Achieved Platelet Counts Research Articles

Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment-free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Initial Report of Part B Phase 1/2 Efficacy and Safety Results for Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Relapsed Immune Thrombocytopenia

Introduction: Rilzabrutinib is a potent oral, reversible Bruton tyrosine kinase inhibitor that can treat hematological autoimmune diseases through multiple putative mechanisms of action: (1) inhibition of B-cell activation, (2) interruption of antibody-coated cell phagocytosis by FcϒR in spleen and liver, and (3) induce sustained anti-inflammatory effects (Langrish J Immunol 2021). Preliminary evidence showed that rilzabrutinib treatment resulted in rapid and durable platelet responses with a favorable safety profile in previously treated patients with immune thrombocytopenia (ITP) as studied in part A of a phase 1/2 clinical study (LUNA 2; Kuter N Engl J Med 2022). This abstract summarizes the results of part B that focused on the durability of response with rilzabrutinib in relapsed ITP patients. Methods: Part B of the multicenter, open-label, phase 1/2 study evaluated the efficacy and safety of rilzabrutinib 400 mg bid in patients with relapsed ITP (NCT03395210). Adult patients aged 18-80 y were eligible with ≥2 baseline platelet counts <30x10 9/L no less than 7 days apart in the 15 days before the first dose. Eligible patients were required to have a past response (achievement of platelet count ≥50x10 9/L) to intravenous immunoglobulin (IVIg)/anti-D or corticosteroid (CS) that was not sustained and failed ≥1 other ITP therapy (that was not IVIg or CS). Stable doses of concomitant CS/thrombopoietin receptor agonists (TPO-RA) were allowed with rilzabrutinib. The primary endpoints for part B were safety and durable platelet response defined as platelet counts ≥50x10 9/L on ≥8 of the last 12 weeks of rilzabrutinib without rescue medication. Patients completing 24 weeks of rilzabrutinib with platelet counts ≥50x10 9/L or ≥30x10 9/L and doubling from baseline in ≥4 of the last 8 weeks of treatment without rescue medication could continue rilzabrutinib in the long-term extension (LTE) period. Results: At baseline, 26 enrolled patients had a median age of 57 y (range, 20-75), 62% were female, and median baseline platelet count was 13x10 9/L (range, 2-24x10 9/L). Patients had a median duration of ITP of 10.3 y (range, 0.7-48.2) and had received a median of 6 prior unique ITP therapies (range, 3-19; 46% splenectomy). Seventeen patients (65%) received concomitant non-rescue CS and/or TPO-RA. Nine patients (35%; 95% CI, 17%-56%) achieved the primary endpoint of durable platelet response. Approximately 25% of patients achieved platelet counts ≥50x10 9/L by day 15 of rilzabrutinib treatment (Figure 1A). In 16 patients who achieved platelet counts ≥50x10 9/L, median time to first platelet count ≥50x10 9/L was 15 days (range, 7-134). Median platelet counts for all patients (responders and non-responders) increased over time, exceeding the platelet count thresholds of 30x10 9/L at day 57 and 50x10 9/L at day 120 (Figure 1B). The mean number of weeks with platelet counts ≥50x10 9/L and/or ≥30x10 9/L and doubling from baseline was both 9.3 weeks (SD, 10.1). Three patients (12%) received rescue medication in the main treatment period. Fifteen patients (58%) completed 24 weeks of rilzabrutinib and 11 (42%) entered the LTE. Over the main treatment period, the median duration of treatment was 167 days (range, 7-169). Sixteen patients (62%) had ≥1 related treatment-emergent adverse event (AE), including 35% diarrhea, 23% headache, and 15% nausea. Most AEs were grade 1 or 2; there was 1 treatment-related AE of grade 3 blood creatinine phosphokinase increase. There was no treatment-related grade ≥2 bleeding/thrombotic events or infections, serious AEs, or deaths. Conclusion: Part B study results were consistent with part A. Rilzabrutinib demonstrated rapid, stable, and durable platelet responses in patients with relapsed ITP, with a favorable safety profile in part B.

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.

Rilzabrutinib versus placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study.

