Background: ITP, characterized by isolated platelet reduction, is classified as persistent within 3-<12 months (mo) of diagnosis and chronic (cITP) when it continues for ≥12 mo. Theoral thrombopoietin-receptor agonist (TPO-RA), EPAG, is approved for the treatment of previously treated (eg corticosteroids, immunoglobulins) cITP patients (pts). Very few analyses have evaluated EPAG treatment specifically in subgroups of persistent ITP pts. To gain better insight into EPAG effects on platelet counts, and long-term safety, in persistent ITP, a subanalysis of a Phase IV, open-label safety study of EPAG in adults with persistent/cITP (Brynes 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 yrs' treatment, in persistent or cITP pts. Methods: Adults ≥18 yrs old diagnosed with persistent ITP (3-<12 mo) or cITP (≥12 mo) were enrolled in this 2-yr, longitudinal, prospective study. Any prior treatment with EPAG or romiplostim must have been completed ≥6 mo before screening. Pts treated with any other TPO-RA, or with baseline (BL) marrow fibrosis (MF) reticulin grade MF-3, were not eligible. All pts started EPAG at 50 mg/day (25 mg for East Asian pts), adjusted to a lower dose or maximum 75 mg dose as required to maintain platelet counts within the clinically indicated range. This analysis evaluated effects of EPAG on platelet counts and MF, and safety during 2 yrs' treatment in persistent or cITP pts. 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 <3 mo. Among persistent ITP pts, 8% were splenectomized, 51% had platelets <30×109/L and 100% had no prior TPO-RA exposure; of those with cITP, 27% were splenectomized, 60% had platelet <30×109/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 ≥50×109/L within 1 wk in both groups (Figure). Overall, 31 (84%) persistent ITP and 109 (88%) cITP pts achieved a platelet count ≥50×109/L without rescue therapy; 19 (51%) and 62 (50%) maintained platelet counts continuously ≥50×109/L for ≥28 wks. In pts with BL platelets <50×109/L who achieved platelet counts ≥50×109/L (on treatment, no rescue therapy; n=25 persistent ITP, n=99 cITP), median (95% CI) time to platelets ≥50×109/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 <5 and 7×109/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.

Eltrombopag has been previously shown to be effective in reversing azacitidine-mediated thrombocytopenia. This was further investigated in the SUPPORT trial, a phase III study assessing the efficacy/safety of eltrombopag plus azacitidine in patients with intermediate- to high-risk myelodysplastic syndromes and thrombocytopenia. The results did not support a clinical benefit for the addition of eltrombopag to azacitidine. We investigated if the somatic mutational profiles in the patient cohort were associated with treatment outcomes. Based on the available data, we observed no imbalance in the mutational profiles between treatment arms or a clear association between identified somatic mutations and clinical outcomes.

BACKGROUND:

The present multicenter retrospective study on eltrombopag administration in Italian children with chronic ITP aims to extend follow-up of our previous study.

MATERIALS AND METHODS:

This retrospective multicenter study was conducted in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). Patients were classified into three subgroups: group 1 included patients who discontinued treatment due to a stable platelet count; group 2 included patients who discontinued treatment due to ineffectiveness; group 3 included patients who did not permanently discontinue treatment.

RESULTS:

56 patients were eligible for analysis. The median duration of eltrombopag treatment was 40 months (7-71 months). Twenty patients (36%) discontinued permanently eltrombopag. The reasons of permanent discontinuation were adverse effects (n = 1), inefficacy (n = 10), stable platelet count (n = 9). All patients of group 1 maintained a durable response without additional treatments after eltrombopag discontinuation. We found that patients of group 2 were on treatment for less time (median treatment time: 13.5 months, min: 6.0 - max: 56.0) than patients of group 1 (median treatment time: 34 months, min: 16.0 - max: 62.0) (p < 0.05). Patients of group 2 mostly did not achieve a stable platelet count in the first 6 months of treatment and underwent concomitant therapies during follow-up respect of group 1 and group 3 (p < 0.01).

CONCLUSION:

Our study found that the benefits of eltrombopag treatment, in terms of platelet count improvement and use of additional therapies, are identifiable from the first 6 months of treatment.

Introduction In AML patients (pts) undergoing 7+3 induction chemotherapy (IC), incomplete platelet (plt) recovery can lead to increased risks of bleeding, prolonged dependence on plt transfusions, plt alloimmunization, and can hinder post-remission therapy. Eltrombopag is a thrombopoietin receptor agonist that stimulates megakaryopoiesis and has anti-leukemic effects (Erickson-Miller 2008; Will 2009; Roth 2012). We present results of an interim, prespecified analysis of an ongoing trial [ClinicalTrials.gov Identifier: NCT02071901] evaluating the efficacy of eltrombopag in accelerating plt count recovery in older AML pts (>60 years) receiving IC. Methods All newly diagnosed AML pts >60 years (yrs) with ECOG scores of 0-2, no active second malignancy, and no evidence of marrow fibrosis at the time of AML diagnosis were included. Acute promyelocytic leukemia, acute megakaryocytic leukemia, and AML out of myeloproliferative neoplasms were excluded. IC consisted of an anthracycline (daunorubicin at 45-mg/m2 or idarubicin at 12 mg/m2 x 3 2 2 days) and infusional cytarabine (100 mg/m2 x 7 days). Eltrombopag was administered starting day 15 (range, day 15-18) of IC in pts who had no morphological evidence of disease (marrow blasts <5%) on day 14 (range, day 14-17). The primary endpoint was the proportion of pts achieving plt>50000/μL by day 24 of IC. Eltrombopag was administered at a dose of 200 mg (100 mg for East Asian [EA] pts) daily with a one-time maximal dose escalation to 300 mg daily (150 mg in EA pts) if plt remained<50,000/μL after 2 weeks on treatment. Eltrombopag was discontinued once plt exceeded 100,000/μL. A two- stage accrual design with a maximum accrual goal of 31 eligible pts was employed with early stopping if>5 of 12 initial eligible pts (42%) failed to achieve plt>50,000/ μL by day 24. Informed consent was obtained prior to start of IC. Results Between 9-2014 and 6-2016, 34 pts were consented of whom 13 met the eligibility criteria. Reasons for failing eligibility (21/34 pts, 62%) included >5% blasts on day 14 marrow (n=15); acute clinical worsening (n=3); marrow fibrosis at AML diagnosis (n=1); active second malignancy (n=1); and elevated transaminases (n=1). Characteristics of the study cohort were: 54% females, 1 pt of EA heritage, median age of 64 yrs (range, 60-71), and 75% with good ECOG status (ECOG 0 or 1). Most pts (62%) had de novo AML, 38% had secondary AML (therapy-related or prior MDS). By CALGB criteria, 82% had intermediate cytogenetics, 9% had adverse karyotype and in 9% cytogenetic analysis was unsuccessful. The median eltrombopag treatment duration was 10 d (range, 8-14 d), and no dose escalations were required. Pts received a median of 4 units of plt (range, 3-11), which equated to 1 unit every 3.6 d, during induction, while during the eltrombopag treatment period, the median requirement decreased to 2 units (range, 0-6) or 1 unit every 4.8 d (p=.04). Pts were transfused with a median of 7 units of red blood cell (RBC) (range, 3-17; 1 unit every 2d) during induction, while on eltrombopag, the median RBC unit transfusion requirement decreased to 4 (range,1-7; 1 unit every 3.6 d) (p=.02). 92% of pts achieved CR at a median time of 32.5 d from IC (range, 29-42). One pt had incomplete CR due to poor ANC recovery. Median times from the start date of IC to plt>20,000/μL,>50,000/μL, and>100,000/μL were 19 d (range, 15-24), 24 d (range, 21-33), and 25 d (range, 23-33), respectively. By day 24 of IC, 8 of 13 pts (62%) had plt>50,000/μL. Trends in the levels of hemoglobin, absolute neutrophil count (ANC), and plt count over time along with median eltrombopag start and stop times are shown in Figure 1. The median peak plt count reached on eltrombopag was 719,000/μL (range, 280-1,935,000/ μL). The median time to reach peak plt count from start date of eltrombopag was 19 d (13-28 d). The reported toxicities were all grade 1/2 and included nausea (n=2), decreased vision (n=1), elevated transaminases (n=1 each), and one each with hypokalemia and hypomagnesaemia. Conclusions Our interim analysis suggests that eltrombopag can hasten plt recovery, potentially reduce plt transfusions and increase CR rates in older AML pts undergoing IC without any limiting toxicities.The initial cohort does not show evidence for acceleration of the leukemic process and progression stopping milestones were not reached. The study met its interim objectives and is currently accruing pts. (Figure Presented).

