Eltrombopag In Combination Research Articles

Thrombopoietin (TPO) Receptor Agonist Eltrombopag in Combination with Azacitidine (AZA) for Primary Treatment of Myelodysplastic Syndromes (MDS) Patients with Thrombocytopenia: Outcomes from the Randomized, Placebo-Controlled, Phase III Support Study

Introduction: Hypomethylating agents (HMA), including AZA, used to treat cytopenias in MDS patients (pts), can exacerbate thrombocytopenia. Such pts are usually treated with repeated platelet transfusions and AZA dose adjustments. Relieving thrombocytopenia may reduce platelet transfusion requirements and allow optimal AZA dosing. Eltrombopag is an oral TPO receptor agonist approved for the treatment of pts with chronic ITP, hepatitis C virus-related thrombocytopenia, and recurrent severe aplastic anemia. SUPPORT was a randomized, double-blind, placebo-controlled trial investigating the platelet supportive care effects of eltrombopag versus placebo in pts with intermediate (int)-1, int-2 or high-risk MDS receiving AZA.Methods:Adult pts with no previous exposure to HMA, baseline (BL) platelets <75x109/L and int-1, int-2 or high-risk MDS by IPSS were enrolled. Pts were randomized 1:1 to eltrombopag/AZA or placebo/AZA. Pts received eltrombopag or placebo starting at 200 mg/day (100 mg/day for East Asians), adjusted by 100 mg increments (50 mg for East Asians) to a maximum 300 mg/day (150 mg/day in East Asians) - to ensure platelet counts remained sufficient to avoid platelet transfusions and bleeding events - for as long as pts received AZA (75 mg/m2 sc once daily for 7 days, every 28 days). Treatment could continue as long as benefit was derived or until disease progression, unacceptable toxicity or death. Primary endpoint was proportion of platelet-transfusion independent pts during AZA cycles 1-4. Key secondary endpoints included overall survival (OS) and disease progression. Adverse events (AEs) were recorded from the first dose of treatment until completion of the 4-week follow-up period following discontinuation of study treatment. Following a planned interim assessment, an independent data monitoring committee recommended stopping the study prematurely because outcomes crossed the pre-defined futility threshold and for safety reasons. Here we report the primary analyses from all randomized pts at the time of trial termination.Results:356 pts (median age 70 [range 24-89] years) received eltrombopag (n=179; n=64 int-1, n=77 int-2, n=38 high-risk) or placebo (n=177; n=61 int-1, n=83 int-2, n=33 high-risk). 29 (16%) eltrombopag and 37 (21%) placebo pts were platelet-transfusion dependent at BL. Median time on AZA plus eltrombopag or placebo was 83 (range 1-477) vs 149 (8-503) days. Most common reasons (≥10%) for treatment discontinuation on eltrombopag or placebo, respectively, were study termination (32 vs 44%), AZA discontinuation (30 vs 26%) and AEs (22 vs 14%). Median eltrombopag or placebo doses were 113 (range 60-148) vs 122 (81-147) mg/day in East Asians and 200 (65-293) vs 262 (107-316) mg/day in non-East Asians.At an interim analysis (n=147 evaluable pts), 13/79 (16%) eltrombopag and 27/68 (40%) placebo pts were platelet-transfusion independent [OR: 0.25, 95% CI: 0.11, 0.61; one-sided P=1.000], crossing the pre-defined futility boundary. At premature (primary and final analysis) study termination (n=356), 28/179 (16%) eltrombopag and 55/177 (31%) placebo pts were platelet-transfusion independent during the first 4 cycles of AZA (OR: 0.37, 95% CI: 0.21, 0.65; one-sided P=1.000).At study closure, 57 (32%) and 51 (29%) pts had died in the eltrombopag and placebo arms, respectively, with 33 (19%) and 29 (16%) deaths within 30 days after end of treatment; the main causes of death (≥10%) were disease under study (16 vs 12%) and sepsis (10 vs 7%). Disease progression (investigator-assessed) had occurred in 38 (21%) and 30 (17%) pts in the eltrombopag and placebo groups, respectively, at the time of study discontinuation. The most common AEs for eltrombopag are summarized (Table).Conclusions: In contrast to published reports on eltrombopag monotherapy inducing platelet transfusion independence in MDS pts, eltrombopag given concomitantly with AZA was inferior to placebo/AZA. There was no difference in overall deaths between the two groups. A complete assessment of disease progression, including AML progression at the time of study termination, is in progress. Pharmacodynamic antagonism between AZA and eltrombopag is proposed as one potential explanation for these results; further analyses and preclinical studies are ongoing to determine a possible mechanism of drug-drug interaction and the impact of drug sequencing on this potential association. [Display omitted] DisclosuresDickinson:GlaxoSmithKline: Consultancy, Research Funding. Fenaux:Celgene, Janssen, Novartis, Astex, Teva: Research Funding; Celegene, Novartis, Teva: Honoraria. Mittleman:Celgene, Novartis, Janssen: Speakers Bureau; Novartis, Pfizer, Janssen, Roche: Consultancy. Portella:Novartis: Employment. Burgess:Novartis: Employment. Platzbecker:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Eltrombopag for the treatment of aplastic anemia: current perspectives.

Aplastic anemia (AA) is a potential life-threatening hematopoietic stem cell (HSC) disorder resulting in cytopenia. The mainstays of treatment for AA are definitive therapy to restore HSCs and supportive measures to ameliorate cytopenia-related complications. The standard definitive therapy is HSC transplantation for young and medically fit patients with suitable donors and immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine for the remaining patients. A significant proportion of patients are refractory to IST or relapse after IST. Various strategies have been explored in these patients, including second course of antithymocyte globulin, high-dose cyclophosphamide, and alemtuzumab. Eltrombopag, a thrombopoietin mimetic, has recently emerged as an encouraging and promising agent for patients with refractory AA. It has demonstrated efficacy in restoring trilineage hematopoiesis, and this positive effect continues after discontinuation of the drug. There are ongoing clinical trials exploring the role of eltrombopag as a first-line therapy in moderate to severe AA and a combination of eltrombopag with IST in severe AA.

Persistent Elevation of Plasma Thrombopoietin Levels in Severe Aplastic Anemia, Even with Hematologic Recovery

In bone marrow failure, levels of circulating hematopoietic growth factors (HGFs) are extremely elevated, in compensation for low blood counts. In general, administration of recombinant HGFs is not effective in aplastic anemia (AA) and related syndromes. We have established the utility of eltrombopag, a thrombopoietin (Tpo) mimetic, in severe AA (SAA) refractory to immunosuppression (IST) (Olnes, N Engl J Med, 2012; Desmond, Blood, 2014). Eltrombopag in combination with standard IST also appears to increase the rate and speed of recovery in treatment-naive SAA (Townsley, EHA. 2015). These clinical results are surprising, as plasma Tpo is markedly increased in SAA (Feng, Haematologica, 2011). In investigating possible mechanisms of action of eltrombopag, we studied HGF dynamics over time in SAA patients undergoing various treatment regimens and manifesting a range of hematologic responses. In a cohort of 37 treatment-naive SAA patients who were treated with either standard IST (horse antithymocyte globulin/cyclosporine A:ATG/CsA, n = 10) alone or with the addition of eltrombopag (n = 27), among whom 8 were non-responders and 29 responders at 6 months, we measured plasma Tpo, granulocyte-colony stimulating factor (G-CSF) and erythropoietin (Epo) using magnetic multiplex assays. Concentrations of these HGFs were greatly elevated before treatment. In a majority of patients, G-CSF declined rapidly to the normal range by 6 months, with no difference between responders and non-responders, and no correlation between G-CSF and absolute neutrophil counts. Epo concentrations decreased to the normal range at 6, 12, and 24 months post treatment in responders, to a significantly greater degree than in non-responders (p = 0.001, 0.0012, 0.038, respectively). There was a negative correlation between Epo and hemoglobin (r2 = 0.3126, p<0.0001). Tpo levels did decrease by 6 months and later, but remained much higher than the normal range, however Tpo levels in responders were significantly lower than in non-responders at 6, 12, and 24 months, respectively (p = 0.0009, 0.0477, 0.0036), with Tpo in non-responders remaining at high baseline levels (Figure 1A). These data suggest that a decrease in Tpo and/or Epo levels following initial IST therapy is an indicator of hematologic response. Linear regression analysis reveals a negative correlation between Tpo levels and platelet counts (r2 = 0.3243, P < 0.0001), consistent with previous reports. In a cohort of 7 SAA patients refractory to IST but who achieved a clinical response to eltrombopag, Epo and G-CSF levels in plasma decreased to the normal range at 3-4 months post initiation of eltrombopag treatment, but Tpo levels remained significantly elevated over the normal range for up to 5 years of follow-up, despite sustained clinical response (Figure 1B). Regression analysis revealed a negative correlation between Tpo and platelet counts (r2 = 0.3696, p < 0.0001). We asked if persistently elevated levels of Tpo even in responders are due to incomplete recovery of platelets or megakaryocytes, and thus followed up Tpo levels up to 7 years post horse ATG/CsA treatment in a cohort of 9 patients who obtained stable complete remission with platelet counts greater than 100 K/uL. Tpo levels in these patients had declined by 3 and 6 months post treatment, gradually decreased, then stabilized at levels still higher than healthy controls (Figure 1C) despite platelet counts of 102-314 K/uL (median, 174 K/uL) by 6 months and later post treatment, and recovery of bone marrow megakaryocyte frequency to normal or only mildly decreased. Tpo levels in these patients negatively correlated with platelet counts (r2 = 0.3904, p < 0.0001. Figure 1D). In conclusion, Epo and G-CSF levels fall promptly in patients with SAA who recover blood counts. In contrast, circulating Tpo levels remain markedly elevated for long periods even after complete response to treatment. Likely, Tpo is high due to low megakaryocyte mass. The consequences of sustained high Tpo levels on primitive progenitors and stem cells in these circumstances are unclear, and may play a role in stem cell exhaustion and clonal evolution. [Display omitted] DisclosuresTownsley:Novartis: Research Funding; GSK: Research Funding. Winkler:Novartis: Research Funding; GSK: Research Funding. Dumitriu:Novartis: Research Funding; GSK: Research Funding. Young:Novartis: Research Funding; GSK: Research Funding.

