Eltrombopag Group Research Articles

Efficacy and Safety of Eltrombopag with or without Immunosuppressant in Patients with Relapsed/Refractory Acquired Aplastic Anemia: A Real-World Experience

Background: Eltrombopag (EPAG) with or without immunosuppressant (IST) has been applied in acquired aplastic anemia (AA), yet data of EPAG+IST in relapsed/refractory AA was limited, and no study has compared efficacy and safety between EPAG+IST and EPAG monotherapy in relapsed/refractory AA patients.Aims: To evaluate and compare the efficacy and safety between EPAG+IST and EPAG monotherapy in relapsed/refractory AA patients in a real-world setting.Methods: Data from patients diagnosed as acquired AA in our center were retrospectively collected. All the enrolled patients were refractory/relapsed to the standard IST for at least 6 months before EPAG. All patients had been treated with EPAG, which was started at 25 mg/day and increased every 2 weeks to a maximum of 150 mg/day until a best response was achieved. Meanwhile, some patients were treated with cyclosporin A (CsA) or tacrolimus (FK506) at the same time. EPAG had to be prescribed for at least 6 months before evaluation. Complete response (CR), overall response (OR) and relapse rate, as well as adverse events and factors which could affect efficacy were analyzed.Results: Totally 99 patients (83 non-severe AA (NSAA) and 16 SAA) were included in the study. The median age at EPAG initiation was 46 (13-88) years old, the median time of EPAG treatment was 11 (6-41) months and the median time of follow-up was 18 (6-41) months. 72 patients were treated with EPAG+IST, including 41 (56.9%) treated with EPAG+FK506 and 31 (43.1%) treated with EPAG+CsA. 27 patients were treated with EPAG alone. No significant difference was found between EPAG+IST group and EPAG group in patient baseline characteristics like age, male proportion, NSAA proportion, presence of PNH clone, proportion of previous ATG+CsA / CsA treatment, previous IST duration and dosage. With compatible follow-up time, EPAG exposure duration and dosage, there was no significant difference in OR/CR rate at 3 rd/6 th/12 th month between patients who was treated with EPAG+FK506 and EPAG+CsA. Under similar compatible baseline conditions, the OR rate was 33.3% vs 22.2% (P=0.284) at 3 rd month, 61.1% vs 37.0% (P=0.032) at 6 th month, and 67.2% vs 42.1% (P=0.051) at 12 th month for patients treated with EPAG+IST and EPAG alone, respectively, but no significant difference was found in time to response (3 (1-12) vs 3 (1-7) months, P=0.679) or CR rate at 3 rd/6 th/12 th month (6.9%/12.5%/20.7% vs 3.7%/7.4%/5.3%, P>0.05) between the two groups. Relapse occurred at 6 th to 12 th month of EPAG treatment, and the relapse rate at 12 th month was 9.8% and 27.3% (P=0.154) for patients treated with EPAG+IST and EPAG alone, respectively. For patients treated with EPAG+IST, responders had a significantly higher baseline reticulocyte count (60.25 (11.5-230.5)×10 9/L vs 16.7 (6.6-56.6)×10 9/L, P=0.040) compared with non-responders. No predictive factors for the overall response were found for patients treated with EPAG alone. Adverse events which led to dosage regulation were gastrointestinal disorders (2.8% vs 3.7%, P=1.000), elevated creatinine (2.8% vs 0, P=0.599), elevated ALT (1.4% vs 0, P=1.000) and arthralgia (0 vs 3.7%, P=0.280) for patients with EPAG+IST and EPAG, respectively. No deaths were found in either group, while the clone evolution rate was 2.8% and 3.7% (P=1.000) in EPAG+IST and EPAG monotherapy group, respectively.Conclusion: EPAG+IST had higher OR rate than EPAG monotherapy with similar side effects for patients with relapsed/refractory acquired AA. Those with higher baseline reticulocyte count were more likely to respond to EPAG+IST.Key words: relapsed/refractory, aplastic anemia, eltrombopag, immunosuppressant, efficacy DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:In the presented study, eltrombopag was prescribed in relapsed/refractory aplastic anemia patients.

