BACKGROUND:

Engraftment of neutrophils and platelets after hematopoietic stem cell transplant (HSCT) is imperative for optimal outcomes. Eltrombopag has been used in adults after HSCT to boost platelet production. Its use in pediatric post HSCT patients has been limited.

METHODS:

The clinical and laboratory details of a post autologous HSCT patient were fetched by a retrospective review of the records.

RESULTS:

A 5-year old male child had primary thrombocytopenia post autologous HSCT for refractory Hodgkin lymphoma. Although the stem cell dose infused was adequate, the child had a delay in the engraftment of platelets. After ruling out the causes of post HSCT thrombocytopenia, eltrombopag was started for the child. With the use of eltrombopag, normal thrombopoiesis was restored in the child.

CONCLUSION:

Eltrombopag was effective and safe in overcoming post-HSCT primary thrombocytopenia in our patient.

INTRODUCTION:

Thrombocytopenia is among the most common complications following hematopoietic stem cell transplantation and is associated with increased mortality and morbidity with no standard treatment yet. In this multicenter and retrospective study, we aim to present our multi-center experience of Eltrombopag treatment in patients with isolated thrombocytopenia following HSCT.

MATERIAL-METHOD:

A total of 73 patients from 5 centers who underwent autologous or allogeneic stem cell transplantation, had no primary disease relapse, all of whom had neutrophil engraftment, complete chimerism, and who were diagnosed with Prolonged Isolated Thrombocytopenia (PIT) or Secondary Failure Of Platelet Recovery (SFPR) were included in the study. The patients were initiated on Eltrombopag at a dose of 50-150 mg. Complete response was defined as a platelet count >50×109/L for 7 consecutive days with no transfusion support.

RESULTS:

A total of 50.3% of the patients underwent Autologous and 49.7% Allogeneic Stem Cell Transplantation, 54.8% were diagnosed with PIT, and 45.2% were diagnosed with SFPR, and the treatment with 50-150 mg/day Eltrombopag was initiated on the median day +42. Complete response was achieved in 71.2% of these patients on the median day 23 of the treatment. No significant effects of the initial dose (50-150 mg/day) were detected in the Complete Response in the multivariate analysis on response. An insufficient number of Megakaryocytes in the bone marrow before Eltrombopag treatment was determined as an independent risk factor in determining the response (OR 3.57, 95% CI 1.21-10.55). The overall survival of the patients who did not respond to Eltrombopag was found to be significantly worse than that of patients who responded (p=0.022, HR.:2.74, 95% CI 1.12-6.54).

CONCLUSION:

As a result of the present study, Eltrombopag treatment was found to be effective and safe in thrombocytopenia that develops following hematopoietic stem cell transplantation. It was concluded that its use may be more effective in patients with sufficient bone marrow megakaryocytes before the treatment and an initial dose of 50 mg/day may be appropriate in terms of cost, effectiveness, and toxicity. Large-scale randomized and controlled prospective studies are needed to determine the roles of Eltrombopag treatment in patients with post-transplant PIT and SFPR.

This was an open label, non-randomized, phase II study of eltrombopag in combination with rabbit ATG/CsA in subjects with moderate or more severe AA who did not received prior ATG/ALG-based immunosuppressive therapy. The objective was to assess additive effects of eltorombopag on overall response rate (ORR) at 6 months (Week 26) of treatment with ATG/CsA. Subjects were assessed at least weekly for safety during the period from the start of ATG/CsA to 4 weeks after the start of administration of eltrombopag. After that, subjects had visits every 2 weeks until Week 26. Subjects in whom the treatment was assessed as effective at Week 26 could continued treatment with eltrombopag after 6 months when clinically indicated at the discretion of the investigator. There were five follow-up visits: at discontinuation of the treatment of eltrombopag, and Weeks 1, 2, 3, 4 and 26 after treatment discontinuation. As this study was the first Japanese phase II study in which this product was administered in combination with ATG/CsA to subjects with naive moderate or more severe AA, the subject number of this study was determined to be 10 based on the feasibility survey.

