinib until official approval. Here we report the results of the 24-week, placebo-controlled, double-blind, parallel-group study. Methods The study enrolled Japanese patients, ≥20 years old, with ITP for ≥6 months, and who had failed or not tolerated ≥1 prior ITP treatment. The mean of 3 screening and baseline platelet counts had to be <30,000/μL, with a platelet count at each visit < 35,000/μL. Patients were randomised 2:1 to fostamatinib or placebo for 24 weeks, stratified by baseline platelet count (< or ≥ 15,000/μL). Dosing was at 100 mg bid for 4 weeks and then 150 mg bid if needed and tolerated. One concomitant treatment was allowed (corticosteroids, azathioprine or danazol). Results The study included 34 patients, fostamatinib (n=22) or placebo (n=12). See Table 1 for baseline characteristics. Stable responses (platelets ≥50,000/μL at ≥4 of 6 visit, weeks 14-24) were observed in 8 (36%) patients on fostamatinib and 0 patients on placebo (P=0.030) (Figure 1). Overall responses (platelets ≥50,000/μL at ≥1 visit, weeks 2-12) were seen in 10 (45%) patients on fostamatinib and 0 patients on placebo (P=0.006). The median platelet counts of stable responders were higher than those of non-responders and patients on placebo throughout weeks 2 to 24. The median platelet counts of responders on fostamatinib increased ≥50,000/μL from the early stage of fostamatinib administration and stayed at around 100,000/μL from weeks 14 to 24, whereas non-responders on fostamatinib and patients on placebo remained below 30,000/μL most of the time. No platelet overshoot (> 400,000/μL) was observed. Rescue medication was required less often with fostamatinib, and fewer bleeding symptoms occurred with fostamatinib than with placebo. Adverse events in ≥10% of patients on fostamatinib were diarrhoea, hypertension, and decreased neutrophil count. Most adverse events were mild or moderate and manageable. There was no difference in the incidence of infection between the fostamatinib and placebo group; no patients developed a severe infection. No thromboembolic events were reported. The safety profile was consistent with prior studies of fostamatinib. Conclusions This study demonstrated the efficacy and safety of fostamatinib in Japanese patients with ITP, including those who had failed or were intolerant to other approved ITP therapies. No new safety signals were identified in Japanese patients with ITP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

SAFETY AND EFFICACY OF SPLENECTOMY FOR THE TREATMENT OF CHRONIC IMMUNE THROMBOCYTOPENIA

To evaluate the short- and long-term safety and efficacy of splenectomy for the treatment of chronic immune thrombocytopenia (ITP). A cohort of ITP patients who underwent splenectomy between 2005 and 2020 was included and followed for up to 10 years. Descriptive analyses of complications (related to the procedure, infections, and thrombosis) and response to treatment were performed. Out of the 87 patients included, 80.5% were women, median age at diagnosis was 33 years (IQR 24 – 50), 28.7% had hypertension and 20.7% had antiphospholipid antibodies. The median time from diagnosis to splenectomy was 19 months (IQR 6.0 – 50.0) and median follow-up duration was 61 months (27 – 108). Post-procedure complications, such as fistula, surgical site infection and bleeding requiring transfusion, occurred in 6 (7%) patients and hospital-associated thrombosis (thrombosis occurring within 90 days after splenectomy) in 3 (3.4%). Two patients had abdominal thrombosis and 1 had abdominal and deep vein thrombosis. During the follow-up, 3 patients had infections requiring hospitalization, resulting in a 5-year cumulative risk of infections of 3.4% (95% CI 0.9 – 9.1). Regarding thrombotic events after splenectomy, the 5-year cumulative incidence was 12.6% (95 CI% 6.8 – 20.9) and the median time from splenectomy to thrombosis was 20 months (IQR 1 – 42). In the subgroup analysis, patients with cardiovascular risk factors, such as hypertension, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, and cerebrovascular disease, showed higher risk for developing a thrombotic event during follow-up. Sixty days after splenectomy, 72 patients (82.5%) had an overall response, of which 55 were complete (63.2%) and 17 partial response (19.3%). The median time for relapse was 12.5 months (IQR 4 - 45.3) and the 5-year treatment free survival was 55.3% (95% CI 45.8 – 66.4). At the end of the follow-up, 77 patients (88.5%) had partial or complete response and 2 (2.3%) had died. This study represents a cohort of patients with ITP from a single center in Brazil that evaluated the short- and long-term safety of splenectomy, in addition to its efficacy. The recent guidelines on ITP treatment recommend splenectomy as one of the main second-line therapies following failure or relapse after corticosteroid use, along with thrombopoietin receptor agonist or rituximab. The perioperative complication rate and mortality in the presented cohort were as low as those described in previous cohort studies. The institution protocol includes pre-splenectomy vaccination but not long-term antibiotic prophylaxis in adults with ITP and, even with this approach, cumulative incidence of infection requiring hospitalization in the current cohort was approximately three times lower than that in previous cohort studies. The rate of venous thromboembolism was similar to another cohort studies and seems to be associated with underlying comorbidities. Splenectomy is an efficacious well-tolerated treatment. The response rate is high, even for those requiring further ITP treatment, suggesting that splenectomy modulates future therapy response. In conclusion, splenectomy-associated rates of efficacy outweigh its rates of complications, which underscores that splenectomy should be regarded as one of the main approaches for long-term ITP remission.