Thrombopoietin receptor agonists for the treatment of severe persistent and chronic immune trombocytopenia in children: clinical data of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology

Thrombopoietin receptor agonists (TPO-RA) – romiplostim and eltrombopag – changed considerably the therapeutic options for severe persistent and chronic immune thrombocytopenia (ITP). The article presents the results of a retrospective study of TPO-RA efficacy and safety in patients under 18 years of age. The study was approved by the Independent Ethics Committee and Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Sixty-eight children had a total of 89 courses of TPO-RA (44 romiplostim and 45 eltrombopag). Their median age was 6.5 years. The median ITP duration was 15.8 months. All patients received previous ITP therapy (1–6 lines). Before the initiation of TPO-RA, the majority of patients had thrombocytopenia with bleeding. In most cases, the platelet response was achieved within the first 2 months of treatment. The average effective doses of romiplostim and eltrombopag were 10 mg/kg per week and 75 mg per day, respectively. Half of patients in romiplostim group and 62% of patients in eltrombopag group did not require extra therapy. The majority of patients (75.6–81.8%) achieved an overall response, but only near 50% achieved a durable (more than 24 weeks) platelet response. Six patients sustained the response after TPO-RA discontinuation. The most common adverse events (AE) of TPO-RA therapy were transient elevation in hepatic enzymes in eltrombopag group (28.9%) and thrombocytosis (18.2–22.2%) in both groups. In 6 cases the therapy was discontinued due to AEs. Two AEs were serious. Our results demonstrate that TPO-RA could safely increase platelet counts and decrease the risk of spontaneous life-threatening bleeding in nearly half of children with severe persistent and chronic ITP. TPO-RA could help to avoid long-term immunosuppressive therapy and splenectomy or delay them and the ITP remission is possible in some cases.

TPO versus TPO: the good, the bad, and the to be determined.

TPO versus TPO: the good, the bad, and the to be determined.

A multicentre double-blind, double-dummy, randomised study of recombinant human thrombopoietin versus eltrombopag in the treatment of immune thrombocytopenia in Chinese adult patients.

We performed a double-blind, double-dummy controlled study to compare the efficacy between recombinant human thrombopoietin (rhTPO) and eltrombopag in rapidly increasing the platelet counts in Chinese patients with immune thrombocytopenia (ITP). A total of 96 patients diagnosed with ITP for ≥6 months who had baseline platelet counts of <30 × 109 /l were randomly assigned (1:1 ratio) to receive eltrombopag 25 mg/day or rhTPO 300 u/kg for 2 weeks. Compared with the eltrombopag group, a significantly higher proportion of patients in the rhTPO group achieved platelet counts of ≥50 × 109 /l [75·00% (36/48) vs. 43·75% (21/48), P = 0·003] or complete response (64·58% vs. 25·00%) on day 15. Moreover, a higher proportion of patients in the rhTPO group either had platelet counts that rapidly increased to twice that of baseline and with platelet counts of ≥30 × 109 /l, or reached ≥50 × 109 /l at least once when analysed on day 9, 12, and 15. However, upon discontinuation of the treatment, the platelet counts reduced to the baseline within 1 week in the rhTPO group, but on the fourth week in the eltrombopag group. Adverse events were similar in patients given rhTPO and eltrombopag. To conclude, rhTPO is superior to eltrombopag at 25 mg/day in rapidly increasing platelet counts in patients with ITP (ClinicalTrials.gov Identifier: NCT03771378).

A Real-World Observation of Eltrombopag and Recombinant Human Thrombopoietin (rhTPO) in Lymphoma Patients With Chemotherapy Induced Thrombocytopenia.

This real-world, observational study aimed to assess and compare the clinical efficacy and safety of eltrombopag with recombinant human thrombopoietin (rhTPO) in the treatment of chemotherapy induced thrombocytopenia (CIT) in patients with lymphoma. One hundred and fifty-three patients who experienced grade 3 or 4 thrombocytopenia after chemotherapy for lymphoma were enrolled, 51 of which were treated with eltrombopag, 50 with rhTPO, and 52 patients with no drug treatment were served as the control group. The lowest platelet level and mean platelet counts at Day 5, Day 7, and Day 10 were significantly higher in both the eltrombopag group (P=.041,.003,.000,.000) and rhTPO group (P=.005,.005,.000,.000) than the control, but there was no difference between treatment with eltrombopag and rhTPO. Similarly, days required for the recovery of platelet counts to ≥50×109/L and ≥75×109/L were not different between the two treatment groups but significantly higher than the control group (P <.05). Rates of bleeding and platelet transfusion were all significantly reduced in patients treated with eltrombopag (P=.031,.032) or rhTPO (P=.017,.009) when compared to the control. Treatment-related adverse events (AEs) were reported in 7 (13.7%) and 6 (12.0%) patients in the eltrombopag and rhTPO groups, respectively, all being mild and transient in nature. In conclusion, both eltrombopag and rhTPO were effective and safe in the treatment of thrombocytopenia after chemotherapy for lymphoma.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

Comparison of Splenectomy and Eltrombopag Treatment in the Second-Line Treatment of Immune Thrombocytopenic Purpura

