Liver cirrhosis is the end stage of chronic liver disease, but no definitive pharmacological treatment is currently available. It has been reported that thrombopoietin (TPO) promotes liver regeneration and improves liver cirrhosis by increasing platelet count. We have shown the direct effect of platelet transfusion on the improvement of liver function in patients with chronic liver disease. However, platelet transfusion often causes adverse events, such as platelet transfusion refractoriness and pruritus. Therefore, we conducted an exploratory clinical trial and administered eltrombopag, an orally bioavailable, small-molecule, non-peptide TPO receptor agonist that has been approved for the treatment of chronic idiopathic thrombocytopenic purpura. The study included five male patients, aged from 49 to 75 years (57.6 ± 10.4 years), with both chronic liver disease and hepatitis C virus infection, who presented with thrombocytopenia but without cancer. Eltrombopag, ranged from 6.25 to 50 mg/day (18.75 ± 18.22 mg/day), was administrated to the five patients during six months. All of the patients maintained platelet counts between 10 and 15 × 10[10]/L during the study. The indicators of liver function in patients were stable throughout the clinical trial, although we had predicted the same degree of the improvement of liver function, compared to platelet transfusion. Importantly, the liver volumes were also stable, and no cancerous lesions were observed. These results indicate the safety of long-term eltrombopag administration for patients with chronic liver disease and hepatitis C virus infection.

The purpose of this study is to evaluate the effect of two different doses of ianalumab added to eltrombopag to prolong Time to Treatment Failure (TTF) in adults with primary ITP who failed previous first-line treatment with steroids.

Background: Myelodysplastic syndromes (MDS) are malignant clinical disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, peripheral cytopenias and a property to transform into acute myeloid leukemia (AML). Standard of care for MDS includes the hypomethylating agents (HMAs) (i.e. azacitidine, decitabine) to improve quality of life, decrease transfusion requirements and improve clinical outcome. However not all patients (pts) respond to HMAs and even in responding pts, cytopenias may persist. HMA-failure MDS has extremely poor prognosis and currently there are no approved therapeutic options for such pts who are often of advanced age with frequent comorbidities. Objectives: The dual primary objectives of this study evaluate the safety and efficacy of the second-generation thrombopoietin-receptor agonist (TPO-RA) eltrombopag (EPAG) for the treatment of MDS pts at the time of HMA-failure. Secondary objectives include incidence of transformation to AML and evaluation of bone marrow fibrosis during therapy. Methods: Eligible pts for this 2-arm phase 2 open-label clinical trial included adults with MDS after completing >4 HMA cycles with failure to achieve at least a partial response, or the presence of ongoing cytopenias per IWG criteria. Arm A includes eltrombopag monotherapy and Arm B includes eltrombopag with continuation of the HMA at the previous dosing schedule. The starting eltrombopag dose is 200mg orally daily, which can be increased to 300mg in the absence of toxicity. First response is assessed after 2 cycles with each cycle lasting 28 days. The primary efficacy endpoint was overall response rate based on the IWG-2006 criteria. Results: To date, 23 pts with a median age of 72 years (range 42-84 years) have been enrolled. Prior to study entry, pts had received a median of 6 (range 4-25) HMA cycles. Cytogenetics were diploid in 12 (53%), intermediate in 7 (30%), and high risk in 4 (17%) pts by IPSS. Median bone marrow blasts at study start was 3% (range 0-15%). Arm A has enrolled 7 pts with a median age of 74 years; Arm B has enrolled 16 pts with median age of 69 years. In Arm B, ongoing HMA therapy includes azacitidine in 7 (44%) and decitabine in 9 (56%). Nine (39%) pts increased to 300mg EPAG after median of 8 weeks on study. Median total cycles received on study is 5 (1-17); median OS has not been reached. Overall, 16 pts are response-evaluable; 7 pts discontinued prior to the first response assessment at 2 months (4 due to AEs including myalgias/fatigue (n=2), hyperbilirubinemia (n=1), and pneumonia (n=1), 2 per pt request and 1 for pt inability to comply with protocol requirements). Of the 16 response-evaluable pts, 3 (19%) in Arm B demonstrated platelet improvement, including one pt necessitating EPAG dose-reduction to 100mg due to platelet count exceeding 450 x109/L with concomitant ANC recovery at 200mg EPAG dose level. An additional 8 (35%) pts have remained on study for a median of 5 cycles (2-17) with stable disease. Two pts discontinued therapy due to disease progression, including 1 (4%) that progressed to AML. The most common non-hematologic AEs regardless of attribution included hyperbilirubinemia (n=14, 61%), fatigue (n=13, 56%) myalgias (n=11, 48%), fever (7, 30%), dyspnea (7, 30%), nausea (6, 26%) and transaminitis (4, 17%). No significant increase in bone marrow fibrosis has been observed. Conclusion: Eltrombopag orally daily appears to be a safe and beneficial supportive adjunct for pts with MDS while receiving HMA-therapy or after HMA-failure due to persistent cytopenias. Treatment on this study continues and larger prospective clinical trials are needed to confirm these preliminary findings.