Immune thrombocytopenia (ITP) is characterized by primarily autoantibody-mediated platelet destruction and impaired platelet production resulting in thrombocytopenia and an increased risk of bleeding. Other manifestations include increased risk of thrombosis and diminished quality of life. Current treatment approaches are directed toward lowering the rate of platelet destruction or stimulating platelet production to prevent bleeding. Rilzabrutinib is an oral, reversible, potent Bruton tyrosine kinase inhibitor that was specifically designed to treat immune-mediated diseases and mediates its therapeutic effect through a dual mechanism of action: (1) inhibiting B-cell activation and (2) interrupting antibody-coated cell phagocytosis by Fc gamma receptor in spleen and liver. A 24-week dose-finding phase I/II study of rilzabrutinib in patients with ITP showed a 40% platelet response (⩾2 consecutive platelet counts of ⩾50 × 109/L and increase from baseline ⩾20 × 109/L without rescue medication use) and a well-tolerated safety profile with only grade 1/2 transient adverse events across dose levels. Assess the efficacy and safety of oral rilzabrutinib in adult and adolescent patients with persistent or chronic ITP. Rilzabrutinib 400 mg BID is being evaluated in the ongoing LUNA 3 multicenter, double-blind, placebo-controlled phase III study. The primary endpoint is durable platelet response, defined as achieving platelet counts of ⩾50 × 109/L for at least two-thirds of ⩾8 available weekly scheduled platelet measurements during the last 12 weeks (including ⩾2 available measurements within the last 6 weeks) of the 24-week blinded treatment period in the absence of rescue therapy. Ethical guidelines and informed consent are followed. The LUNA 3 trial will further investigate rilzabrutinib's safety and efficacy in adult and adolescent patients, with the primary goal of addressing a major objective in treating patients with ITP: durability of platelet response. ClinicalTrials.gov NCT04562766: https://clinicaltrials.gov/ct2/show/NCT04562766; EU Clinical Trials Register EudraCT 2020-002063-60: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-002063-60.

Avatrombopag for the treatment of thrombocytopenia induced by chemotherapy in patients with solid tumors: A multicenter, open-label, single-arm trial.

Objective: To explore the effect and safety of avatrombopag for chemotherapy-induced thrombocytopenia (CIT). Methods: This multicenter, open-label, single-arm trial enrolled CIT patients in eight centers from October 2020 to April 2021. The participants received avatrombopag tablets 60 mg once a day for 5–10 days. The main endpoint was the proportion of patients with platelet count ≥100×109/L or increased by ≥ 50×109/L or increased by ≥ 100% in the cycle after the start of treatment. Results: Seventy-four participants were enrolled with a mean age of 59.8 ± 11.62.2% were males. The cumulative effective rate (any criteria) was 70.3% at 4 weeks. 42 (56.8%) achieved platelet count ≥100×109/L, 44 (59.5%) increased by ≥ 50×109/L, and 27 (36.5%) increase by ≥ 100% from baseline. The duration of grade III and IV platelet reduction was 4.2 ± 5.3 days. The time of PLT recovery to ≥75×109/L was 9.4 ± 6.6 days. The time of PLT recovery to ≥100×109/L was 10.2 ± 6.4 days. The platelet count nadir was 57.9 ± 45.3×109/L. The most common adverse events were nausea (8.1%), fatigue (5.4%), and abdominal pain (1.4%). There were no cases of fever, headache, or peripheral edema. Conclusion: Although it was a single-arm trial without a control group, the application of avatrombopag in patients with CIT can increase the platelet count of the patients compared with baseline. Avatrombopag is safe and tolerable. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04609891?term=04609891&draw=2&rank=1, identifier [NCT04609891]

Eltrombopag in pediatric chronic and refractory ITP: data from a retrospective multicenter study from Lebanon.

About 20% to 30% of pediatric patients with immune thrombocytopenia (ITP) develop chronic or refractory disease lasting 12months or more that can be challenging to treat. Eltrombopag is being used after failure of previous lines of therapy with good results at tertiary healthcare centers in Lebanon, a developing country with available multidisciplinary treatment modalities. This is a retrospective multicenter observational study that analyzed data on pediatric patients with chronic or refractory ITP who were given eltrombopag as second- or third-line therapy in 6 large referral hospitals in Beirut (country capital located in mid Lebanon), South, North, and Mount Lebanon between October 2016 and May 2020. The primary end point of the study was a proportion of patients achieving platelet counts of ≥ 50 × 109/L for at least 6weeks without requiring rescue therapy during the observation period. Data from 36 patients treated for chronic and refractory ITP, 20 (55.6%) males and 16 (44.4%) females, were analyzed. The median age at the eltrombopag dose was 11years (2-18years). All the patients had failure of the first-line therapy with steroids, 3 patients received eltrombopag as second-line therapy, and the remaining patients had failure of at least 2 previous lines of therapy, including steroids. The primary end point was achieved in 21 (58.3%) of 36 patients. The treatment was discontinued in 3 patients due to no response. Hepatotoxicity and all other adverse events (headache, weakness, and diarrhea) were mild and transient. All the patients who achieved the target platelet count of ≥ 50 × 109/L maintained the response for the treatment duration, which was a minimum of 5months up to 3years, with median/mean observation periods of 12months and 14months, respectively. This study confirms the findings of randomized controlled trials that eltrombopag as second- or third-line therapy in pediatric patients with chronic and refractory ITP is effective and safe, reinforcing its role in the real-world management of these patients.