Objective:Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by isolated thrombocytopenia. While first-line treatments focus on inhibiting autoantibodies and platelet destruction, second- and third-line treatments include splenectomy and thrombopoietin receptor agonists. In this study, we aimed to compare the efficiency and toxicities of splenectomy and eltrombopag as second-line treatments in ITP.Materials and Methods:We retrospectively analyzed patients who were diagnosed with ITP and followed between 2015 and 2020. Patients who underwent splenectomy or received eltrombopag treatment as second-line or further therapy were included. For subgroup analyses, patients were further stratified according to whether they received eltrombopag in the second or third line of treatment.Results:There were 38 patients in the splenectomy group and 47 patients in the eltrombopag group. The mean age of patients in the splenectomy and eltrombopag groups was 43.2 and 50.5 years, respectively. Time to response was significantly shorter in the splenectomy arm (p=0.001). However, response rates at the 3rd, 6th, 12th, and 24th months did not exhibit a statistically significant difference between groups; nor did total duration of response and adverse events. Response rates at the 1st, 3rd, 6th, 12th, and 24th months and the total duration of response did not exhibit a statistically significant difference between eltrombopag subgroups. Eltrombopag treatment was ceased for 20 patients after a median of 54.1 months (range: 1-151). Among them, 12 patients (60%) did not experience a loss of response.Conclusion:Comparing the splenectomy and eltrombopag arms, even though time to achieve response was in favor of the splenectomy group, this advantage disappeared when overall response rates and response rate at the 2nd year were considered. Using eltrombopag in the second or third line of therapy does not yield any difference in terms of time to achieving response.

Management of primary immune thrombocytopenia in a real-world setting in Japan: eltrombopag versus corticosteroids.

This real-world study in Japan assessed the long-term safety of persistent use of eltrombopag compared to corticosteroids. Overall, 1887 patients with primary immune thrombocytopenia were included in the study cohort, based on hospital claims data. Eltrombopag was frequently used as a second- or third-line therapy (monotherapy: 13.1% and 25.7%; combination: 24.39% and 16.52%, respectively). The risk of bleeding was approximately 30% lower in the eltrombopag group (as monotherapy and in combination with other drugs including corticosteroids) than the corticosteroid group (hazard ratio, 0.66; 95% confidence interval, 0.45-0.96). Results from univariate and multivariate Cox models indicated that patients aged ≥ 60years, male patients and patients who received the drugs for peptic ulcer or gastroesophageal reflux disease have a higher risk of cerebral haemorrhage or gastrointestinal bleeding. Surgeries were more common among patients on corticosteroids compared to patients on eltrombopag (39.1% vs 34.6%, P = 0.004), while splenectomies were very rare. There was no significant difference in the costs of scheduled, emergency, or any type of hospitalisations between the exposure groups. The risk of infections, cataracts, and thrombosis did not differ between the exposure groups.

Efficacy and safety of immunosuppressive therapy with or without eltrombopag in pediatric patients with acquired aplastic anemia: A Chinese retrospective study

To determine the efficacy and safety of eltrombopag (E-PAG) combined with intensive immunosuppressive therapy (IST) for the treatment of pediatric patients with severe aplastic anemia (SAA). A total of 57 pediatric patients with newly diagnosed severe aplastic anemia were enrolled in this study. Thirty nine patients were treated with IST alone, consisting of porcine anti-human thymocyte globulin (30 mg/kg/day × 5 days) and cyclosporine A (CsA) (treated for 2 years, with a trough concentration maintained at 200–250 ng/mL), and 18 patients were treated with IST + E-PAG (12.5–50 mg/day, maintained for 6 months). We found no statistical difference between the response rates at 3 months for the two groups (CR: 12.8% vs. 22.2% p > 0.05, ORR: 56.4% vs. 77.7% p > 0.05). However, we found a statistical difference between the response rates at 6 months for the two groups (CR: 17.9% vs. 50% p < 0.05, ORR: 69.2% vs. 94.4% p < 0.05). The main side-effect during treatment with E-PAG was having a slightly to moderately elevated bilirubin level, which was temporary and controllable, accounting for approximately 66.6% (12/18) of patients in the IST + E-PAG group vs. 20.5% (8/39) of those in the IST group (p < 0.05). IST + E-PAG therapy appears to be more effective than IST alone for the treatment of pediatric SAA, with good tolerability and compliance. This approach deserves further exploration.

Safety and efficacy of eltrombopag in the treatment of children with immune thrombocytopenia: a Meta analysis.

To systematically assess the efficacy and safety of eltrombopag in the treatment of children with immune thrombocytopenia (ITP). PubMed, Embase, Cochrane Library, Weipu Data, CNKI, and Wanfang Data were searched for studies on eltrombopag used for the treatment of children with ITP. RevMan 5.3 and R version 3.6 were used to perform a Meta analysis of included studies. A total of 11 studies were included, with 2 randomized controlled trials and 9 cohort studies. The Meta analysis of the 9 cohort studies showed that eltrombopag had a response rate of about 70% (95%CI: 65%-76%) in the treatment of children with ITP, with no serious adverse events. The Meta analysis of the randomized controlled trials showed that the eltrombopag group had a higher response rate than the placebo group (RR=2.64, 95%CI: 1.58-4.44, P<0.05), while there was no significant difference in the incidence rates of adverse events and serious adverse events between the two groups (P>0.05). Eltrombopag has good efficacy and safety as a second-line treatment regimen for children with ITP.

Eltrombopag Effectiveness and Tolerability in Chronic Immune Thrombocytopenia: A Meta-Analysis.

Eltrombopag is an orally administered, non-peptide, thrombopoietin receptor agonist which initiates thrombopoietin signaling and stimulates the production of normally functioning platelet. We aimed to do a systematic review and meta-analysis of currently available published data to verify whether eltrombopag treatment in patients with chronic immune-mediated thrombocytopenia can prolong survival. We searched for published, randomized, controlled trials in PubMed, Cochrane and Scopus databases using the following search strategy (“Eltrombopag” OR “Benzoates” OR “Hydrazines”) AND (“Idiopathic Thrombocytopenic Purpura” OR “immune thrombocytopenia” OR “Idiopathic Thrombocytopenic Purpuras” OR “Immune Thrombocytopenia” OR “Autoimmune Thrombocytopenia” OR “Werlhof”). The pooled relative risk (RR) showed that eltrombopag group has significantly higher overall platelet response than placebo group (MD = 3.42, 95% CI [2.51, 4.65], P > .0001); pooled results were homogenous (P = .27, I2 = 22%). The pooled relative risk showed that eltrombopag group has lower incidence of any bleeding than placebo group (MD = 0.65, 95% CI [0.48, 0.87], P = .003); pooled results were heterogenous (P = .001, I2 = 75%) and the detected heterogeneity was best resolved after excluding Bussel et al (P = .10). Homogeneous results were still favored eltrombopag group (MD = 0.75, 95% CI [0.60, 0.93], P = .008).

Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia: a non-inferiority, multicentre, randomised trial

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. 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. 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. 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. GlaxoSmithKline and Novartis.

A Non-Inferiority Trial of Perioperative Eltrombopag or Intravenous Immune Globulin for Immune Thrombocytopenia

Background: Patients with immune thrombocytopenia (ITP) are at risk of bleeding during surgery. Intravenous immune globulin (IVIG) is a blood product that is commonly used to increase platelet counts before surgery or invasive procedures for patients with ITP; however, eltrombopag, an oral thrombopoietin receptor agonist, may be an effective alternative. Methods: We conducted a multicenter randomised trial to determine whether eltrombopag was non-inferior to IVIG for the achievement of perioperative platelet count targets without the use of rescue treatment. We did an intention to treat and per-protocol analysis using an absolute non-inferiority margin of -10%. Secondary endpoints were thrombosis, bleeding, adverse events and treatment satisfaction. We enrolled 74 patients with ITP who had a planned major or minor surgery and with a platelet count below 100 x109/L or 50 x109/L respectively. Patients were randomised to receive oral daily eltrombopag from 21 days preoperatively, or IVIG (1 or 2g per kg) seven days preoperatively. Findings: By intention to treat, perioperative platelet targets were achieved by 30 of 38 patients (78·9%) assigned to eltrombopag and 22 of 36 patients (61·1%) assigned to IVIG (absolute difference, 17·8%; one-sided lower limit of the 95% confidence interval, 0·4%; p=0·005 for non-inferiority). Results were similar for patients who completed the protocol. One patient in the eltrombopag group developed a pulmonary embolism 14 days after minor surgery, and one patient in the IVIG group developed a distal deep vein thrombosis 30 days after major surgery. There was no difference in bleeding or adverse events. Patients reported higher treatment satisfaction with eltrombopag. Interpretation: Eltrombopag was no worse than IVIG for the achievement of platelet count targets around the time of surgery for patients with ITP. This population may be at increased risk of thrombosis. Trial Registration: www.clinicaltrials.gov number as NCT01621204. Funding Statement: This trial was funded by GlaxoSmithKline and Novartis. Declaration of Interests: N.M.H., R.J.C., M.B., J.K., A.T., M.S., M.W., P.V., J.C., N.L., S.L., and J.G.K. report no competing financial interests. D.M.A. reports grants from GlaxoSmithKline and Novartis during the conduct of the study; grants and/or personal fees from Novartis, Amgen, Bristol Myers Squibb, UCB, Principia, and Rigel outside the submitted work. C.H. reports personal fees from Novartis, Amgen, and GSK, outside the submitted work. E.J. reports personal fees from Novartis, outside the submitted work. M.S. reports personal fees from Novartis, outside the submitted work. Y.L. reports grants from Novartis during the conduct of the study, and other fees from Pfizer, outside the submitted work. L.L. reports personal fees from Novartis during the conduct of the study. S.A. reports grants from Novartis NL during the conduct of the study; grants from Amgen, outside the submitted work. W.L. reports personal fees from Novartis, outside the submitted work. Ethics Approval Statement: The trial was approved by the research ethics boards at each participating center. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.

