The purpose of this study is to assess the ability of eltrombopag to elevate platelet counts thereby reducing the need for platelet transfusions in chronic liver disease patients with thrombocytopenia undergoing elective invasive procedures. The clinical benefit of eltrombopag will be measured by the proportion of subjects who avoid platelet transfusions, before, during and up to 7 days after undergoing an invasive procedure. In addition, bleeding events will be monitored during this time. The number of transfusions, safety events and medical resource utilisation will be monitored during this time and for up to 30 days after undergoing an invasive procedure to help further evaluate clinical benefit.

Background: Pre-existing thrombocytopenia in MDS/AML is worsened during the initial cycles of azacitidine (AZA) therapy, resulting in bleeding risk and possible platelet transfusion. Eltrombopag (EPG) is an oral TPO-receptor agonist. In vitro, it has anti-proliferative effects on AML blasts.Aim: 
To assess the safety of escalated doses of EPG in patients undergoing AZA for MDS/AMLMethod
An investigator-initiated phase-II, single arm, study of EPG with AZA. Inclusion: relapsed or de-novo MDS/CMML/AML (blasts 5-30%); or symptomatic cytopenia; or blasts 31-50% if >/=65 years or previously-treated disease; and plateletsResult
Of 25 patients, 10 had prior therapy, which was chemo in 7; of these 6 had blasts >/=10%, 2 with blasts 20% or above. Of the 15 de-novo patients, 7 had blasts >/=20% (AML) and a further 2 had blasts between 10 and 19%. The median platelet count was 38x10^9/L (range 8-127). A median 11(2-24) cycles AZA and 6 cycles of EPG were delivered. One patient developed GrII EPG-related LFT abnormalities (resolved). Grade 3 fatigue was attributed to the combination in one patient. Thrombocytosis (>450 x109/L) resulting in EPG cessation occurred in 6 (at 50, 50, 150 and three at 200mg), without complications. 10 patients experienced reversible skin yellowing. Response/improvement was seen in 18 (72%): 7CR, 3CRm, 5HI-P,1 HI-N,2 with >50% blast reduction from >20% (8%). 5 patients had progression at first response. There were 19 events in total (17 progressions, 2 with worsening haematology). Median PFS was 12.0 months (95% CI 5.6 to 24.3 months). Median OS was 15.3 months (95% CI 11.9 to 31.7 months).Platelet improvement was seen in 54% (13/24) of patients with baseline platelets <100 at median (range) at 46d (7-107) following commencement of AZA. Only one patient (4%) had an improvement in platelets following the monotherapy phase.Conclusion
Eltrombopag could be safely delivered at these doses. A phase III international study has commenced to better define the role of this combination as supportive care for patients undergoing treatment with azacitidine. Table:Characteristics and best responses observed.MDS/AML CharacteristicsBest ResponseMDS <20% Blasts, De Novo (N=7)5CR, 1SD, 1 HI-NAML >/=20%, De Novo (N=8)1CR, 1PR, 3 Hi-P, 1SD, 2 PDPrior therapy for MDS/AMLBlasts <20% (N=7)1CR, 3CRm, 1SD, 1PD, 1Hi-PPrior therapy for MDS/AMLBlasts >/=20% (N=3)2PD, 1 Hi-PFigure:Overall survival of the trial population.Figure:. Overall survival of the trial population.Dickinson:

GSK:

Consultancy; Celgene: Honoraria. Off Label Use: Eltrombopag for MDS. Sardjono:

GSK:

Employment. Seymour:Celgene: Consultancy, Honoraria, Speakers Bureau. Kenealy:Celgene: Honoraria, Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding.

Background: Eltrombopag, an orally bioavailable thrombopoietin receptor agonist, is approved for the treatment of chronic idiopathic thrombocytopenic purpura (adults and children), hepatitis C virus-related thrombocytopenia, in multiple countries. In the US, eltrombopag is also approved for severe aplastic anemia (SAA) in patients with insufficient response to immunosuppressive therapy. In SAA, patients frequently take cyclosporine (CsA), concurrently with eltrombopag. Eltrombopag is a substrate of breast cancer resistance protein (BCRP), and CsA is reported to be an inhibitor of this transporter. To assess this BCRP interaction further, the effect of CsA on plasma pharmacokinetics (PK) of eltrombopag was assessed in a clinical drug-drug interaction study in healthy human subjects. Methods: In a phase 1, open-label, randomized, three-period crossover study, healthy subjects were randomized to one of the three treatment sequences: (D0, D1, D2), (D1, D0, D2), or (D1, D2, D0), where D0 = 50 mg eltrombopag, D1 = 50 mg eltrombopag + 200 mg CsA, and D2 = 50 mg eltrombopag + 600 mg CsA. Eltrombopag was administered on the first day of each treatment period. On Day -1 of each treatment period, subjects checked into the clinical research unit, where they remained until the 72-hour PK blood draw on Day 4. After a 3- to 10-day washout period, they returned for Day 1 of the next treatment period. The total duration of a subject's participation in the study from screening to final discharge was approximately 6 weeks (assuming 3-day washouts between treatment periods). Safety and PK were analyzed during each period. Results: Thirty-nine healthy subjects were randomized to receive treatment (13 subjects per treatment sequence); 28 (72%) were men and 11 (28%) were women. All 39 subjects completed the study; all subjects were included in the PK and safety analyses. In general, the plasma eltrombopag PK profiles were consistent across the three treatment arms and consistent with that previously reported for eltrombopag in healthy adult subjects (see Figure). Plasma eltrombopag PK parameters and their statistical comparisons are shown in the Table below. On average, eltrombopag AUC(0-inf) and Cmax decreased by 18% and 25%, respectively, when coadministered with 200 mg CsA and decreased by 24% and 39% when coadministered with 600 mg CsA. Median time to Cmax (tmax) of eltrombopag increased from 3 hours to 4 hours in the presence of 200 mg and 600 mg CsA. The most common adverse events (AE) were hot feeling (62%), headache (36%), and nausea (18%). Except for one subject who had a Grade 2 headache, all AEs reported during the study were Grade 1 events. No clinically significant abnormal electrocardiograms were reported. There were no severe adverse events in this study. Conclusions: Given that the eltrombopag dose adjustment is permitted during the course of treatment for achieving the target platelet count, the decrease in exposure following co-administration of 200 mg or 600 mg CsA was not considered clinically meaningful, and therefore no starting dose adjustment is recommended when eltrombopag is co-administered with CsA.

Eltrombopag may improve the cell collection available for Autologous Stem Cell Transplant(ASCT). The overall goal is to determine if adding Eltrombopag to the standard ASCT will increase the number of blood cells collected and reduce the number of times blood needs to be collected. This study will also determine the highest dose of Eltrombopag that can be used without causing serious side effects.

Objective In Japan, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG), and cyclosporine A (CsA) is the standard of care in patients with aplastic anemia (AA) who are not indicated for stem-cell transplantation, although some patients may experience relapse. This study assessed the efficacy and safety of eltrombopag in combination with rabbit-ATG/CsA in IST-naïve patients with non-severe or severe AA in Japan. Methods In this non-randomized, open-label, single-arm, phase II study, rabbit-ATG/CsA and eltrombopag were initiated on Days 1 and 15 (±3 days), respectively, and continued for ≥26 weeks; rabbit-ATG was given for 5 days (Days 1 to 5). The primary endpoint was the overall response rate (ORR) at Week 26. Patients Patients with AA who were IST-naïve and ≤70 years old or between 71 and 75 years old based on the recommendation of the investigator were enrolled in Japan. Results Of the 11 enrolled patients, 10 started treatment with eltrombopag. The ORRs at Weeks 26 and 52 were 70.0% and 60.0%, respectively. The ORR at Week 26 was 100% (all 3 patients) in patients with non-severe AA and 57.1% (4/7) in patients with severe AA. Among transfusion-dependent patients, 66.7% (4/6) and 62.5% (5/8) became red blood cell- and platelet-transfusion independent, respectively. The most common adverse events were nausea and headache. No deaths or hematologic malignancies were reported. A cytogenetic abnormality was reported in one patient. Conclusion This study confirmed the clinical benefit of eltrombopag plus rabbit-ATG/CsA in IST-naïve patients with non-severe or severe AA in Japan.