Dose tapering to withdrawal stage and long‐term efficacy and safety of hetrombopag for the treatment of immune thrombocytopenia: Results from an open‐label extension study

BackgroundThe efficacy of hetrombopag in Chinese patients with immune thrombocytopenia (ITP) has been demonstrated in a randomized, double‐blind, placebo‐controlled, multicenter, phase III trial (NCT03222843). ObjectiveThis study aimed to report comprehensive data on a ≤6‐week dose tapering to withdrawal (Stage 3) and an additional 24‐week long‐term extension period (Stage 4) in this phase III trial. Patients/MethodsPatients who fulfilled the screening criteria were eligible to enter Stage 3 or 4. During Stage 3, hetrombopag was gradually tapered to withdrawal. During Stage 4, hetrombopag treatment was initiated at 2.5, 3.75, 5, or 7.5 mg once daily. The efficacy endpoints during Stage 3 or 4 and the safety profile during the entire treatment period were reported. ResultsAmong 194 patients who entered Stage 3, 171 (88.1%) relapsed. The median time to the first relapse since the start of Stage 3 was 15.0 days (95% CI, 14.0–16.0). In Stage 4, 144 (42.5%) patients responded at ≥75% of their assessments and 254 (74.9%) patients achieved platelet count ≥30 × 109/L at least once, which was at least twice their baseline platelet count in the hetrombopag group (n = 339). The most common adverse events were upper respiratory tract infection (53.1%), thrombocytopenia (27.1%), and urinary tract infection (21.2%) in the hetrombopag group. ConclusionThe majority of patients who experienced dose tapering to withdrawal experienced a relapse. Long‐term treatment with hetrombopag was effective in increasing and maintaining platelet count within the desired range in Chinese adults with ITP. Hetrombopag was well tolerated.

Safety and efficacy of hetrombopag in patients with chronic immune thrombocytopenia: a single-arm, open-label, multi-center phase 1 study.

BackgroundThrombopoietin receptor agonists (TPO‐RAs) are promising therapeutic strategy for patients with immune thrombocytopenia (ITP). We conducted this phase 1 trial (NCT02614846) to evaluate the preliminary efficacy and safety of hetrombopag (a TPO-RA) in patients with ITP.MethodsPatients with ITP who had an insufficient response or had progressed on at least one standard treatment for ITP were given hetrombopag orally at an initial dose of 5 mg once daily for up to 6 weeks. The primary endpoint was the proportion of patients who achieved platelet counts of ≥50×109/L at week 6.ResultsA total of 37 eligible patients received hetrombopag treatment. This study met its primary endpoint, 22 (59.5%, 95% CI: 42.1–75.3) patients responded to hetrombopag, achieving platelet counts ≥50×109/L at week 6. Of the 29 (78.4%, 95% CI: 61.8–90.2%) patients who responded at least once during the study, the median time from treatment initiation to first response was 2.1 weeks (95% CI: 1.3–4.1 weeks). The median accumulative response duration was 3.1 weeks [interquartile range (IQR), 2.1–4.1 weeks]. The incidence of bleeding was reduced with hetrombopag treatment compared to the baseline. Adverse events (AEs) occurred in 32 (86.5%) patients and treatment-related AEs occurred in 13 (35.1%) patients. Two (5.4%) serious AEs were reported, but neither were treatment related. The dose was modified in one (2.7%) patient due to an AE. There were no incidences of treatment discontinuation/interruption or death.ConclusionsHetrombopag showed preliminary activity in elevating platelet counts and reducing bleeding in patients with chronic ITP who had received at least one standard therapy. It was well-tolerated.

Targeted therapies for immune thrombocytopenic purpura: a meta-analysis of randomized controlled trials.

Several targeted therapies have been approved in recent years for second-line treatment of immune thrombocytopenic purpura (ITP), providing an alternative to rituximab and splenectomy. The extent to which these drugs reduce bleeding risk has not been well defined. Targeted therapies recently approved for the treatment of ITP in adults were identified through a search of recently published professional guidelines. Randomized controlled trials (RCTs) supporting regulatory approval were identified through a search of drug labels on FDA@gov. Odds ratios (ORs) and associated 95% confidence intervals (CIs) were computed for pre-specified efficacy outcomes including platelet recovery to ≥ 50,000/µL, major and minor bleeding events, and survival. ORs for all adverse events were also computed. Four targeted therapies were identified, including three thrombopoietin receptor agonists and one tyrosine kinase inhibitor. Six RCTs, comprising 752 patients, were included in the meta-analysis. More patients treated with targeted therapies for ITP as compared to placebo achieved platelet counts over ≥ 50,000/µL (OR 8.29, 95% CI 5.59-12.29). Compared to placebo, targeted therapies for ITP were associated with significantly lower odds for major bleeding (OR 0.43, 95% CI 0.21-0.91), minor bleeding (OR 0.66, 95% CI 0.45-0.97), and with numerically lower mortality rates (OR 0.24, 95% CI 0.05-1.07). The odds for adverse events were comparable between the two arms (OR 1.43 95% CI 0.76-2.67). Compared to placebo, targeted therapies for ITP increase platelet counts, decrease bleeding events, and show a trend towards lower mortality, without increased toxicity. These findings support their use as a second-line ITP treatment.

A multicentre double-blind, double-dummy, randomised study of recombinant human thrombopoietin versus eltrombopag in the treatment of immune thrombocytopenia in Chinese adult patients.

We performed a double-blind, double-dummy controlled study to compare the efficacy between recombinant human thrombopoietin (rhTPO) and eltrombopag in rapidly increasing the platelet counts in Chinese patients with immune thrombocytopenia (ITP). A total of 96 patients diagnosed with ITP for ≥6 months who had baseline platelet counts of <30 × 109 /l were randomly assigned (1:1 ratio) to receive eltrombopag 25 mg/day or rhTPO 300 u/kg for 2 weeks. Compared with the eltrombopag group, a significantly higher proportion of patients in the rhTPO group achieved platelet counts of ≥50 × 109 /l [75·00% (36/48) vs. 43·75% (21/48), P = 0·003] or complete response (64·58% vs. 25·00%) on day 15. Moreover, a higher proportion of patients in the rhTPO group either had platelet counts that rapidly increased to twice that of baseline and with platelet counts of ≥30 × 109 /l, or reached ≥50 × 109 /l at least once when analysed on day 9, 12, and 15. However, upon discontinuation of the treatment, the platelet counts reduced to the baseline within 1 week in the rhTPO group, but on the fourth week in the eltrombopag group. Adverse events were similar in patients given rhTPO and eltrombopag. To conclude, rhTPO is superior to eltrombopag at 25 mg/day in rapidly increasing platelet counts in patients with ITP (ClinicalTrials.gov Identifier: NCT03771378).

Eltrombopag (EPAG) Treatment Improved Platelet Counts in Patients with Persistent or Chronic Immune Thrombocytopenia during a 2-Year, Phase IV, Open-Label Study

Background: ITP, characterized by isolated platelet reduction, is classified as persistent within 3- et al. Acta Haematol 2017;137:66-72) was performed. Aims: To evaluate the effects of EPAG on platelet counts, and long-term safety, during 2 yrs9 treatment, in persistent or cITP pts. Methods : Adults ≥18 yrs old diagnosed with persistent ITP (3- Results: At BL, 37/162 (23%; mean ± SD age 44 ± 16 yrs; 57% female) and 124 (77%; mean ± SD age 43 ± 16 yrs; 66% female) pts had persistent or cITP, respectively. One pt (1%) had ITP diagnosis duration 9 /L and 100% had no prior TPO-RA exposure; of those with cITP, 27% were splenectomized, 60% had platelet 9 /L and 90% had no prior TPO-RA exposure. 13 persistent ITP pts (35%) and 31 cITP pts (25%) withdrew early from the study, most commonly because of AEs (n=8, 22% and n=13, 10%, respectively) and lack of efficacy (n=4, 11% and n=7, 6%). Median exposure duration was 2.0 yrs (range 31 days to 2.1 yrs) and 2.0 yrs (range 21 days to 2.2 yrs); mean daily dose was 48.8 (range 11-75) mg/day and 48.8 (range 5-75) mg/day. Median platelet counts in all pts increased to ≥50×10 9 /L within 1 wk in both groups (Figure). Overall, 31 (84%) persistent ITP and 109 (88%) cITP pts achieved a platelet count ≥50×10 9 /L without rescue therapy; 19 (51%) and 62 (50%) maintained platelet counts continuously ≥50×10 9 /L for ≥28 wks. In pts with BL platelets 9 /L who achieved platelet counts ≥50×10 9 /L (on treatment, no rescue therapy; n=25 persistent ITP, n=99 cITP), median (95% CI) time to platelets ≥50×10 9 /L was 4.0 (1.3-14.4) wks in persistent ITP and 2.1 (1.4-2.1) wks in cITP pts. Sixteen (43%) persistent and 50 (40%) cITP pts received rescue therapy, most frequently a new ITP medication (n=9 [24%] and n=34 [27%], respectively). Compared with BL, 17/18 persistent ITP pts (94%) remained MF-0 at 2 yrs, 1 (6%) had a 1-grade increase; in cITP pts, 62/75 (83%) remained MF-0, 8 (11%) had a 1-grade increase, 2 had a 1-grade decrease and 1 (1%) remained MF-1. No pts had symptoms or abnormalities typical of MF. AEs were reported in 32 (86%) persistent ITP pts and in 108 (87%) cITP pts (Table). Serious AEs occurred in 12 (32%) persistent ITP pts, most frequently (≥5%) nausea (n=2, 5%) and fatigue (n=2, 5%), and in 29 (23%) cITP pts, most frequently (≥2%) gastrointestinal hemorrhage, gingival bleeding, tooth abscess, cerebral hemorrhage, lethargy, thrombocytopenia and menorrhagia (all n=2, 2%). No pt with persistent ITP died while on treatment (+ 1 day), and 3 (2%) cITP pts died (cerebral hemorrhage, n=2 [platelets 9 /L, not considered drug-related] and acute respiratory distress syndrome, n=1). Summary/conclusions: The effects of EPAG on platelet counts in persistent ITP pts were consistent with that seen in the cITP population, with sustained platelet increases. Overall AE rates were similar in both subgroups and AEs reported were consistent with the known EPAG safety profile or underlying disease. While there appeared to be an increase (>10% difference) in some AEs (vertigo, dyspepsia, arthralgia) in persistent ITP pts, this could be attributed to the limited pt number in this subgroup. These results are encouraging; outcomes following EPAG treatment in persistent ITP are consistent with reports in cITP. Disclosures Wong: Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding; Merck Sharp & Dohme: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Biogen-Idec: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Brynes: Novartis: Research Funding. Arikan: Novartis: Employment. Maier: Novartis: Employment. Shamsi: Fresenius Germany: Research Funding; Novartis Pharma Pakistan: Consultancy; Roche Diagnostic Pakistan: Consultancy.