Eltrombopag and High-Dose Dexamethasone As First Line Treatment For ITP

IntroductionPrimary immune thrombocytopenia (ITP) is an acquired autoimmune disorder that involves antibody and cell mediated destruction of platelets as well as suppression of their production. Prednisone is the initial standard therapy in adults1. High-dose dexamethasone as front-line therapy given as pulses of 40 mg per day for 4 consecutive days, was effective in 85% of patients, nevertheless, 50% relapsed within six months2. The prices of ITP drugs for 1 month of treatment in an adult range from prednisone; $16, eltrombopag; $5,934, intravenous immune globulin (IVIG) (80 g); $9,648, to rituximab (2 g); $15,5963. Only prednisone/dexamethasone and eltrombopag are available in oral presentation, for this reason, ambulatory treatment is an alternative for these patients.The trombopoietin receptor agonists are effective for the treatment of patients with chronic ITP, although response is dependent on continued administration. Eltrombopag is a small molecule agonist of the c-mpl (TpoR) receptor, which is the physiological target of thrombopoietin. This drug effectively raises the platelet count in adult patients (aged 18 years and over) as second/third line therapy, that is for patients refractory to corticosteroids and IVIG who have had their spleen removed or when splenectomy is not an option4. Our group, as well as others, has previously sought to improve response rates in these patients, particularly with the use of rituximab5, 6. To our knowledge neither eltrombopag nor romiplostim have been used as front line therapy in ITP, therefore the purpose of this study was to assess the efficacy of eltrombopag and dexamethasone in this setting. Patients and MethodsThis was a prospective, phase 2 study, using the combination of eltrombopag (50 mg PO once a day for 4 weeks) and high-dose dexamethasone (40 mg PO days 1,2,3,4) in untreated adult patients with immune thrombocytopenia or in patients with less than 7 days of treatment with corticosteroids.Complete response (CR) was defined as an increase in platelet count >100×109/L. Partial response (PR) was defined as an increase in the platelet count greater to 30 ×109/L according to standard criteria. Duration of response was considered from the day of initial administration to the first time of relapse (platelet count <30×109/L). ResultsTwelve consecutive patients were enrolled from June 2012 to June 2013, 6 women and 6 men. The median age at diagnosis was 50 years (range, 20 - 80 years). The median platelet count at diagnosis was 7 x 109/L (range, 2 - 29 x 109/L). Patients were followed for a median of 2.5 months (range 1.1 - 13). After steroid treatment at day +5, ten patients had responded (83.3%), five had achieved CR (41.7%), and five PR. After completing treatment with eltrombopag at day +34, all patients responded (100%), nine patients achieved CR (75%) and three PR (25%). Two patients relapsed in a median time of 39.5 days (range, 30.1 - 49), both regaining CR after treatment with another high-dose dexamethasone course and low-dose rituximab (4 doses of 100 mg every week). At 3 months follow-up 66.7% remained in CR and 33.3% in PR (n=6). At 6 months follow-up two patients remained in CR and two in PR (n=4). Time to best response achieved was 34 days from diagnosis (range, 19 – 64.1). At the end of follow-up 9 patients (75%) remained in CR and 3 patients in PR (25%). Total treatment cost per patient was $1,640 approximately. ConclusionCurrently the initial treatment of ITP patients is based on prednisone or high dose dexamethasone with or without IVIG. This approach is associated with high cost and high relapse rate. The results from our pilot study suggest that high dose dexamethasone and eltrombopag are very effective as first line treatment for acute ITP in adults. This treatment is ambulatory, affordable and well tolerated; however, we still don't know if this approach will have a favorable impact on the relapse rate of this disease. Disclosures:Off Label Use: Eltrombopag as first line treatment for ITP.