INTERVENTION:

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

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: range Concentration number: 25‐100

CONDITION:

Patients with lower and intermediate‐1 risk myelodysplastic syndromes. Therapeutic area: Diseases [C] ‐ Blood and lymphatic diseases [C15]

PRIMARY OUTCOME:

Main Objective: Evaluation of the proportion of patients with an increase of the platelet count (eltrombopag effect on platelet count), according to the international criteria.; Measurement of survival, differentiation and maturation characteristics of BMMCs & megakaryotic progenitor cells throughout the study’s duration. Primary end point(s): Evaluation of the platelet count throughout the duration of the study and evaluation of the type of response according to international criteria.; Measurement of platelet response parameters before treatment and at end of month 3, month 12 and month 24. Secondary Objective: 1. Safety and tolerability of eltrombopag.; 2. Change in bone marrow blast counts from baseline and as well as differences in % of bone marrow blasts between the two groups.; 3. Progression of disease. ; 4. Overall survival.; 5. Number of platelet transfusions.; 6. Duration of platelet transfusion‐independence.; 7. Incidence and severity of bleeding.; 8. Changes in hemoglobin levels and neutrophil counts. Timepoint(s) of evaluation of this end point: Throughout the duration of the study.

SECONDARY OUTCOME:

Secondary end point(s): • Clinical examination findings, clinical follow‐up, vital signs, laboratory tests and reported adverse events (including bleeding and transfusion‐related AEs). ; • Percentage of blasts in blood or/and bone marrow. ; • Percentage of neutrophils, platelets, haemoglobin, appearance of chloroma, appearance of B symptoms. ; • Disease response, disease progression, final outcome. ; • Number of platelet transfusions. ; • Duration of platelet transfusion‐independence. ; • Incidence and severity of bleeding (according WHO Bleeding Scale). ; • Improvement in haemoglobin levels, platelets and neutrophil counts. Timepoint(s) of evaluation of this end point: Throughout the duration of the study.

INCLUSION CRITERIA:

1. Adult subjects (= 18 years old) with low and intermediate‐1 MDS type according to the WHO classification and IPSS. 2. Mean baseline platelet count <30x Gi/L or <50 Gi/L with bleeding manifestations. 3. Patients with data on platelet count, bleeding and platelet transfusions covering a period of at least 4 weeks before enrolment. 4. Bone marrow examination 4 weeks before randomization. 5. Supportive/palliative therapies such as cytokines (except for IL‐11; oprelvekin), valproic acid and all‐trans retinoic acid are allowed, provided those therapies have been at a stable dose for 4 weeks or were completed 4 weeks prior to enrolment into this study. 6. ECOG Status 0‐2. 7. Adequate baseline liver and renal function defined by the criteria below: • total bilirubin (except for Gilbert’s Syndrome) = 1.5xULN • ALT and AST = 3xULN • serum creatinine = 1.5mg/dl or calculated creatinine clearance = 40ml/min (calculated buy the Cock

Thrombosis in patients with thrombocytopenia has several risk factors, both disease-related and treatment-associated. Recently, COVID-19 infection was recognized as an additional risk factor, further complicating the delicate balance between thrombosis and bleeding in these patients. Here we describe the case of a patient with aplastic anaemia on eltrombopag who developed pulmonary embolism during COVID-19 pneumonia, despite receiving oral anticoagulation with edoxaban. Notably, he was also carrying a large paroxysmal nocturnal haemoglobinuria clone, although without evidence of haemolysis. The presented case recapitulates some of the open questions in thrombotic risk management of cytopenic patients, such as the management of thrombopoietin receptor agonists and the choice of anticoagulation in PNH, while also accounting for the additional thrombotic risk linked to COVID-19.