Occurrence and Management of Cataracts in Adult Patients (pts) with Chronic Immune Thrombocytopenia (cITP) during Long-Term Treatment with Eltrombopag (EPAG): Results from the Extend Study

Occurrence and Management of Cataracts in Adult Patients (pts) with Chronic Immune Thrombocytopenia (cITP) during Long-Term Treatment with Eltrombopag (EPAG): Results from the Extend Study

Efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia: stage 2 results from a multicenter phase III study

This phase III, randomized, placebo-controlled study conducted in three stages (6-week, randomized, placebo-controlled stage 1; 24-week, open-label stage 2; and continuous extension stage 3) assessed the long-term efficacy and safety of eltrombopag use in Chinese patients with chronic immune thrombocytopenia (ITP). This article presents the results from stage 2. Overall, 150 patients (placebo-eltrombopag [P-E], 50; eltrombopag-eltrombopag [E-E], 100) received open-label eltrombopag. The median platelet count was maintained between 41 × 109/L and 80 × 109/L. Most patients in both groups (P-E, 90.0%; E-E, 81.8%) achieved platelet counts ≥30 × 109/L and ≥2 times the baseline platelet count at least once with eltrombopag treatment. Overall, 32% of patients achieved platelet counts ≥50 × 109/L in ≥75% of platelet count assessments. Both groups showed a decreased tendency to infrequent bleeding and clinically significant bleeding events during stage 2 compared with baseline. Among patients who received ≥1 ITP medication at baseline, 70.4% in the P-E group and 40.8% in the E-E group reduced or permanently stopped ≥1 of their ITP medications. The stage 2 results further demonstrated a sustainable long-term efficacy and good tolerability of eltrombopag with a favorable benefit–risk ratio in Chinese chronic ITP patients. Trial registration: Clinicaltrials.gov NCT01762761. Registered 8 January 2013, https://clinicaltrials.gov/ct2/show/NCT01762761

Fine-tuning the treatment toolbox of immune thrombocytopenia: fostamatinib as a second-line therapy.

Fine-tuning the treatment toolbox of immune thrombocytopenia: fostamatinib as a second-line therapy.

Eltrombopag for the treatment of primary immune thrombocytopenia in 23 pediatric patients

目的评估艾曲泊帕治疗儿童原发免疫性血小板减少症（ITP）的疗效和不良反应。方法回顾性分析2015年5月至2019年3月接受艾曲泊帕治疗的23例儿童ITP患者临床资料。结果23例患者中，男11例，女12例，中位年龄11（2~17）岁。新诊断ITP 4例（17.39%），持续性ITP 8例（34.78%），慢性ITP 11例（47.83%）。艾曲泊帕中位起始剂量为25.0（12.5~50.0）mg/d。基线中位血小板计数为14（2~82）×109/L，治疗后第2周（23例）、第4周（23例）、第3个月（16例）、第6个月（11例）的中位血小板计数分别为40（4~170）×109/L、20（4~130）×109/L、60（4~110）×109/L、70（18~160）×109/L，均高于基线水平（z=-3.440，P=0.001；z=-1.964，P=0.049；z=-4.339，P<0.001；z=-5.794，P<0.001）。7例（30.43%）患者的起效时间≤7 d，10例（43.48%）患者的起效时间≤2周，总有效率为60.87%（14/23）。<6岁（6例）、6~12岁（10例）、13~17岁（7例）组的总有效率分别为33.33%（2/6）、60.00%（6/10）、85.71%（6/7），组间比较差异均无统计学意义（P>0.05）。23例患者基线WHO出血评分0、1、2级分别有4、12、7例，治疗后分别为13、7、3例，出血症状得到明显改善（χ2=7.558，P=0.006）。治疗过程中发生转氨酶、胆红素增高各4例，轻度恶心、呕吐及头晕各1例，对治疗均未造成影响。结论艾曲泊帕作为二线用药治疗儿童ITP疗效及耐受性均较好。

