Background In a randomized study of single-agent eltrombopag (EPAG; n=64) versus placebo (PBO; n=34) in thrombocytopenic patients with advanced myelodysplastic syndromes or acute myeloid leukemia (AML), median overall survival (OS) was 27 weeks for EPAG versus 15.7 weeks for PBO (hazard ratio [HR]: 0.73). In addition to standard supportive care, disease-modifying treatments were generally permitted at any time at the investigator's discretion. To explore the role of concomitant anticancer therapy in this study population, a post hoc subgroup analysis was conducted in patients in each treatment group who received anticancer treatment. Methods Anticancer treatment was grouped post hoc into the following categories: palliative treatment (eg, hydroxyurea, low-dose cytarabine), hypomethylating agents (HMAs; eg, azacitidine and decitabine), induction chemotherapy (eg, 7 + 3; mitoxantrone, etoposide, and cytarabine, etc), and other (eg, lenalidomide). Baseline characteristics and safety/efficacy parameters were examined in this subgroup of patients. Results While on study treatment, a similar proportion of patients in both treatment arms of the trial received anticancer therapy (EPAG, n=28 [44%]; PBO, n=13 [38%]). The majority of patients receiving anticancer therapy in both the EPAG (64%) and PBO (54%) arms received palliative treatments (primarily hydroxyurea and low-dose cytarabine) followed by HMAs (Table). Induction chemotherapy was received by 11% of patients in the EPAG subgroup, compared with no patients in the PBO subgroup. For the subgroup of patients who received anticancer therapy, EPAG patients had higher baseline median platelet counts and absolute neutrophil counts, and a lower incidence of poor prognosis karyotype (Table). The percentage of patients with AML and those who were platelet transfusion dependent were similar between treatment arms at baseline (Table). All patients in both treatment groups experienced ≥1 adverse event (AE) while on study treatment. A lower proportion of EPAG patients experienced a serious AE (SAE) on therapy compared with PBO patients, and proportionately fewer infection-related SAEs were reported in EPAG versus PBO patients (Table). Pyrexia SAEs were higher in the EPAG (5 [18%]) arm versus the PBO (1 [8%]) arm. In the subgroup of patients receiving anticancer therapy, a similar proportion of EPAG and PBO patients experienced Grade ≥3 hepatobiliary events (3 [11%] vs 1 [8%]). Three (11%) EPAG patients experienced Grade ≥3 renal and 2 (7%) thromboembolic events on study drug, whereas no PBO patients experienced these events. A lower proportion of patients on EPAG (18%) experienced AEs that led to discontinuation of study treatment compared with those on PBO (46%). A lower proportion of EPAG patients (32%) died on therapy compared with PBO (69%); the primary cause of death in both arms was the underlying disease. Median platelet counts for EPAG patients receiving anticancer treatment increased above baseline, whereas median platelet counts remained stable at baseline levels for PBO patients. A higher proportion of EPAG patients than PBO patients achieved platelet (50% vs 31%) and red blood cell (RBC; 29% vs 8%) transfusion independence for ≥8 weeks (Table). Bleeding events (Grade ≥3) were reported in fewer EPAG patients (11%) versus PBO patients (38%). When censoring patients at the start of anticancer treatment, no apparent difference in OS was observed between treatment arms (HR: 0.97). Summary/conclusion In the subgroup who received anticancer therapy, EPAG patients had higher incidences of platelet and RBC transfusion independence, higher median platelet counts, and lower incidences of bleeding and infectious complications compared with PBO patients, with selected SAEs occurring at higher rates. These results support the safety profile of EPAG in combination with a variety of anticancer agents. In addition, these data suggest a possible beneficial supportive care effect in patients receiving concomitant therapy with EPAG and anticancer treatment. Further studies of EPAG in combination with anticancer therapy are warranted to confirm these hypotheses.