Outcome of Standard Immunosuppressive Therapy with or without Eltrombopag for Chinese Patients with Severe Aplastic Anemia in the Real World

BACKGROUND Immunosuppression is the current standard therapy for patients with severe aplastic anemia(SAA), whereas allogeneic haematopoietic stem cell transplantation (HSCT) is recommended for patients younger than 50 years old, if donors are available. Immunosuppression with antithymocyte globulin (ATG) and ciclosporin results in an overall response rate (ORR) of about 70%. In Chinese SAA patients, porcine ATG and rabbit ATG resulted apparently in similar ORRs and survivals. The low CR rate of immunosuppression with ATG suggests that other strategies are needed to improve outcome. Eltrombopag is an oral thrombopoietin receptor agonist. In a recent study of newly diagnosed SAA patients, combined standard immunosuppressive therapy (IST) with eltrombopag, the patients in one of three cohorts who received eltrombopag from day 1 to 6 months achieved higher ORR at 6 months (94%) and CR rate(58%). The results showed a higher rate of treatment response than in the past. But the data of eltrombopag in SAA have so far been limited to clinical trials, and its efficacy in routine practice remains undefined, especially for Chinese SAA patients. Recently, we retrospectively analyzed the results of 48 cases suffer from SAA received standard immunotherapy combined with or without eltrombopag in our center, so as to explore the effects and adverse reactions in the real world. METHODS 48 consecutive newly diagnosed patients with severe aplastic anemia were enrolled in this study. Out of 48 cases, 27 were male, and 21 were female. The median age was 46 years old (ranged from 18 to 69 years old). SAA patients who received ATG combined with cyclosporine A (CsA) therapy with or without eltrombopag were analysed retrospectively. The patients were divided into a eltrombopag group (n = 14) and a without eltrombopag group (n = 34). The eltrombopag group received eltrombopag (median daily dose 75 mg) from the beginning of IST and for at least 3 months. The primary outcome was complete hematologic response at 6 months. At the same time, overall response, survival, relapse, and clonal evolution to myeloid cancer were observed. RESULTS After three months, the eltrombopag group and without eltrombopag group had an ORR of 69.5% and 47.2%, respectively (P = 0.063); after six months, the ORR reached 85.7% and 73.6%, respectively (P = 0.078). The rates of complete response at 6 months was 35.7% in the eltrombopag group and 29.4% in without eltrombopag group. The complete and overall response rates in the eltrombopag group were higher than in without eltrombopag group. However, due to the small number of cases, there was no statistical difference. At a median follow-up of 2 years, the survival rate was 97.9%; one patient died from a hematologic cause. Rates of relapse and clonal evolution were similar in two gruops. Adverse effects included reversible rashes, dyspepsia, and liver function derangement. CONCLUSIONS Rates of hematologic response among chinese patients with severe aplastic anemia treated with standard immunosuppressive therapy plus eltrombopag was markedly higher than without eltrombopag. 【Key words】 Aplastic anaemia; newly diagnosed; eltrombopag; antithymocyte globulin; Disclosures No relevant conflicts of interest to declare.

Outcomes in Pediatric Patients with Severe Aplastic Anemia Treated with Standard Immunosuppression and Eltrombopag