Abstract 4267: Eltrombopag, a non-peptide thrombopoietin receptor agonist, enhances the ex vivo expansion of human hematopoietic stem cells

Abstract Hematopoietic stem cells (HSCs) are characterized by their capacity for self-renewal and pluripotency, allowing them to replenish all mature, differentiated cells of the hematopoietic lineage. HSCs are not immortal but have a limited replicative potential and finite lifespan, properties which may be further negatively influenced by increased age or malignant disorders of the bone marrow. To overcome this problem, various combinations of cytokines, including recombinant human thrombopoietin (rhTPO), have been developed to support in vitro culture as well as ex vivo expansion of HSCs. Although rhTPO appears to enhance the mobilization of hematopoietic progenitors, its use in humans has been limited due to the generation of neutralizing antibodies. Eltrombopag is an orally-active, non-peptide small molecule TPO receptor agonist that has been shown to promote megakaryocyte proliferation and differentiation in a manner similar to that seen with rhTPO. We hypothesized that eltrombopag may enhance the ex vivo expansion of human HSCs to a degree equivalent to that of rhTPO. To test this hypothesis, human bone marrow derived CD34+ cells isolated from 5 healthy individuals were incubated in serum-free expansion medium containing SCF (50 ng/ml), IL-3 (10 ng/ml), IL-6 (10 ng/ml), LDL (40 μg/ml) and various concentrations of eltrombopag (0 - 100 μM) or rhTPO (0 - 100 ng/ml) and CD34+ cell numbers determined using FACS analysis over the course of a 14-day ex vivo culture. Both eltrombopag and rhTPO exhibited dose-dependent increases in CD34+ cell numbers, with 10 μM eltrombopag and 100 ng/ml rhTPO providing the most robust CD34+ cell expansion. Under these conditions, both 10 µM eltrombopag and 100 ng/ml rhTPO resulted in a five-fold greater CD34+ cell expansion compared with control (p &amp;lt; 0.05), an effect seen most prominently at day 11 of liquid culture. To confirm that expanded CD34+ cells maintained their pluripotency, hematopoietic colony-forming assays were performed in methylcellulose cultures containing SCF (50 ng/ml), IL-3 (10 ng/ml), G-CSF (10 ng/ml) and erythropoietin (1 U/ml). CD34+ cells expanded with eltrombopag or rhTPO increased the total number of granulocyte, monocyte, and erythroid colony forming units (CFUs) by 81% and 95%, respectively, compared to control (p &amp;lt; 0.01). The difference in total CFU formation observed between eltrombopag- and rhTPO-treated CD34+ cells was not statistically significant (p = 0.59). Taken together, these results serve as proof-of-principle showing eltrombopag to be an effective alternative to rhTPO for promoting the ex vivo expansion of human HSCs. Furthermore, these pre-clinical studies support the design of future clinical trials examining the use of eltrombopag in combination with G-CSF for the enhanced mobilization of human CD34+ hematopoietic progenitors in patients undergoing peripheral blood stem cell transplantation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4267.