Background: Thrombopoietin receptor-agonists (TPO-RAs), eltrombopag (ELT) and romiplostim, are effective drugs licensed for relapsed/refractory ITP, leading to 70-80% response rates. As they stimulate the Mpl receptor on megakaryocytes, increasing platelet production, their effect is expected to be dependent on their continuous administration. However, durable remissions after TPO-RAs discontinuation have been described in 10-30% of patients (pts). This evidence pointed out a possible curative role for these agents, suggesting a mode of action that goes beyond the mere increase of platelet count, and interferes with the immune dysregulation underlying the disease, which worsens as ITP becomes chronic. The aim of this prospective study is to explore the role of ELT given for a defined period of time as second-line treatment in pts with newly diagnosed (ND) or persistent (P) ITP, thus interfering with the pathogenesis of the disease at an early stage, either offering a possible curative option for pts or a steroid-sparing drug as a bridge to chronic phase (CP). Methods: Pts aged ≥18 years with ND or P ITP not responsive or in relapse after standard first-line therapy, with active disease (platelet count <30x109/L or steroids/IVIG dependence to maintain a platelet count ≥30x109/L and/or avoid bleeding) were included. The study was divided into a period of treatment (PT), during which pts received ELT at a starting dose of 50 mg/day, then adjusted according to platelet count, for 24 weeks, a period of tapering and discontinuation (PTD) (week 25 - 32), and a period of observation (PO) (week 33 - 52). Complete response (CR) was defined as a platelet count ≥100x109/L; response (R) as a platelet count ≥30x109/L and at least doubling of baseline count. Only pts in R or CR at the end of week 24 entered the PTD. The primary end-point was the proportion of pts who, being in remission at the end of PT, were able to taper down and discontinue ELT, maintaining the remission for all the PO, without requiring any concomitant therapies. Secondary objectives included the relationship between baseline TPO serum level and response to treatment, exploring modifications of immunological parameters across study phases and their correlation with responses. Results: Between 24/02/16 and 05/05/2018, 55 pts were enrolled by 10 GIMEMA Italian Centers. 3 pts didn't meet the inclusion criteria and 1 was excluded from study population because of protocol violation. Of the 51 evaluable pts, 31 (61%) were females. Median age was 65 years (range 21- 90). 22 pts (44%) had ND ITP. Median baseline platelet count was 19x109/L (range 1-227). At the time of data cut-off, 10 pts were still in PT and 1 was not evaluable. Out of the remaining 40 pts, 2 were discontinued for reasons other than failure, and were excluded from response analysis. Of the 38 evaluable pts, at the end of 6 months of therapy 14 (37%) were in CR and 12 (32%) in R, with an ORR of 69%; 12 pts were non responders. All the 26 responders started the PTD. Of the 18 pts who completed the PTD, 7 maintained the response (ORR 39%), with 5 CR (28%) and 2 R (11%). At time of data cut-off, 11/26 pts have not completed yet the PO. 15/26 pts were evaluable at the end of the PO.: 3 maintained the response (ORR 20%), with 1 CR and 2 R. 12 pts relapsed: 11 during the PTD and 1 during the PO. 17 pts (33%) reported a total of 58 adverse events (AEs), 8 pts (16%) reported a total of 11 grade ≥3 AEs. 4 AEs were considered treatment related, only 1 of them was grade ≥3 (deep vein thrombosis). 2 pts (3.9%) died during the study, for reasons not related to treatment. Conclusions: These preliminary data confirm the previously reported efficacy of ELT in primary ITP, with an ORR of 69%. Almost 40% of pts maintained the response at the end of PTD, which is slightly higher than expected. These data suggest that the use of ELT at an earlier phase of the disease (ND or P ITP) is a more effective approach and that 6 months of therapy is a sufficient period to think about ELT tapering and discontinuation. Long-term remission was achieved in 20% of pts, but probably this data is biased by the fact that at the time of data cut-off only a small proportion of pts completed the PO, also considering that only 1 pt lost the response during the PO. For pts who don't maintain the response, ELT can still be a steroid-sparing agent used as a bridge to CP or other treatment options. This analysis is too early to define a correlation between the response and immunological parameters (including TPO levels). (Figure Presented).

Background Eltrombopag is an orally bioavailable small molecule agonist of the thrombopoietin receptor (TPO‐R), stimulating platelet production. Preclinical and early clinical data have shown its anti‐leukemic activity in myeloid malignancies in addition to improved platelet counts, making eltrombopag a suitable candidate treatment following induction therapy for acute myeloid leukemia (AML). Preliminary data suggest that eltrombopag‐mediated iron chelation could be involved in its anti‐tumoral activity rather than apoptosis induction (Roth M, Blood 2012). In a randomized, double blind placebo controlled study conducted in advanced MDS and AML patients (pts) in relapse, refractory or ineligible to receive standard treatments, eltrombopag yielded a trend for improved overall survival (Frey N, ASH, 2012). Methods EPAG 2015 was designed as a randomized phase II multicenter trial aiming at assessing the impact on outcome of eltrombopag administered to elderly AML pts receiving induction chemotherapy (NCT 03603795). Inclusion criteria were: ≥ 60 years of age, newly diagnosed AML (de novo or therapy‐related) except AML3 (APL) and AML7, favorable or intermediate cytogenetic risk (MRC 2010 classification), ECOG performance status < 3; HCT‐CI score < 3, adequate baseline organ function. Exclusion criteria were: AML with adverse cytogenetic risk, or arising from MDS, MPN/CMML, or with BCR‐ABL1, known active central nervous system leukemia, history of thromboembolic event or ongoing use of anticoagulation. The induction chemotherapy regimen consisted of one cycle of daunorubicin 60 mg/m²/day (d), d1 to d3, cytarabine 100 mg/m²/d, CIV d1 to d7, lomustine 200 mg/m², orally d1. Eltrombopag 200 mg orally (100 mg/day for pts with East Asian heritage) or placebo (blinded) was given once daily from day 11 until AML response evaluation or platelet counts > 100 x 109/L (maximum d45). The use of GCS‐F, anti‐fungal, anti‐viral and anti‐pneumocystis jiroveci prophylaxis was recommended. Pts who failed to reach complete remission (CR/CRi) after this cycle of induction were off‐study whereas CR/CRi patients were planned to receive up to 6 courses of mini‐consolidation every 30 to 45 days with daunorubicin 60mg/m², d1, cytarabine 50 mg/m²/12h, subcutaneous, d1 to d5. Pts then received 6 months of maintenance therapy alternating mercaptopurin and methotrexate. The addition of midostaurin in patients with FLT3‐ITD or FLT3‐TKD mutations was not allowed during induction. Allogeneic stem‐cell transplantation (ASCT) was allowed after 2 to 4 cycles in pts with intermediate or adverse risk (European LeukemiaNet 2017). Results From October 2018 to June 2021, 110 pts of a median age of 70 y (range 61‐84). were included (55 per arm). There were 71 males (64.5%). Median complete blood count was 2.7x109/L (0.7‐142). Pts randomized to receive eltrombopag had significantly less previous histories of cancer (3 vs 12; p = 0.01). Most pts had intermediate risk cytogenetics (77.9%). NPM1 and FLT3 mutations (per local analysis) were observed in 26 (23.6%) and 27 pts (15.4%), respectively. High throughput sequencing of a myeloid gene panel, performed centrally will be presented at the meeting. Following induction, 90 pts (81.8%) achieved CR/CRi (45 in each group), including 74 CR (38 in the eltrombopag group and 36 in the placebo group), while 11 failed (5 and 6) and 6 died early (4 and 2). During induction, a similar rate of grade III‐IV adverse events was observed in the two arms (N=29, 52.7% vs 33, 60%, p = 0.4). Severe hemorrhage occurred in 2 pts who received placebo and 1 who received eltrombopag. Central nervous system toxicity was observed only in 2 placebo pts. The number of platelet transfusions was significantly reduced in the eltrombopag group 9.76+ 5.38 vs 12.56 + 9.69, p = 0.063 (10% risk). Of the 90 CR/CRi pts, 85 entered the consolidation phase. Twenty‐eight pts received ASCT in first CR, respectively 13 after eltrombopag and 15 after placebo. The median follow‐up time for alive pts was 20.9 months. Forty‐two pts (77.9%) who received eltrombopag were alive at 12 months vs 46 (85.3%). Event‐free survival at 12 months was 52.7% after eltrombopag vs. 50.5%. These differences are not statistically significant. Conclusion In older AML pts eligible for intensive treatment, adding eltrombopag to induction is feasible and safe, reduces significantly the need of platelet transfusions, yet did not impact survival in this study. [Formula presented] Disclosures: Pigneux: Sanofi: Other: travel;

MSD:

Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizzer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz pharmaceutical: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;

BMS:

Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dumas: Astellas: Honoraria; Daiichi‐Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Abbvie: Honoraria; BMS Celgene: Honoraria; Janssen: Honoraria. Vey: Roche: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria;

BMS:

Honoraria; Amgen: Honoraria. Hunault: abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; clinigen: Honoraria, Membership on an entity's Board of Directors or advisory committees; jazz pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carre:

BMS:

Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Guieze: Abbvie, Beigene, Janssen, Gilead, Roche, AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Desbrosses: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees;

BMS:

Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Simand: amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; jazz pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; astellas: Honoraria. Leguay: clinigen: Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jourdan: Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees;

BMS:

Membership on an entity's Board of Directors or advisory committees. Recher: Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie, Janssen, Jazz Pharmaceuticals, Novartis, BMS‐Celgene, Otsuka, Astellas, Daiichi‐Sankyo, Macrogenics, Roche, Takeda, Servier, Pfizer: Other: Advisory role; AbbVie, Amgen, Novartis, BMS‐Celgene, Jazz Pharmaceuticals, Agios, MaatPharma, Astellas, Roche, Iqvia, Daiichi‐Sankyo: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;

BMS:

Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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INTERVENTION:

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

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐

CONDITION:

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

C PRIMARY OUTCOME:

Main Objective: To evaluate the safety and tolerability of open‐label eltrombopag when administered once daily. Primary end point(s): Assessment of safety and tolerability of eltrombopag as measured by the nature and frequency of adverse events, laboratory abnormalities, ocular examinations and clinical monitoring/observation. Secondary Objective: • To evaluate platelet counts before and during antiviral therapy.; • To evaluate maintenance of antiviral therapy.; • To evaluate achievement of antiviral treatment milestones.;

INCLUSION CRITERIA:

1. Male and female subjects, =18 years of age. 2. Evidence of chronic HCV infection (quantifiable HCV RNA, lower limit of detection of 50 IU/ml). 3. Subjects must be previous participants of TPL103922 (ENABLE 1) or TPL108390 (ENABLE 2) and successfully initiated antiviral treatment in those studies. 4. Subjects must have permanently discontinued all investigational products for ENABLE 1 or 2 within 12 weeks from randomisation in ENABLE 1 or 2 due to reasons of thrombocytopenia. Subjects who continued antiviral therapy beyond 6 weeks must have had some degree of thrombocytopenia during this time, defined as having at least a 50% dose reduction of pegylated IFN (for reasons of thrombocytopenia) for a minimum period of 4 weeks. 5. All subjects must have completed the final 6 month (24 week) SVR and ocular follow‐up assessments in ENABLE 1 or ENABLE 2. 6. Subjects who, in th

Este artículo no tiene resumen

Este artículo no tiene resumen

INTERVENTION:

Product Name: Eltrombopag Product Code: SB497115 Pharmaceutical Form: Tablet INN or Proposed

INN:

eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 25‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Product Name: Eltrombopag Product Code: SB497115 Pharmaceutical Form: Tablet INN or Proposed

INN:

eltrombopag CAS Number: CASRN496775 Current Sponsor code: SB‐497115 Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use

CONDITION:

Idiopathic thrombocytopenic purpura (ITP) ; MedDRA version: 8.1 Level: LLT Classification code 10051057 Term: Idiopathic thrombocytopenia

PRIMARY OUTCOME:

Main Objective: To determine the efficacy of oral eltrombopag, when administered once daily, for 6 months duration, to previously treated adult subjects with chronic ITP Primary end point(s): The primary endpoint is the odds of achieving a platelet count at or 50,000/microL and = 400,000/microL during the 6 month treatment period, for subjects receiving eltrombopag relative to placebo Secondary Objective: • To assess ability of eltrombopag to prevent use of rescue treatment ; • To describe pharmacodynamics & durability of eltrombopag response; • To determine efficacy of oral eltrombopag, when administered once daily for 6 weeks ; • To assess safety & tolerability of eltrombopag when administered for 6 months; • To describe effect of eltrombopag on reduction of concomitant ITP medications from baseline; • To assess impact of eltrombopag on incidence & severity of bleeding symptoms of thrombocytopenia when administered once daily for 6 months ; • To assess impact of eltrombopag on health related QoL & patient reported outcomes;

EXPLORATORY OBJECTIVES:

; • To assess effect of administration of eltrombopag on anti‐platelet antibody levels; • To use proteomic analysis to identify proteins that may correlate with safety & tolerability and/or predict response to eltrombopag

INCLUSION CRITERIA:

1. Subject has signed and dated a written informed consent. 2. Adults (?18 years) diagnosed with chronic ITP according to the American Society for Hematology/British Committee for Standards in Hematology (ASH/BCSH) guidelines [George, 1996; BCSH, 2003], and platelet count < 30,000/?L on Day 1 (or within 24 hours prior to dosing on Day 1). In addition, a peripheral blood smear should support the diagnosis of ITP with no evidence of other causes of thrombocytopenia (e.g. pseudothrombocytopenia, myelofibrosis). The physical examination should be normal or at least not show signs suggestive of any disease other than ITP which may cause thrombocytopenia. 3. Subjects who have previously received one or more prior ITP therapies. Previous treatments for ITP include but are not limited to corticosteroids, immunoglobulins, azathioprine, danazol, cyclophosphamide and/or rituximab. 4. Subjects must have either initially responded (platelet count > 100,000/?L) to