Background: Immune aplastic anemia (SAA) disproportionally affects children and young adults. Immunosuppression (IST) remains the treatment of choice for patients less than 40 years of age without a fully human leukocyte antigen (HLA) matched sibling. In the pediatric population (aged &amp;lt;18 years), from NIH historic studies, horse antithymocyte globulin (h-ATG) and cyclosporine(CSA) regimes have produced good results, with an overall response rate (ORR) of 74% at 6 months, a relapse rate of 33% at 10 years, and an overall survival (OS) of 80% at 10 years (Scheinberg P, J Pediatrics 2008), generally better outcomes than in adults. Eltrombopag (EPAG) is an oral thrombopoietin-receptor agonist that has been shown to significantly improve response rates when combined with h-ATG and CSA for treatment-naïve patients (Townsley D, NEJM 2017). We report here a pediatric subgroup analysis of our clinical trial (NCT01623167) to assess whether the addition of EPAG to IST improved ORR in children with SAA. Methods: Between 2012 and 2018 a total of 39 patients &amp;lt;18 years of age with SAA were treated with front line EPAG in combination with h-ATG and CSA. We assessed ORR at 6 months, relapse rate, rate of clonal evolution, and OS. Additionally, we monitored for the development of clonal evolution and for the emergence of somatic clones. Germline testing for inherited marrow failure was performed in all patients. Response was defined by blood counts no longer satisfying criteria for SAA. Outcomes were compared to two treatment-naive cohorts: adult patients aged 18 years and older who received EPAG in combination with immunosuppression (adult EPAG group), and a historical cohort (from 1989 to 2010) of 87 pediatric patients aged &amp;lt;18 years who were treated with immunosuppression (pediatric IST group). The pediatric IST group included all patients treated with a h-ATG based regimen including h-ATG with CSA, and h-ATG with CSA and additional immunosuppression (either mycophenolate mofetil or sirolimus). A historical adult group (Adult IST group) of 322 patients treated from 1989 to 2010 with the same IST regimens as the pediatric IST group was also used as a comparator. Analyses were based on intention-to-treat. Results: Median age in the pediatric EPAG group was 15 years and in the pediatric IST group 11 years. Thirty-two patients (of an initial 39) were evaluable for response at 6 months. Seven patients (18%) were taken off study prior to 6 months to undertake bone marrow transplant, due to either failure to respond by 3 months or clinical urgency in count recovery. Overall, 28 (72%) of all treated patients achieved a response at 6 months, by comparison, responses were observed in 74% of the pediatric IST group (p=0.836) and in 83% in the adult EPAG group (p=0.143). In contrast, patients in the adult EPAG group had a significant difference in 6 month ORR compared with the adult IST group (83% versus 58%, p= &amp;lt;0.0001). The PK analysis of EPAG suggested comparable exposure in pediatric (6-17 years) and adult population. Of the 28 patients who achieved a response at 6 months, 43% relapsed, compared to 28% in the pediatric IST group (p=0.252). Median time to relapse in the pediatric EPAG group was 565 days from IST. There was no significant difference in survival between the pediatric EPAG group and either the pediatric IST group or the adult EPAG group. Clonal evolution occurred in 3 (8%) of patients (monosomy 7, del 5q, and translocation 5:12); 7% of patients evolved in the pediatric IST group. Somatic mutation testing was performed in 36 patients at baseline and was negative in all. At the 6 month timepoint, 5 patients had developed new somatic mutations (2 ASXL1, 2 ATRX, 1 BCOR), three clones appeared in responders and two in non-responders. Germline testing did not reveal any pathogenic variants. Conclusion: Eltrombopag added to immunosuppression did not improve ORR at 6 months in pediatric patients with SAA compared to our historical cohort of pediatric IST patients. In contrast, adults had much improved responses with EPAG. Some patients were taken off study prior to 6 month evaluation (18% compared to 6% in the pediatric IST group) to pursue BMT, likely reflecting recent improvements in outcomes and donor availability. In our study the addition of eltrombopag to IST did not provide any obvious therapeutic benefit to pediatric patients with severe aplastic anemia. This research was supported in part by the Intramural Research Program of the NIH and NHLBI. Disclosures No relevant conflicts of interest to declare.

Long-Term Durability of Eltrombopag Clinical Benefit for Advanced Myelodysplastic Syndromes or Acute Myeloid Leukemia and Severe Thrombocytopenia (ASPIRE Part 3)

Thrombocytopenia is a common complication in patients (pts) with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) that is associated with significant morbidity, a clinically significant bleeding risk, and early death. There are only limited treatment options for this high-risk population. Previous trials (Frey et al. ASH 2012) of thrombopoietin receptor agonists (TPO-RAs) for thrombocytopenia treatment in these pts suggested reduced thrombocytopenia-associated bleeding. ASPIRE (NCT01440374) was a multicenter, phase 2 trial. Eligible pts were ≥18 years, with high-risk MDS or AML, thrombocytopenia (platelets ≤25 x 109/L) due to bone marrow insufficiency, bone marrow blasts ≤50%, and an Eastern Cooperative Oncology Group status of 0-2. Exclusion criteria included platelets ≤10 x 109/L for reasons other than bone marrow insufficiency; leukocyte count ≥25 x 109/L; previous TPO-RA treatment. Pts were severely ill, on no other anti-MDS/AML therapy, with an expected median survival of ~6 months on treatment. Part 1 was an 8-week open-label study of eltrombopag 100 mg/day with dose escalation up to 300 mg/day (Mittelman et al. ASH 2012). Part 2 was a 12-week randomized, double-blind trial, during which pts received eltrombopag or placebo (Mittelman et al. Lancet Haematol 2018). Pts who completed both parts continued to Part 3, an extension phase of 10 months (for pts from Part 1) and 9 months (for pts from Part 2) (Fig. 1A). In ASPIRE Part 2, eltrombopag reduced the frequency of clinically relevant thrombocytopenic events (CRTEs) (one or more ≥Grade 3 hemorrhagic adverse events [AEs], platelets ≤10 x 109/L, or platelet transfusions) compared with placebo during weeks 5-12 in pts with advanced MDS or AML. Here we present data on the long-term durability of clinical benefit, overall survival (OS) and progression-free survival (PFS) for Part 2 pts within Part 2 and Part 3, and safety and tolerability of eltrombopag monotherapy in pts with advanced MDS or AML. Mean pt age was 72.2 years. Pts received a median eltrombopag daily dose of 298.8 mg with a median exposure of 11.1 weeks. At baseline, 40% of pts had an abnormal karyotype and 68% were platelet transfusion-dependent. OS (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.64-1.48) and PFS (HR 0.99, 95% CI 0.68-1.43) were not significantly different between long-term eltrombopag and placebo to eltrombopag switchers in Part 3 (median OS of 4.3 months vs 4.6 months, respectively). Median PFS was 0.94 months and 1.08 months for the placebo and eltrombopag group, respectively. CRTEs were summarized by week with the proportion of pts plotted by visit. Pts experienced large variability in CRTEs during weeks 1-40 with inconclusive results due to low number of pts at some time points (Fig. 1B). Hematological improvement (HI) was defined as improvement (platelets, neutrophils, hemoglobin) on treatment compared with placebo (Cheson et al. Blood 2006). Overall, 33% of pts showed HI with long-term eltrombopag use, compared with 10% during the double-blind phase. However, HI did not reach statistical significance compared with placebo in the double-blind phase. 46% of pts completed treatment. The main reasons for treatment discontinuation were physician decision (24%) and AEs (22%). Overall, 97% of pts experienced an AE during the extension phase plus 30 days. The most common AEs (≥20% of pts) were pyrexia, nausea, diarrhea, and epistaxis. Overall, 56% of pts died, with the disease under study being the most common cause (36%), and 37% of pts had treatment-related AEs. 31% of pts experienced Grade 3 or 4 AEs. The most commonly reported (&gt;5%) were pneumonia, febrile neutropenia, anemia, hypokalemia, and urinary tract infection. Overall, 66% of pts experienced a serious AE (SAE). The most common (≥10%) were pneumonia, pyrexia, febrile neutropenia, and sepsis. The most common fatal SAEs (≥5%) were sepsis, pneumonia, and cardiac failure. ASPIRE Part 3 did not identify any new safety signals. The most common AEs were consistent with those expected for the disease under study and with eltrombopag treatment. There was no evidence of reduced OS or PFS. More pts met the criteria for HI with long-term eltrombopag use compared with those in the double-blind phase. The large CRTE variability observed with eltrombopag during Part 3 requires further assessment in adequately powered trials of high-risk MDS or AML pts and in a less seriously ill population. Figure 1 Disclosures Mittelman: Novartis: Honoraria, Research Funding, Speakers Bureau. Platzbecker:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Portella:Novartis: Employment. Zhu:Novartis: Employment. Selleslag:Celyad: Other: Clinical trial research (no honoraria recieved); Novartis: Consultancy, Honoraria, Speakers Bureau. OffLabel Disclosure: Eltrombopag is used for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag is not indicated for the treatment of patients with myelodysplastic syndrome (MDS).