Platelet Response to Avatrombopag in Patients with Chronic Immune Thrombocytopenia: Additional Analyses from a Phase 3 Study and Its Extension

Background: Avatrombopag (AVA) is a novel, oral thrombopoietin receptor agonist (TPO-RA) recently FDA approved for the treatment of chronic immune thrombocytopenia (ITP) in patients who have not responded to prior therapies. Additionally, AVA is approved for the treatment of thrombocytopenia in chronic liver disease patients undergoing a procedure. AVA is unique in that it does not have a boxed safety warning for hepatoxicity, is administered with food, and does not have any dietary restrictions. Further, it does not interact with polyvalent cations (calcium, magnesium, iron, selenium, zinc, etc.) in foods, mineral supplements, or antacids that could reduce systemic exposure and efficacy. Methods and Aims: A 6-month, multicenter, randomized, double-blind, Phase 3 study (Core Study) enrolled 32 AVA- and 17 placebo (PBO)-treated patients with ITP. The mean platelet count at Baseline was 13,600/µL for the study population. The starting dose for AVA was 20 mg QD, with subsequent dose titration (5 to 40 mg) to maintain platelet counts between 50,000 to 150,000/µL. The primary endpoint was the median cumulative number of weeks achieving a platelet count ≥50,000/µL, and AVA was shown to be superior to PBO (12.4 vs. 0.0 weeks, p&lt;0.0001). Achieving a platelet count of ≥50,000/µL on Day 8 was a key secondary endpoint with 65.6% of AVA-treated patients meeting this endpoint versus 0% for PBO (p&lt;0.0001). AVA had a favorable safety profile with the most frequently reported adverse events including headache, fatigue, contusion, epistaxis and upper respiratory tract infection. In addition, patients could enter the Extension Phase if they completed the 6-month Core Study, or if they experienced a lack of efficacy during that period. Reaching a target platelet count of ≥50,000/µL at any time is a common endpoint for therapies in clinical studies as well as in clinical practice, with a platelet count of ≥100,000/µL often being defined as a complete response. The objective of the analyses of these endpoints for the Phase 3 study was to provide previously unreported data, and further evaluate the efficacy of AVA in patients with ITP, i.e., the percentage of patients who achieved platelet counts ≥50,000/µL or ≥100,000/µL at any time during the Core Study and its Extension Phase. Results: In the Core Study, a high proportion of AVA patients achieved a platelet count ≥50,000/µL relative to PBO by Day 28 (84.4% vs. 0.0%, respectively) and Week 26 (87.5% vs. 5.9%). In an integrated analysis of the Core Study and its Extension Phase, 93.8% of patients initially randomized to AVA achieved a platelet count of ≥50,000/µL at any time, and 64.7% of PBO patients who rolled-over to AVA in the Extension Phase also reached this metric. In addition, a high proportion of patients in the Core Study achieved platelet counts categorized as a complete response, with 81.3% of patients reaching a platelet count ≥100,000/µL at any time by Month 6, versus 5.9% with PBO. Across the Core Study and its Extension Phase, 84.4% of patients initially randomized to AVA and 58.8% of those who initially received PBO achieved a complete response at any time. During the Extension Phase out through 36 weeks, both patients who were initially randomized to AVA and the PBO patients who rolled over to AVA in the Extension Phase maintained mean platelet counts ≥ 50,000/µL, demonstrating the consistency of efficacy for AVA; i.e., both PBO-treated patients responded to active drug and those previously administered AVA maintained platelet counts in the target range in the Extension Phase. Conclusions: Analysis of these previously unreported alternative efficacy endpoints that are standard across other clinical studies demonstrated a high proportion of AVA-treated patients in the Phase 3 study as responders or complete responders. Further, the integrated analyses of the Phase 3 Core Study and Extension Phase data provides additional information regarding the durability of the AVA response, and illustrates the consistency of effect with PBO-treated patients also responding to subsequent treatment with AVA. Table Disclosures Nagalla: Alnylam: Membership on an entity's Board of Directors or advisory committees. Vredenburg:Dova Pharmaceuticals: Employment, Other: Shareholder. Allen:Dova Pharmaceuticals: Equity Ownership, Other: Chief Medical Officer .

Long-Term Response Rates in Patients with Chronic Immune Thrombocytopenia Treated with Avatrombopag: Additional Analyses from a Phase 3 Study and Its Extension Phase

Background: Avatrombopag (AVA) is a novel, oral thrombopoietin receptor agonist (TPO-RA) recently FDA approved for the treatment of chronic immune thrombocytopenia (ITP) in patients not responding to prior therapies. Additionally, AVA is approved for the treatment of thrombocytopenia in chronic liver disease patients undergoing a procedure. Unlike eltrombopag, AVA absorption is not affected by dietary fat or polyvalent cations (e.g., calcium, magnesium, iron, etc.) facilitating ease of use by patients and it also has not been associated with hepatotoxicity. A randomized, controlled, double-blind phase 3 study including 32 ITP patients treated with AVA and 17 treated with placebo (PBO) for 6 months was previously published (Jurczak et al., 2018), demonstrating the superiority of AVA to PBO in median cumulative weeks achieving platelet counts (Plt) ≥50,000/µL (12.4 vs. 0.0 weeks, p&lt;0.0001), and a rapid onset of action (65.6% achieved Plt ≥ 50,000/µL on Day 8 for AVA vs. 0% for placebo (p&lt;0.0001). In addition, AVA had a favorable safety profile with headache, fatigue, petechiae, contusion, and upper respiratory tract infection reported as the most common adverse events. Long-term AVA response rates in ITP have not previously been published. Methods and Aims: After the phase 3 core study, patients had the option to continue on to receive AVA in an open-label extension phase. Patients were eligible for the extension phase if they had completed the 6-month core study or discontinued treatment due to lack of efficacy in the core study. We analyzed the response rates for patients utilizing two classes of response: 1) a Plt response was defined as Plt ≥50,000/µL as measured during an on-study patient visit, and 2) a complete Plt response was defined as Plt ≥100,000/µL as measured during an on-study patient visit. A subset of "durable responders" who achieved a Plt response for 6 of the final 8 weeks of the core study (34.4% of AVA patients qualified as durable responders), was also analyzed separately to assess for maintenance of this high response rate in the extension phase. Results: The mean duration of study participation was 23 weeks in the core study and 44 (range, 8-76) weeks overall (core plus extension) including 21 and 19 scheduled visits per patient in core and extension, respectively, for patients completing both studies. In the core study, a Plt response (Plt ≥50,000/µL) was achieved at 48.6% of patient visits for AVA, compared with &lt;0.01% for PBO. In the open-label extension phase for those patients continuing AVA treatment, a Plt response was achieved at 44.2% of visits. For PBO patients who rolled over to AVA in the extension phase, a Plt response was achieved at 41.4% of visits. For all patients ever exposed to AVA (core phase AVA arm and PBO patients rolled over to AVA) during the core study and extension phase, 46.4% of visits achieved a Plt response. In durable responders from the core study (as defined above), a Plt response was achieved at 96.1% of the extension phase visits. During the core study, a complete Plt response (Plt ≥100,000/µL) was achieved at 25.6% of visits in AVA-treated patients versus &lt;0.01% in the PBO treatment group. During the open label extension phase for patients treated with AVA, a complete Plt response was achieved at 24.2% of visits. For the PBO-treated patients in the core study who rolled over to AVA in the extension phase, a complete response was achieved in 18.3% of the extension phase visits. In total for all patients ever treated with AVA (core phase AVA arm and PBO patients rolled over to AVA), a complete Plt response was achieved at 23.5% of AVA study visits throughout the core study and extension phase. In durable responders from the core study, a complete Plt response was achieved at 60.0% of the extension phase visits. Response rates for AVA-treated patients are summarized in the table below. Conclusions: Plt response rates were similar in the core study and extension phase. Durable responders maintained a high rate of Plt response and complete Plt response in the extension phase, providing evidence that AVA-responding patients will continue to respond for extended treatment periods. Additionally, consistent efficacy was noted, as patients in the PBO group who rolled over to active drug demonstrated similar efficacy as AVA-treated patients. AVA-treated patients had substantially higher Plt response and complete Plt response rates than those treated with PBO. Figure Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Moderna: Consultancy; Agios: Consultancy, Research Funding. Aggarwal:Dova Pharmaceuticals: Employment. Vredenburg:Dova Pharmaceuticals: Employment, Other: Shareholder. Allen:Dova Pharmaceuticals: Equity Ownership, Other: Chief Medical Officer .