Background: Eltrombopag is a a thrombopoietin receptor agonist (TPO-RA) approved for chronic primary immune thrombocytopenia (ITP) patients. However, ITP clinical practice in more than 65 years old patients could not reflect efficacy and safety of clinical trials results. Aims: To evaluate the safety and efficacy results of eltrombopag in older than 65 years old patients in a real world setting Methods: 81 equal or more than 65 years old primary ITP patients from 23 Spanish centers who had been treated with eltrombopag and included in the Spanish Eltrombopag ITP Registry were retrospectively evaluated. Results: -The median age of the whole cohort was 75 (IQR, 69-79) years. Our case series included 16 newly-diagnosed, 16 persistent and 49 chronic primary ITP patients [78 (IQR, 73-81), 78 (IQR, 74-85) and 73 (IQR, 68-76) median years, respectively]. There were 51 women and 30 men. 23% of patients had a Charlson Comorbidity Index score of 2 or more at diagnosis. The median time from ITP diagnosis to eltrombopag initiation was 36 (IQR, 4-47) months [1(IQR,0-1.25), 4(IQR,6-8) and 57(IQR, 22-73) months, for each of the groups]. The median number of therapies before starting eltrombopag was 2 (IQR, 1- 3), including rituximab (18%), romiplostim (17%) and splenectomy (10%). At the time of treatment start, 22 of 81 patients (27%) patients were receiving concomitant medication for primary ITP, mainly including corticosteroids (20%) or immunoglobulins (11%). 24 of 81 (30%) patients had bleeding symptomatology during the month preceding the starting eltrombopag. At eltrombopag initiation the median platelet count was 27 x 109/L (IQR, 7-26 x 109/L). 68 of 81 (84%) patients had a response (R) to eltrombopag treatment whilst 62 patients (76%) achieved a complete response (CR; platelet count >100 x 109/L). [R and CR rates were 94% and 87% in newly-diagnosed ITP; 75% and 68% in persistent ITP; 84% and 75% in chronic ITP]. Women reached 86% and 78% of R/CR while 80% and 73% of men. Responses were 91% in patients who received concomitant ITP medication at baseline and 64% in patients without other added treatments. The proportion of patients achieving a platelet response was quite similar regardless bleeding at starting eltrombopag (79% and 86% for patients with and without bleeding, respectively). Of the 82 patients, 20 (24.4%) experienced one or more adverse events during treatment with eltrombopag. Adverse events were mainly grade 1-2 in severity. The commonest adverse effects reported during eltrombopag treatment were diarrhea and headache. Eight percent of patients (7 of 82) had hepatobiliary laboratory abnormalities (HBLAs). On the other hand, we observed seven deaths: three of them were caused by ITP severity (cerebral bleedings), two were due to progression of COPD (chronic obstructive pulmonary disease), one was a gram-negative sepsis and one patient suffered an arrhythmia related sudden death. A subanalysis of primary ITP patients with more than 80 years (6 male and 14 female), revealed as high efficacy rates as younger patients (85% of CR with 75% of responses). This kind of patients are expected to be a very frail patients. Nevertheless, only 7 (35%) patients of this population reported adverse events. Summary/Conclusions: Our case series describe the great efficacy and safety results observed with the use of eltrombopag in our more than 65 years old ITP patients. However more studies are needed to confirm the possible usefulness of TPO-RAs in this variety of primary ITP cases.