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Purpose: Prolonged intervals of thrombocytopenia are common after hematopoietic stem cell transplantation (HSCT), and platelet transfusions are the only effective therapy. Risk of thrombocytopenia is greater in patients (pts) receiving total body irradiation (TBI) in their conditioning regimen. Eltrombopag (ePag) is a small-molecule, nonpeptide oral agent that functions as an agonist of the thrombopoietin receptor. It is approved by FDA for the treatment of chronic ITP and is being developed as a treatment for thrombocytopenia of other various etiologies. We report results of an ongoing Phase I clinical trial assessing the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of once daily oral ePag in pts undergoing HSCT with a conditioning regimen containing TBI ≥ 400 cGy. Methods: A Phase I dose-escalation clinical trial was conducted to evaluate the safety and PK of ePag at 4 different dose levels: 75, 150, 225, and 300 mg, once daily for 27 days, starting 24-48 hours post HSCT to eligible pts ≥18 yrs old. Pts with various indications for stem cell transplantation, KPS ≥70%, and TBI ≥ 400 cGy were eligible. Pts receiving either an autologous (Auto) or allogeneic (Allo) HSCT from a sibling, related donor, or matched unrelated donor (MUD) were eligible. Stem cells from peripheral blood (PBSC) or bone marrow were permitted; however, cord blood transplant was not permitted. Pts at risk of thromboembolism, or with a history of thromboembolic disease in the preceding 6 months, were excluded. PK sampling was obtained over a 24 h period after the first dose of ePag, as well as during the second week of treatment (steady-state). Results: As of July 1 2011, a total of 10 subjects (4 AML, 2 lymphoma, 1 CML, 1 MDS, 1 myelofibrosis, and 1 CLL/SLL) were enrolled, and 9 completed protocol treatments. All 9 were PBSC transplants with 6 MUD, 2 Allo and 1 Auto. Three subjects were completed at each dose level up to 225 mg. Enrollment is continuing at the 300 mg dose level. To date, 6/9 are alive while 3/9 died of non-relapse related causes (CMV pneumonitis and respiratory failure in 1, and steroid refractory GI GvHD in 2, f/u interval: 4.4 - 6.9 mo). No dose limiting toxicities (DLTs) have been observed. Most common adverse events up to 225 mg dose level were related to standard stem cell transplantation, which included low blood counts, fatigue, headache, diarrhea, nausea, peripheral edema, hypoalbuminemia, hyperglycemia, hypocalcemia, and hypomagnesemia. There were 9 SAEs observed in 5 pts, which included infection (3/9), pulmonary embolism (PE) (1/9), acute renal failure (2/9), gastrointestinal (2/9), and ARDS (1/9). Most SAEs were considered unrelated or unlikely related to ePag treatment except for the PE, which was considered possibly related to ePag but not considered a DLT. This subject had other risk factors for PE and the PE occurred 9 days after ePag had stopped at a platelet count of 252K. Time to platelet engraftment and number of platelet transfusions were documented for each enrolled pt. PK sampling demonstrated a dose dependent increase in plasma concentration of ePag (Figure 1). PK parameters for the 75, 150, and 225 mg dose levels are summarized in Table 1. [Image Presented] [Table Presented] Conclusions: 27-day once daily dosing of ePag to enhance platelet recovery for post-transplant thrombocytopenia is well tolerated, with no DLTs observed up to the 225 mg dose level to date. Most AEs were transplant related. PK and the plasma exposure of ePag appears dose proportional over the studied dose range after single-dose and steady-state administration. Once-daily administration of up to 225 mg ePag for the transplant population receiving TBI ≥ 400 cGy as part of the conditioning regimen appears to be safe and well tolerated. Acknowledgement: The study is supported by Biomedical Advanced Research and Development Agency (BARDA), and by GlaxoSmithKline who also provided the study drug.

Introduction: Lenalidomide (LEN) is approved for treatment of Myelodysplastic Syndrome (MDS) with chromosome 5q deletion (del 5q) as it has shown to induce disease remission and transfusion independence in close to 65% of this population. For patients (pts) without del 5q, LEN has shown to reduce transfusion needs in one-quarter of pts, but its use is limited by significant thrombocytopenia, and pts with platelet counts (PLTs) <50,000 have been excluded from these trials. Eltrombopag (ELT), a TPO-R agonist, has proven to be effective increasing PLTs in MDS. Furthermore, preclinical data has demonstrated that ELT can reverse anti-megakaryopoietic effects of LEN in MDS patient samples. Based on this rationale, we conducted a study to determine the safety and efficacy of the combination of eltrombopag and lenalidomide (ELT/LEN) in low and intermediate (low/int) risk MDS (NCT01772420). Methods: Pts aged ≥18 years with low/int risk MDS per IPSS, or non-proliferative chronic myelomonocytic leukemia (CMML), with bone marrow blasts <10% at baseline, without prior exposure to LEN or ELT and with symptomatic anemia were enrolled. Pts with PLTs ≥50,000 (Arm A) received LEN alone at 10mg PO daily (qd) on days 1-21. If PLTs fell <50,000, LEN was discontinued and ELT PO qd given until PLTs ≥50,000 for 2 weeks (wks). Pts then resumed LEN. If PLTs fell <50,000 again, pts received ELT as before and then received concomitant LEN and ELT. Pts with PLTs <50,000 (Arm B) received ELT alone qd on days 1-28 until PLTs ≥50,000 for 2 wks. Pts then received treatment as in arm A. Both arms had 28-day cycles. ELT was initiated at 100mg PO qd and escalated up to 300mg PO qd until response was achieved. The primary objectives of the study were to evaluate the rate of hematologic improvement (HI) of ELT/LEN as per 2006 IWG criteria, and to evaluate the safety and tolerability of the combination. Results: 51 pts were accrued, with 44 evaluable pts. Of evaluable pts, most were male (70%), median age was 71 years (range 34-93). 42 (95%) pts had MDS and 2 (5%) CMML. 24 (55%) pts were low-risk per IPSS-R score. 28 (64%) pts were treatment-naïve and 16 (36%) had received ≥1lines of treatment, including erythropoiesis stimulating agents. 24 (55%) pts were assigned to arm A and 20 (45%) pts to arm B. ELT/LEN was well tolerated. Non-hematological grade 3-4 treatment-related adverse events were few, including G3 hyperbilirubinemia (7%), G3 transaminitis (2%), G3 diarrhea (2%), G3 arthralgias (2%). 2 pts had major bleeding events; there were 2 deaths, one attributable to pneumonia and one to gallbladder cancer. 1 of 31 pts who received ELT had a reversible increase in peripheral blasts while on treatment, and 1 pt had development of marrow fibrosis after 6 years of ELT. ITT analysis of total population (51) revealed an objective response (ORR) of 35%; ORR of 32% (9/28) in arm A (PLTs ≥50,000),and 39% (9/23) in arm B (PLTs <50,000).Of the 44 evaluable pts, ORR was 40.9% (18/44); 37.5% (9/24) in arm A and 45% (9/20) in arm B. 13 (30%) pts achieved RBC transfusion-independence (RBC-TI), 11 (25%) pts had platelet HI, 6 (14%) pts had bilineage responses, and 3 (7%) achieved complete remission (CR). 17 pts received ELT alone, among these ORR was 41% (7/17), with 29% achieving bilineage responses, 1 CR. 13 pts received LEN alone, ORR was 46% (6/13), of these 100% achieved RBC-TI. 14 pts received ELT/LEN combination, ORR was 36%, 2 (14%) achieved bilineage responses and 2 (14%) CR. There were 2 HIV-positive MDS pts, both achieved sustained CRs, one with ELT alone and one with ELT/LEN combination. Mean time to response was 9.4 wks (range 6-12.4) for ELT alone, 10.9 wks (range 2.4-16) for LEN alone, and 9.9 wks (range 2-20) for ELT/LEN combination. Mean duration of response was 102 wks for ELT (range 8-ongoing), 63 wks (range 25-ongoing) for LEN, and 66 wks (range 8.3-ongoing) for ELT/LEN as of last follow-up. Conclusions: Treatment with ELT/LEN demonstrates good efficacy with ORR of 40.9%, response durability and an acceptable safety profile for evaluable pts with low/int risk MDS. ELT can lead to single agent responses with an acceptable safety profile and sizable proportion of multilineage responses. One patient developed bone marrow fibrosis and one patient had a transient increase in blasts, hence, undermining these pre-existing safety concerns. Lastly, using our study schema 32% of pts were able to initiate or continue LEN achieving a 36% ORR whereas in prior studies these pts would have been excluded. [Formula presented] Disclosures: Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Gritsman: iOnctura: Research Funding. Shastri: Kymera Therapeutics: Research Funding; Onclive: Honoraria;

GLC:

Consultancy; Guidepoint: Consultancy. Verma: Celgene: Consultancy; Acceleron: Consultancy; Novartis: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Eli Lilly: Research Funding; Curis: Research Funding; Medpacto: Research Funding; Incyte: Research Funding; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company;

GSK:

Research Funding;

BMS:

Research Funding. OffLabel Disclosure: Lenalidomide has shown to be effective achieving RBC Transfusion Independence in Myelodysplastic Syndromes without deletion 5q Eltrombopag is a TPO-R agonist, its purpose in this trial is to evaluate if it would increase platelet counts in patients with Myelodisplastic Syndrome.

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