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INTERVENTION:

Trade Name: Revolade Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 (Eltrombopag) Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 (Eltrombopag) Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use

CONDITION:

acute myeloid leukemia AML ; MedDRA version: 20.0 Level: PT Classification code 10000880 Term: Acute myeloid leukaemia System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04]

PRIMARY OUTCOME:

Main Objective: To study whether supportive treatment with eltrombopag improves treatment change‐free survival (TCFS) in AML patients =65 years of age when added to standard treatment with DAC Primary end point(s): Treatment change‐free survival (TCFS) Secondary Objective: • overall survival (OS) ; • relapse free survival (RFS); • overall response rate (CR, PR, SD); • number of bone marrow blasts after 5, 9 and 12 months; • quality of life (QLQ‐C30 and SF‐36) ; • bleeding events; • median platelet counts; • number of platelet transfusions ; • hospitalization rate ; • safety and tolerability of treatment with EPAG / placebo; • impact of comorbidities on predicting overall survival Timepoint(s) of evaluation of this end point: date of treatment change or death

SECONDARY OUTCOME:

Secondary end point(s): • Overall Survival (OS) in presence of competing risk treatment change ; • Overall response rate (CR, PR, SD) ; • Relapse free survival (RFS) ; • Median platelet counts ; • Number of platelet transfusions during cycles 1‐4 ; • Incidence of bleeding events ; • Number of bone marrow blasts from baseline and after 5, 9 and 12 months ; • Hospitalization rate (days in hospital) ; • Safety and tolerability of treatment with EPAG / placebo ; • Quality of life ; • impact of comorbidities on predicting overall survival Timepoint(s) of evaluation of this end point: • whole study ; • date of relapse, death ; • cycles 1‐4, 5, 9 and 12 ; • follow up after treatment discontinuation: week 2, month 3, 6, 9, 12, 24, 36, and 48

INCLUSION CRITERIA:

• Newly diagnosed AML (including therapy‐related or after antecedent MDS) other than APL according to WHO criteria, i.e. bone marrow aspirate or biopsy must contain =20% blasts of all nucleated cells or differential blood count must contain =20% blasts. In AML defined by cytogenetic aberrations according to WHO the proportion of blasts may be <20% • Age = 65 years • ECOG performance status 0‐3 • Patients not eligible for intensive induction therapy • Planned therapy with DAC • Platelet count <75 Gpt/L taken within 4 weeks prior to randomization • Signed Informed Consent • Adequate liver function as assessed by the following laboratory requirements: o Total bilirubin = 3 times the upper limit of normal (except for Gilbert’s Syndrome) o ALT and AST = 3 times upper limit of normal Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) no F.1.2.1 Number of s

INTRODUCTION:

Immune thrombocytopaenia (ITP) is an acquired disorder of low platelets and risk of bleeding. Although many children can be observed until spontaneous remission, others require treatment due to bleeding or impact on health-related quality of life. Standard first-line therapies for those who need intervention include corticosteroids, intravenous immunoglobulin and anti-D globulin, though response to these agents may be only transient. Eltrombopag is an oral thrombopoietin receptor agonist approved for children with chronic ITP who have had an insufficient response to corticosteroids, intravenous immunoglobulin or splenectomy. This protocol paper describes an ongoing open-label, randomised trial comparing eltrombopag to standard first-line management in children with newly diagnosed ITP.

METHODS AND ANALYSIS:

Randomised treatment assignment is 2:1 for eltrombopag versus standard first-line management and is stratified by age and by prior treatment. The primary endpoint of the study is platelet response, defined as ≥3 of 4 weeks with platelets >50×109/L during weeks 6-12 of therapy. Secondary outcomes include number of rescue therapies needed during the first 12 weeks, proportion of patients who do not need ongoing treatment at 12 weeks and 6 months, proportion of patients with a treatment response at 1 year, and number of second-line therapies used in weeks 13-52, as well as changes in regulatory T cells, iron studies, bleeding, health-related quality of life and fatigue. A planned sample size of up to 162 randomised paediatric patients will be enrolled over 2 years at 20 sites.

ETHICS AND DISSEMINATION:

The study has been approved by the centralised Baylor University Institutional Review Board. The results are expected to be published in 2023.

TRIAL REGISTRATION NUMBER:

NCT03939637.

This is a phase II, open label, multi-center, intra-patient dose escalation study to characterize the pharmacokinetics (PK) after oral administration of eltrombopag in combination with immunosuppressive therapy in pediatric patients with previously untreated or relapsed/refractory severe aplastic anemia or recurrent aplastic anemia.