An updated evaluation of avatrombopag for the treatment of chronic immune thrombocytopenia

ABSTRACT Introduction Multiple agents are available for the management of chronic immune thrombocytopenia (ITP), including thrombopoietin-receptor agonists (TPO-RAs), rituximab, and fostamatinib. Although TPO-RAs are often selected as treatments for chronic ITP, when choosing between the TPO-RAs, clinicians must balance safety profile, dosing restrictions, and method of administration incorporating patient preference. Areas covered We provide an overview of the thrombopoietin receptor agonists with a particular focus on avatrombopag, the newest agent in this class. In phase II and III clinical trials, avatrombopag was shown to offer durable improvement in platelet counts. We also include recent real-world evidence describing avatrombopag effectiveness in patients with poor response to prior treatments (including other TPO-RAs). Expert opinion Compared with other TPO-RAs used to treat ITP, avatrombopag offers practical oral dosing with a single pill strength, does not require long-term dietary restrictions, and has no warning for hepatotoxicity. It is frequently effective after use of other TPO-RAs in ITP. The primary downside with avatrombopag use at present is the lack of longer-term safety data in ITP that presently exists for romiplostim and eltrombopag.

Cost-Effectiveness of Treatment for Pediatric Immune Thrombocytopenia

&#x0D; Limited evidence from 1 cost-consequence analysis study showed that eltrombopag was the preferred thrombopoietin receptor agonist over romiplostim (i.e., less expensive and more effective) for treatment of chronic immune thrombocytopenia in pediatric patients.&#x0D; No cost-effectiveness studies of dapsone or rituximab were identified.&#x0D;

Phase I Dose-Finding Study of Eltrombopag Following High Dose Cytarabine and Mitoxantrone Chemotherapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Phase I Dose-Finding Study of Eltrombopag Following High Dose Cytarabine and Mitoxantrone Chemotherapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Multi-Arm Trial of Inflammatory Signal Inhibitors (MATIS) for Hospitalised Patients with Mild or Moderate COVID-19 Pneumonia: A Structured Summary of a Study Protocol for a Randomised Controlled Trial

Multi-Arm Trial of Inflammatory Signal Inhibitors (MATIS) for Hospitalised Patients with Mild or Moderate COVID-19 Pneumonia: A Structured Summary of a Study Protocol for a Randomised Controlled Trial

Evaluation of Treatment Patterns Among Patients with Newly Diagnosed, Persistent, and Chronic Immune Thrombocytopenia (ITP) Treated with Eltrombopag in Real World Setting in the US