Phase 2 Study of Efgartigimod, a Novel FcRn Antagonist, in Adult Patients with Primary Immune Thrombocytopenia

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder, characterized by a low platelet count (<100 × 109 /L) in the absence of other causes associated with thrombocytopenia. In most patients, IgG autoantibodies directed against platelet receptors can be detected. They accelerate platelet clearance and destruction, inhibit platelet production, and impair platelet function, resulting in increased risk of bleeding and impaired quality of life. Efgartigimod is a human IgG1 antibody Fc-fragment, a natural ligand of the neonatal Fc receptor (FcRn), engineered for increased affinity to FcRn, while preserving its characteristic pH-dependent binding. Efgartigimod blocks FcRn, preventing IgG recycling, and causing targeted IgG degradation. In this Phase 2 study, 38 patients were randomized 1:1:1 to receive four weekly intravenous infusions of either placebo (N = 12) or efgartigimod at a dose of 5 mg/kg (N = 13) or 10 mg/kg (N = 13). This short treatment cycle of efgartigimod in patients with ITP, predominantly refractory to previous lines of therapy, was shown to be well tolerated, and demonstrated a favorable safety profile consistent with Phase 1 data. Efgartigimod induced a rapid reduction of total IgG levels (up to 63.7% mean change from baseline), which was associated with clinically relevant increases in platelet counts (46% patients on efgartigimod vs 25% on placebo achieved a platelet count of ≥50 × 109 /L on at least two occasions, and 38% vs 0% achieved ≥50 × 109 /L for at least 10 cumulative days), and a reduced proportion of patients with bleeding. Taken together, these data warrant further evaluation of FcRn antagonism as a novel therapeutic approach in ITP.

Rozanolixizumab, an Anti-FcRn Antibody: Final Results from a Phase II, Multiple-Dose Study in Patients with Primary Immune Thrombocytopenia

Rozanolixizumab, an Anti-FcRn Antibody: Final Results from a Phase II, Multiple-Dose Study in Patients with Primary Immune Thrombocytopenia

Deviation from Guidelines in Use of Eltrombopag and Romiplostim in Clinical Practice for Children with Primary Immune Thrombocytopenia; Multi-Center Egyptian Experience

Background: Primary immune thrombocytopenia (ITP) has been treated with steroids or immune-suppressive. Thrombopoietin receptor agonists (TPO-RAs), changed the treatment landscape for ITP. Romiplostim and Eltrombopag were FDA approved for use in pediatric patients ≥1 year with ITP of &gt;6 months' duration and insufficient response to previous therapy. Following the guidelines is not always feasible in practice. Aim and Methodology Centers treating more than 25 new cases/year with good recording system were included; aiming to report outcome, adverse events (AEs) and deviation from guidelines. Newly diagnosed ITP children were excluded. Data was collected from January 2017- June 2019; children age &gt;1 to 18 years with persistent ITP (3-&lt;12 months) or chronic (≥12 months), who had previously been treated with ≥1 previous ITP therapy, and had platelet counts (PC) persistently &lt;30×109/l with moderate-severe bleeding. Eltrombopag was described in a dose of 25 mg/day for those &gt; 1 to 12 years; or in 50 mg/day for those &gt;12-18 years; dose was escalated to 50 or 75mg/day for those 6-12 and &gt;12 years respectively on failure to have PC &gt; 50 x 109/L. Weekly CBC and self-record of bleeding for 1st 24 week then bi-weekly. Failure to show a good response; Eltrombopag dosing should be adjusted to achieve that goal and not to exceed 200 × 109/L. Romiplostim was used in 1 ug/kg and escalated up to 10 ug/kg according to response. Serious AEs were reported to ethical committee within 24 hours. Results Two years Observational study of 204 out of 1080 primary ITP (268 persistent and 812 chronic); 55% females median age 8 years, received Eltrombopag (n=186), Romiplostim (n= 18) from 3-30 months was prescribed after failure of 1-5 lines of therapy in 15% of Persistent ITP and 20% of chronic ITP. Adequate response at 24 weeks in 60% on Eltrombopag or Romiplostim had a significant reduction in both skin-related and non-skin-related bleeding symptoms). However 50% discontinued treatment; (40% due to inadequate response, 8% irregular availability and 2% due to SAEs). Deviation from guidelines in 40%; (15% started Eltrombopag early between 3-6 months who showed a higher response rate; half of them could stop it without drop of PC); while 20% continued Eltrombopag for &gt;12 month with lack of response after dose escalation at 24th week and 5% were not following the described dose or the regular monitoring. 40% of chronic ITP patients achieved platelet counts of &gt;50 x 109/L or more at least twice. Common adverse events included; headache (10%). myalgia (10%), rhinitis (8%), diarrhea 8% Serious adverse events occurred in 4 (1 elevated transaminases, one unrelated life-threatening bleeding and two high PC; &gt;1000 x109/L). Conclusion: TPO-RAs were used in almost 15% of persistent and 20% of chronic ITP as 2nd line or more therapy and in 90% was Eltrombopag; which produced an excellent response for those 3-6 months; deviating from guidelines. It showed a sustained platelet response in 40% of patients with chronic ITP, however it should be stopped if showing poor response after dose escalation. Disclosures No relevant conflicts of interest to declare.