Retrospect Reviews of PNH Tests with Long-Term Follow-up in a Single Institution

I ntroduction : Paroxysmal nocturnal hemoglobinuria (PNH) often presents as hemolysis and/or bone marrow failure. Flow cytometric testing can accurately detect PNH. However, the long term studies on PNH clone size and how it relates to clinical course are few. We sought to understand how PNH clone size correlates with clinical course over time and the impacts on clone size with different treatments. Here we report long term clone size monitoring and clinical data of 57 patients with PNH in a single intuition. Methods : High sensitivity PNH flow cytometry (0.01% limit of detection) was performed with FLAER-FITC, CD64-PE, CD14-ECD, CD15-PC5, CD24-AA7500, CD45-KO for neutrophils &amp; monocytes; CD59-PE and CD235a-AA750 for RBCs. Retrospective analysis was done in the positive PNH cases from 2008-2019 at OHSU. Total 173 cases for 57 patients; including 27 females and 30 males, 52 adults and 5 pediatrics, with a mean age of 45 (range 9-78). We also reviewed results of serum LDH, bone marrow biopsies and molecular/cytogenetics of these patients. Among of these patients, 18 patients (11 females and 7 males, mean age 49.33, age range 29-73) with long term (at least over 4 years) follow-up have more than 3 PNH tests. Besides PNH clone on RBC and PMN, we also reviewed results of WBC count (x103/ul), Hb (g/dL), PLT (x103/ul) serum LDH (U/L), bone marrow biopsy reports and molecular/cytogenetics findings in these patients. Results: Among 57 patients, there are 30 aplastic anemia (AA) patients (53.63%), 7 AA patients progressing to PNH (AA&amp;PNH, 12.28%), 5 myelodysplastic syndromes (MDS, 8.77%), 12 PNH patients (21.05%), 1 pancytopenia, 1 autoimmune disease, 1 thrombosis. The diagnosis of AA and MDS were confirmed by bone marrow biopsy and molecular/cytogenetics. Significantly higher levels of all PNH clones were observed in PNH and AA/ PNH, compared to AA (all P &amp;lt;0.001) and MDS (all P&amp;lt;0.05) shown in Figure A-D. LDH was higher in PNH and AA/PNH than AA and MDS groups (P&amp;lt;0.001, Figure E). LDH demonstrated positive correlation with PNH clone size in RBC-type-III, neutrophils and monocytes (all P&amp;lt;0.0001, R= 0.4447, 0.5469, 0.5711, respectively, Figure F). No correlation was observed between LDH and RBC-type-II. Long term (4-11 years ) follow up include 18 patients were divided into 4 groups: 5 AA treated with immunosuppressant only, 5 AA treated with immunosuppressants and/or eltrombopag, 5 classic PNH or AA that progressed to PNH treated with immunosuppressants and/or eculizumab, and 3 PNH with observation and supplements only. The study showed immunosuppression only has lowest PNH clone size for both RBC and WBC (Figure G-H). As for the Hb and WBC count, there were no statistics differences among 4 groups (Figure I-J). Decreased PLT was detected in eltrombopag group (Figure K). Significantly, increased LDH was observed in the observation/supplement group (Figure L). Interestingly, all these 3 patients without special treatment have high PNH clones and LDH from diagnosis to now over 10 years. Despite receiving basic supportive care, the patients' clinical courses have been stable with only supplementation of vitamin B12 and Folic Acid. Conclusions : Positive PNH test was most frequently seen in AA patients. AA has lower PNH clone size and LDH than those of PNH patients or AA progressed to PNH patients. For all patients, PNH population showed positive correlation with LDH. Our study suggest that it is necessary to follow PNH clone size, as this may impact the decision of when to start therapy with what agents. Figure Disclosures No relevant conflicts of interest to declare.

Long Term Effects of Eltrombopag Treatment Versus Placebo for Low-Risk Myelodysplastic Syndromes with Thrombocytopenia (EQoL-MDS): Interim Results of a Single-Blind, Randomised, Controlled, Phase 2 Superiority Trial

Long Term Effects of Eltrombopag Treatment Versus Placebo for Low-Risk Myelodysplastic Syndromes with Thrombocytopenia (EQoL-MDS): Interim Results of a Single-Blind, Randomised, Controlled, Phase 2 Superiority Trial

Eltrombopag treatment during induction chemotherapy for acute myeloid leukaemia: a randomised, double-blind, phase 2 study

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

Thrombopoietin Receptor Agonists in the Treatment of Chronic Resistant Primary Immune Thrombocytopenia: Efficacy and Safety Data in Real Clinical Practice.

To analyze the long-term efficacy and safety of ATR in adult patients with primary resistant ITP in real-world clinical practice. The article contains long-term results analysis of ATR application under real clinical practice conditions in 138 patients (40 men and 98 women) whose median age at the beginning of therapy was 59 (18-86) years. Two ATR medicines-romiplostim (100 patients) and eltrombopag (38 patients) were used. During the first month of therapy, the median platelet count in the romiplostim group increased from 17·109 / L to 60·109 / L (9-600·109 / L), and the elethrombopag from 16.109 / L to 56.109 / L (9-400·109 / L). The minimal response (reaching platelet counts over 30·109 / L) was achieved in 92% of cases in both groups. Partial response (achievement of platelet count more than 50·109 / L) was achieved in 91 and 84% of patients in the rhombostim and eltrombopag groups, respectively. The frequency of complete response (an increase in platelet counts above 100·109 / L) was noted somewhat more often in the rhy- ploistim group-69% compared to 47% in the eltrombopag group (P = NS). Most patients demonstrated a long-term stable effect in the form of an increase in blood platelet count to a safe level during months and years of ATR treatment. The achievement of at least partial remission for 3 months or more was 70 and 71% in romiplostim and elthrombopag groups, respectively. Patients who started ATR- therapy are currently continuing treatment: 51% - in romiplostim group and in eltrombopag group-39%. The main reason of discontinuation the initially effective therapy were the loss of platelet response, toxicity, withdrawal from treatment (withdrawal with preservation of remission) and patients death. The tolerability of drugs with long-term admission was satisfactory. The most common AE were headache, bone pain, thrombosis, increased blood pressure and petechial hemorrhagic eruptions. The overall incidence of complications did not differ significantly between the romiplostim and eltrombopag groups -15.6 and 15.8%, respectively. Long-term ATR-therapy using in patients with resistant chronic ITP is an effective and largely safe treatment option.