INTERVENTION:

Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Tablet INN or Proposed

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 25‐ INN or Proposed

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ INN or Proposed

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ INN or Proposed

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use

CONDITION:

Thrombocytopenic subjects with hepatitis C viral infection ; MedDRA version: 9.1 Level: LLT Classification code 10019744 Term: Hepatitis

C PRIMARY OUTCOME:

Main Objective: To evaluate the effect of eltrombopag treatment on Sustained Virological Response (SVR) in thrombocytopenic subjects (platelets <75,000/microL) with hepatitis C virus (HCV) infection Primary end point(s): Sustained virological response (SVR) rate defined as percentage of subjects with non‐detectable HCV‐RNA at 24 weeks post‐completion of the planned treatment period (i.e., Week 48 for genotype 2/3 or Week 72 for non‐genotype 2/3). Secondary Objective: 1. To evaluate ability of eltrombopag to enable initiation of antiviral therapy in thrombocytopenic subjects with HCV infection; 2. To evaluate ability of eltrombopag to maintain antiviral therapy in thrombocytopenic subjects with HCV infection; 3. To evaluate safety/tolerability of eltrombopag when administered once daily in thrombocytopenic subjects with HCV infection; 4. To evaluate effect of eltrombopag on platelet counts in thrombocytopenic subjects with HCV infection; 5. To describe PK of eltrombopag and explore its relationship with relevant safety & efficacy endpoints; 6. To evaluate effects of eltrombopag treatment on antiviral treatment outcome measures (RVR, EVR and ETR in thrombocytopenic subjects with HCV infection; 7. To evaluate impact of eltrombopag on subject reported symptoms and HRQo

L INCLUSION CRITERIA:

1. Male and female subjects, =18 years of age. 2. Evidence of chronic HCV infection (quantifiable HCV RNA). 3. Subjects who, in the opinion of the investigator, are appropriate candidates for peginterferon alfa‐2b and ribavirin combination antiviral therapy. 4. A baseline platelet count <75,000/microL 5. Haemoglobin concentration equal to or >11.0g/dL for men or at least 10.0g/dL for women 6. Absolute neutrophil count (ANC) at least 750/mm3 and no history of infections associated with neutropenia 7. Alpha‐fetoprotein up to 200ng/mL at screening. 8. Creatinine clearance at least 50mL/minute. 9. All fertile males must use two forms of effective contraception during treatment and during the 24 weeks after treatment end. 10. A female is eligible to enter and participate in the study if she is of: • Non‐childbearing potential (i.e., physiologically incapable of becoming pregnant) including any female who: • Has had a hyste

Objectives: To examine burden of BREs in ITP patients treated with EPAG or ROMI. Methods: We investigated BREs, a complication of ITP that leads to significant morbidity and mortality, using a syndicated electronic medical records network that contains records for inpatient and outpatient services and procedures, diagnoses, adverse events (AEs), prescriptions and labs for > 27 million patients from 26 US hospital institutions. Adult patients diagnosed with primary ITP and treated with EPAG or ROMI with prior steroid treatment were included. Patients with secondary ITP, history of HBV, HCV, HIV, malignancy, severe aplastic anemia, myelodysplastic syndrome, myelofibrosis and splenectomy were excluded. BREs were identified based on bleeding codes [BE] and/or uses of rescue therapy [RES] (intravenous (IV) immunoglobulin administration, IV steroid administration, or platelet transfusion (PT) using a combination of diagnosis, procedure, and medication codes. BREs requiring PT were considered severe (sBRE). BREs after initiation of EPAG or ROMI were compared using Z-tests (two-tailed α = 0.05). Results: 140 patients were identified: EPAG (90) or ROMI (50). Mean age (standard deviation) was similar: EPAG 53 (21) /ROMI 56 (23). Liver function tests ALT (EPAG 16.50 (7.97) / ROMI 16.00 (5.96) U/L) , AST (

EPAG:

18.75 (1.79) / ROMI 18.00 (4.85) U/L), and mean platelet volume (EPAG 10.67

/ ROMI:

10.60 fL) were also similar across cohorts. The BREs identified through RES were not significantly different between ROMI and EPAG (20 vs 22%, p= 0.759), while those identified through BE were significantly higher in ROMI vs. EPAG (40 vs 22%, p= 0.026). Conclusions: This retrospective RWE study emphasizes the significant burden of BREs in ITP patients despite treatment which aims to prevent these episodes. BRE rates identified as BE after controlling for confounding, were significantly higher in ROMI-treated patients as compared to EPAG-treated patients.