BACKGROUND: The thrombopoietin receptor agonist (TPO-RA) eltrombopag was approved for the treatment of chronic immune thrombocytopenia (cITP), >12 months after initial ITP diagnosis. The registration trials however included patients with ITP duration >6 months. Moreover, with increasing familiarity and confidence with the use of TPO-RAs in ITP, the use of these agents in real world has not been restricted to cITP.OBJECTIVE: The objective of this study was to describe treatment characteristics of eltrombopag use among adult patients diagnosed with ITP initiating treatment ≤6, 7-12, and >12 months after their initial ITP diagnosis in the real-word setting.METHODS: A retrospective cohort study was conducted using MarketScan® - Commercial and Medicare Supplemental Database, and PharmetricsPlusTM Adjudicated Claims Database. Adult patients (≥18 years) with ≥2 non-diagnostic outpatient claims separated by ≥30 days or ≥1 inpatient claim carrying a diagnosis code for ITP during Jul 1, 2010 - Jun 30, 2014 were eligible for inclusion. The index date was the date of the first ITP diagnosis. Patients were excluded if they had continuous enrollment in medical and pharmacy benefits for <24 months prior and <18 months following the index date, or had a medical claim for secondary thrombocytopenia during the pre-index period. Timing of eltrombopag initiation was calculated from the index date to the date of first eltrombopag claim. Patients were categorized into 1 of 3 cohorts, those initiating treatment ≤6, 7-12, or >12 months after index date. Treatment outcomes were assessed among a subset of patients regardless of follow-up period post the index ITP diagnosis but who had ≥6 months of continuous enrollment in medical and pharmacy benefits after initiating treatment with eltrombopag; treatment duration, medication possession ratio (MPR), time to treatment discontinuation and time to treatment restart were compared among patients initiating treatment ≤6, and 7-12 after ITP diagnosis to those initiating treatment >12 months after their index ITP diagnosis. MPR was calculated as the sum of the days' supply for all fills divided by the number of days between the first and last fill plus days' supply of the last fill. Outcomes compared between cohorts using t-tests and chi-square tests. RESULTS: A total of 7,068 patients - 3,264 patients in MarketScan and 3,804 in PharMetrics - were eligible for inclusion in the study; 117 (3.6%) and 139 (3.7%), respectively, received eltrombopag. More than half of patients in both MarketScan and PharMetrics initiated treatment ≤12 months after their index diagnosis (see Table 1). The average treatment durations were similar among patients initiating treatment ≤6 months (120.8±57.1; P =0.456) and 7-12 (110.5±59.5; P =0.991) months after index diagnosis compared to those initiating treatment >12 months after index diagnosis (110.3±64.7). The MPR was 0.9 in all 3 cohorts; 84.0%, 73.7% and 78.3% patients initiating treatment ≤6 months, 7-12 months and > 12months after index diagnosis, respectively were considered to be adherent based upon an MPR≥0.8. The proportion of patients who discontinued treatment were not statistically significant between cohorts (≤6 months: 53.3% [ P =0.816]; 7-12 months: 57.9% [ P =1.000]; >12 months 56.5%). Time to treatment discontinuation was statistically longer among patients initiating treatment ≤6 months compared to those initiating treatment >12 months after index diagnosis (63.7±37.3 days vs 39.5±26.4 days; P =0.035); however the difference between patients initiating treatment 7-12 and >12 months after index diagnosis (50.3±30.5 days vs 39.5±26.4 days; P =0.365) was not significant. Twelve percent (P =0.307), 26.3% (P =1.000) and 21.7% of patients initiating treatment ≤6 months, 7-12 and >12 months after index diagnosis restarted eltrombopag. The average time to treatment restart was approximately 50 days across all 3 cohorts. CONCLUSION: Although eltrombopag is currently approved for patients with chronic ITP, results of this study indicate that in real world setting physicians have been using it in patients with newly diagnosed and persistent ITP, with overall treatment patterns being very similar to those in patients with cITP. These data, supported by other real world studies underscore the clinical utility of eltrombopag in early-stage ITP and warrant further exploration in more robust prospective studies. [Display omitted] DisclosuresStafkey-Mailey:Xcenda: Employment. Roy:Novartis: Employment, Equity Ownership. Lokhandwala:Xcenda: Employment. Yuan:Xcenda: Employment. Landsman-Blumberg:Xcenda: Employment. Siddiqui:Novartis: Employment, Equity Ownership. Ghaznawi:Novartis: Employment, Equity Ownership.

Thrombopoietin Receptor Agonists (TPO-RAs): Drug Class Considerations for Pharmacists.

The thrombopoietin receptor agonists (TPO-RAs) romiplostim, eltrombopag, avatrombopag, and lusutrombopag carry unique US Food and Drug Administration (US FDA)- and European Medicines Agency (EMA)-approved indications and may be used to increase platelet counts in a variety of conditions. Current indications for available TPO-RAs include treatment of chronic immune thrombocytopenia (ITP) in cases of insufficient response to prior treatment (avatrombopag, eltrombopag, romiplostim), management of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure (avatrombopag, lusutrombopag), management of severe aplastic anemia (eltrombopag), and management of thrombocytopenia associated with interferon-based therapy for hepatitis C (eltrombopag). Across current indications, pharmacists can assist in stabilizing platelet counts and help to reduce large undulations commonly seen when starting, stopping, or transitioning between these agents. If therapy modifications may benefit the patient, pharmacists should discuss possible changes with the patient’s treatment team or treating physician. When used for ITP, romiplostim, eltrombopag, and avatrombopag stimulate TPO receptors on hematopoietic stem cells (also known as c-Mpl, or CD110) to promote platelet production; however, romiplostim is the only TPO-RA that binds at the same site as endogenous TPO. These subtle mechanistic differences may explain why switching TPO-RA may be clinically advantageous in some situations. As pharmacists are called to counsel patients on TPO-RA use, a deep understanding of potential adverse events and management strategies, as well as appropriate monitoring, will increase the likelihood that patients meet their goals of therapy in the shortest timeframe. Other uses of TPO-RAs are also discussed in this review, including use following hematopoietic stem cell transplant, use in myelodysplastic syndrome, and use in chemotherapy-induced thrombocytopenia.