Background:Although splenectomy remains an appropriate treatment for ITP, it is associated with adverse events (AEs). The most recent guidelines for ITP indicate that splenectomy should be designated a second-line treatment and delayed for 6-12 months. Eltrombopag is an oral thrombopoietin receptor agonist (TPO-RA) approved in Europe for treatment of splenectomized adult chronic ITP patients who are refractory to other treatments, and as a second-line treatment for adult nonsplenectomized patients in whom surgery is contraindicated. The EXTEND study assessed long-term safety and efficacy of eltrombopag in ITP patients previously enrolled in 6-week or 6-month placebo-controlled trials. Aims: To compare the safety and efficacy of long-term eltrombopag treatment in patients with or without splenectomy in the EXTEND trial. Methods: Eltrombopag was started at 50 mg weekly and titrated to maintain platelet counts 50-200 Gi/L. Results: Among patients enrolled in EXTEND (N=302), 115 splenectomized (38%) and 187 nonsplenectomized (62%) patients had similar characteristics at baseline, except that more splenectomized patients were receiving ITP medications at baseline (47% vs 25%) and more had a history of bleeding (23% vs 13%). Greater than half of both groups received eltrombopag for ≥24 months. After eltrombopag treatment, a greater proportion of nonsplenectomized patients achieved platelets ≥50 Gi/L than splenectomized ones, and was consistent by age group (Table). Nonsplenectomized patients experienced proportionately fewer serious bleeding AEs (Table). Rates of any bleeding AE were experienced by 49 (26%) and 35 (30%) nonsplenectomized and splenectomized groups, respectively. Events occurring in ≥4% of patients in the splenectomized and nonsplenectomized groups, respectively, included mouth hemorrhage (4% and 1%), epistaxis (14% and 6%), petechiae (8% and 2%), ecchymosis (2% and 4%), contusion (3% and 4%), and hematuria (2% and 4%). In each group, 13% had a sustained reduction or permanently stopped at least one concomitant ITP medication without having received any on-treatment rescue medication. Splenectomized patients had higher rates of Grade 1-4 World Health Organization bleeding at baseline (64% vs 52%), but rates declined in both groups over time. Summary/Conclusions: Long-term treatment with eltrombopag increased platelets in both nonsplenectomized and splenectomized patients, with numerically higher response rates in the former. Rates of AEs were similar to those in patients with splenectomy. (Table Presented).

Aim: To evaluate the efficacy and safty of TPO in combination with eltrombopag in the treatment of solid tumor chemotherapy-induced thrombocytopenia (CIT). Methods: 7 patients with thrombocytopenia after standard solid tumor chemotherapy were enrolled in this study, including gastric cancer(n=1), breast cancer(n=1), lung cancer(n=3) and liver cancer(n=2). They were treated with TPO (15000IU q.i.d.) in combination with eltrombopag (25mg t.i.d.) until the platelet count was recovered to 100 × 109 / L or the medication time was up to 14 days. The time required for platelets to recover to > 50 × 109 / L and ≥ 100 × 109 / L, platelet transfusion times and adverse reactions were observed. Results: After the treatment, the platelet counts of all patients were recovered to > 50 × 109 / L, and 3 of them ≥ 100 × 109 / L. The adverse reactions include muscle soreness(n=1), liver and kidney dysfunction(n=1), no case of them was above grade 3 according to WHO classification criteria for adverse reactions. Conclusion: TPO in combination with eltrombopag is an effective and safe method for the treatment of solid tumor chemotherapy-induced thrombocytopenia (CIT). Disclosures: No relevant conflicts of interest to declare.

Evaluate the safety and tolerability of avatrombopag given for 90 days after stopping treatment with eltrombopag or romiplostim.

The goal of this clinical research study is to learn if eltrombopag can help to control MDS. The safety of this drug will also be studied.

TE-ITP study: Compare the efficacy and safety of optimized rhTPO treatment versus Eltrombopag treatment in previously treated primary immune thrombocytopenia patients.

Background Patients who develop severe thrombocytopenia while treated with TK inhibitors may be forced to stop them, face a worse prognosis, and eventually require a treatment with a bone marrow transplant. Eltrombopag is a TPO receptor agonist that stimulates megakaryocytic proliferation. Case 62-year-old man presented in October 2008 with splenomegaly and leukocytosis. The bone marrow biopsy was diagnostic of CML. Imatinib was started at 400 mg daily resulting in hematological response and resolution of splenomegaly, but severe thrombocytopenia necessitated 50 % dose reduction. Thrombocytopenia was not responsive to Prednisone, and a trial of platelets transfusions with the standard dose of Imatinib had to be stopped because of thrombocytopenia below 10 K and the risk of bleeding - reducing the dose of the TKI was improving the platelet count. Treatment with Dasatinib and with Nilotinib also necessitated 50 % dose reductions because of thrombocytopenia. These reduced TKI dosing resulted in the best Quantitative RT-PCR for bcr/abl product reduction level at - 1.01. Bone marrow biopsy in December 2010 showed no morphologic evidence of CML, and no dysplasia; it was normocellular marrow with erythroid hyperplasia and megakaryocytic hypoplasia. Cytogenetic analysis and FISH showed presence of the Philadelphia chromosome rearrangement. The patient declined the treatment with a Bone marrow transplant. In April 2011 a TPO agonist Eltrombopag 50 mg daily was started, given on two weeks on two weeks off schedule. As platelets remained adequate since then, the Nilotinib was escalated to the full dose of 400 mg twice daily. The patient tolerated the treatment well. Results The patient required about half-a-year support with Eltrombopag; after that it was discontinued as the platelet count remained above 40 K. No dose reduction of Nilotinib was necessary. In January 2012 the patient reached the milestone of Complete Cytogentic Response with the level of bcr/abl transcript minus 2 or less, which continued to decrease and now the patient is achieving a Major Molecular Response. Conclusion Treatment of CML with Tyrosine Kinase Inhibitors - Imatinib, Dasatinib, or Nilotinib in our patient - can be complicated by severe thrombocytopenia. These patients' next treatment option may be a Bone marrow transplant. Limited use of Eltrombopag can improve thrombocytopenia, and allow these patients to continue TKIs with attainment of the treatment milestons.