Background:

* Myelodysplastic syndromes (MDS) are bone marrow disorders characterized by anemia, neutropenia, and thrombocytopenia (low red blood cell, white blood cell, and platelet counts). Patients with MDS are at risk for symptomatic anemia, infection, and bleeding, as well as a risk of progression to acute leukemia. Standard treatments for MDS have significant relapse rates. MDS patients with thrombocytopenia who fail standard therapies require regular, expensive, and inconvenient platelet transfusions, and are at risk for further serious bleeding complications.
* Eltrombopag is a drug designed to mimic the protein thrombopoietin, which causes the body to make more platelets. Eltrombopag has been able to increase platelet counts in healthy volunteers and in patients with chronic ITP (a disease where patients destroy their own platelets very rapidly and thus develop thrombocytopenia), but researchers do not know if the drug can increase platelet counts in patients with MDS.

Objectives:

* To find out whether eltrombopag can improve platelet counts in patients with MDS.
* To determine whether eltrombopag is safe for patients with MDS.

Eligibility:

* Patients 18 years of age and older who have consistently low blood platelet counts related to MDS that has not responded to conventional treatment.
* Platelet count ≤ 30,000/μL or platelet-transfusion-dependence (requiring at least 4 platelet transfusions in the 8 weeks prior to study entry); OR hemoglobin less than 9.0 gr/dL or red cell transfusion-dependence (requiring at least 4 units of PRBCs in the eight weeks prior to study entry) OR ANC≤500

Design:

* Treatment with eltrombopag tablets once per day for 16-20 weeks.
* Participants will be monitored closely throughout the initial treatment, with weekly blood tests and separate evaluations at the National Institutes of Health (NIH) treatment center every 4 weeks. Bone marrow biopsies may be conducted to check for abnormalities in bone marrow.
* If patients show signs of improved platelet counts after 90 days, treatment will continue with additional doses of eltrombopag.
* Patients who discontinue taking eltrombopag will be evaluated at the NIH treatment center 4 weeks after ending treatment, and again 6 months after ending treatment to check for potential side effects.

BACKGROUND:

Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin.

METHODS:

We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 109 cells per L before major surgery or less than 50 × 109 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 109 cells per L before major surgery or 45 × 109 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov, NCT01621204.

FINDINGS:

Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49-55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; pnon-inferiority=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI -2·1%; pnon-inferiority=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred.

INTERPRETATION:

Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles.

FUNDING:

GlaxoSmithKline and Novartis.

BACKGROUND:

Patients with acute myeloid leukaemia frequently have thrombocytopenia during induction chemotherapy. Eltrombopag, an oral thrombopoietin receptor agonist, stimulates platelet production by a similar mechanism to endogenous thrombopoietin. This study investigated safety and efficacy of eltrombopag versus placebo during anthracycline-based induction treatment of patients with acute myeloid leukaemia.

METHODS:

In this randomised, double-blind, phase 2 study, treatment-naive patients were recruited from clinical centres across 10 countries (Australia, Belgium, Canada, Greece, Hungary, Israel, South Korea, Poland, Russia, and the USA). Patients with acute myeloid leukaemia of any subtype except M3 and M7 were stratified by antecedent malignant haematological disorder (yes or no) and age (18-60 years or >60 years) and were then randomly assigned (1:1) using an automated interactive voice-response system randomisation schedule. Investigators and patients were blinded to study treatment. Starting on day 4, patients received standard induction chemotherapy (daunorubicin bolus intravenous infusion on days 1-3 [90 mg/m2 for patients aged 18-60 years or 60 mg/m2 for patients aged >60 years], plus cytarabine continuous intravenous infusion on days 1-7 [100 mg/m2]), with eltrombopag 200 mg (100 mg for east Asians) or placebo once daily, until platelet counts were 200 × 109/L or higher, until remission, or after 42 days from the start of induction chemotherapy. The primary objective of the study was safety and tolerability assessed by adverse events, changes in left ventricular ejection fraction (LVEF), and clinical laboratory parameters in all treated patients. This study has been completed and is registered with ClinicalTrials.gov, number NCT01890746.

FINDINGS:

Between Sept 7, 2013, and Jan 30, 2015, 149 patients were assessed for eligibility and 148 were then randomly assigned to receive eltrombopag (n=74) and placebo (n=74). Groups were matched in mean (SD) age (56·7 years [12·3] in the eltrombopag group vs 56·6 years [11·6] in the placebo group), mean (SD) initial platelet count (59·5 × 109/L [43·3] vs 63·7 × 109/L [48·0]), and poor-risk karyotype (16 [22%] of 74 patients in both groups). The most common grade 3-4 adverse events (≥10% in either group) were febrile neutropenia (31 [42%] vs 28 [39%]), decreased white blood cell count (8 [11%] vs 5 [7%]), and hypophosphataemia (3 [4%] vs 9 [13%]). Serious adverse events occurred in 24 (32%) patients in the eltrombopag group compared with 14 (20%) patients in the placebo group. 39 (53%) patients in the eltrombopag group died versus 29 (41%) patients in the placebo group. Thromboembolic events (5 [7%] vs 4 [6%]) and mean (SD) change in LVEF (-2·5% [7·8] vs -4·3% [8·5]) were similar.

INTERPRETATION:

Data from this trial do not support combining eltrombopag with induction chemotherapy in patients with acute myeloid leukaemia.

FUNDING:

Novartis Pharma AG.

INTERVENTION:

Trade Name: REVOLADE*28CPR RIV 25MG Pharmaceutical Form: Coated tablet INN or Proposed

INN:

ELTROMBOPAG OLAMINE CAS Number: 496775‐62‐3 Concentration unit: mg milligram(s) Concentration type: up to Concentration number: 150‐

CONDITION:

Immune ThrombocytoPenia (ITP) secondary to Chronic Lymphoproliferative Disorders (LPDs) ; MedDRA version: 15.0 Level: PT Classification code 10050245 Term: Autoimmune thrombocytopenia System Organ Class: 10005329 ‐ Blood and lymphatic system disorders Therapeutic area: Diseases [C] ‐ Blood and lymphatic diseases [C15]

PRIMARY OUTCOME:

Main Objective: Proportion of responders to eltrombopag as defined by changes in the platelet count, in platelet transfusion requirements and/or in the bleeding symptoms during the 6 months of treatment. Primary end point(s): Proportion of responders to eltrombopag as defined by changes in the platelet count, in platelet transfusion requirements and/or in the bleeding symptoms during the 6 months of treatment. Secondary Objective: Assessment of the safety profile of eltrombopag in patients with LPD using the CTCAE criteria. Timepoint(s) of evaluation of this end point: during the 6 months of treatment.

SECONDARY OUTCOME:

Secondary end point(s): Assessment of the safety profile of eltrombopag in patients with LPD using the CTCAE criteria. Timepoint(s) of evaluation of this end point: for the duration of the study

INCLUSION CRITERIA:

1) Diagnosis of any of the following B‐cell chronic LPD, as defined by WHO 2008 classification: small lymphocytic lymphoma/chronic lymphocytic leukemia, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, Hodgkin’s lymphoma. 2) Occurrence of ITP diagnosed on the basis of predefined criteria. 3) Not likely to necessitate any cytotoxic treatment for the following 6 months, according to clinical stage and performance status. 4) Platelet count less than 30,000/µL; patients with platelet count between 30 and 50,000/µL only in case of bleeding signs or symptoms. 5) Age greater than or equal to 18 years. 6) Absence of a personal or family (up to first degree relatives) history of venous or arterial thromboembolism. 7) ECOG performance status =2. 8) Adequate liver and renal function. 9) Absence of active Hepatitis B (HBsAg+ or HBV‐DNA+), Hepatitis C (HCV‐Ab+), or HIV infection. 9) Pr