Background: In myelodysplastic syndromes (MDS), thrombocytopenia is an adverse risk factor. Treatments in this setting are scarce. In a randomized international phase 2 trial (EQoL-MDS, EudraCT number 2010-022890-33), we reported effecacy and safety of eltrombopag for the treatment of thrombocytopenia in the first 90 patients with lower-risk MDS with a platelet (PLT) count < 30 Gi/L (Oliva et al. Lancet Hem 2017). However, there are concerns of regulatory agencies regarding the use of thrombopoetin rececptor agonists in MDS due to previous reports signalling disease progression in clinical trials with the use of romiplostim and of eltrombopag, the latter in high risk MDS. Objective: We are further evaluating safety by conducting a comprehensive analysis of mutations in a panel of major driver or candidate driver genes in cases enrolled in the EQoL-MDS trial using targeted-capture sequencing. Methods: Serial (every 3 months) sequencing was performed using the SureSelect custom kit (Agilent Technologies), for which 350 genes were selected from known oncogenes or tumour suppressor genes in haematological malignancies. Relevant somatic mutation data with (i) VAF > 0.05; (ii) depth > 100; (iii) P value for EBCall < 0.0001, were filtered by exclusion based on (i) synonymous SNVs; (ii) variants present only in unidirectional reads; (iii) variants occurring in repetitive genomic regions; (iv) missense SNVs with VAF of 0.4-0.6 or <0.04; and (v) known variants listed in SNP databases. The present analysis has been conducted at baseline, at 12 and 24 weeks. Results: We present preliminary results of the first 21 cases (13 eltrombopag, 9 placebo) enrolled in the trial and with biological samples. Mean age was 62 (± 15) and 13 patients were male. According to the WHO 2016 classification, 11 patients had MDS with single lineage dysplasia (SLD), 7 had multi lineage dysplasia (MLD), 1 placebo case had excess blasts-1, and 1 placebo case had unclassifiable. IPSS-R risk was very low, low and intermediate in 4, 8 and 1 eltrombopag cases, respectively, and 5, 2 and 1 placebo cases, respectively. Karyotype was normal in 16 cases, del(20q) was detected in 4 cases and +14 in 1 case. At study entry, in total 49 genes were mutated (Figure), where one or more of the 49 driver genes were mutated in all but 1 placebo patient (Table). The table shows characteristics and events of patients according to treatment arm. Noteworthy, in the eltrombopag arm, two cases experienced a loss of gene mutations, one obtaining International Working Group defined complete remission of MDS, while 1 MDS EB-1 case had a gain in ZRSR2. Two placebo cases experienced a gain in mutations Conclusions: Treatment with eltrombopag in lower risk MDS is effective and safe. Preliminary analyses do not suggest that eltombopag induces disease progression neither at a clinical, nor a molecular level. Loss of mutations may occur during eltrombopag treatment with complete remission. [Formula presented] Disclosures: Oliva: Novartis: Other: Advisory Board; Celgene

BMS:

Consultancy, Other: Advisory Board, Patents & Royalties; Alexion: Other: Advisory Board; Argenx: Other: Advisory Board; Daiichi: Other: Advisory Board; Amgen: Other: Advisory Board. Nannya: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Kulasekararaj: Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau. Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria. Santini: Astex: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ogawa: Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kan Research Laboratory, Inc.: Consultancy, Research Funding; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Research Funding; Ashahi Genomics: Current holder of individual stocks in a privately-held company. OffLabel Disclosure: Eltrombopag (Revolade) is indicated for chronic immune (idiopathic) thrombocytopenic purpura (ITP) patients aged 1 year and above who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy.Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation.