Abstract

Since the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed.

Learning Objectives
  • Review the data on eltrombopag in severe aplastic anemia patients with insufficient response after initial immunosuppressive therapy

  • Review the data of combination of eltrombopag with immunosuppressive therapy in first-line for severe aplastic anemia

Introduction

For many years, the focus in the clinical development of novel nontransplant therapies for severe aplastic anemia (SAA) has been on intensifying immunosuppressive therapy (IST). The accumulation of data supporting an immune pathogenesis along with large prospective trials defining the success of IST in SAA formed the rationale for this development.1  Earlier efforts in which immunosuppression was increased led to higher hematologic response rates. Although hematologic recovery with antithymocyte globulin (ATG) was observed in 40% to 50%, the addition of cyclosporine (CsA) increased this rate to 60% to 70%.2-4  The ATG formulation most studied was that of horse serum, which is only a modest immunosuppressant.1  This opened the possibility of intensifying immunosuppression further by adding a third drug to the horse ATG/CsA or substituting horse ATG for more lymphocytotoxic agents, such as cyclophosphamide, rabbit ATG, or alemtuzumab.

Indeed, this hypothesis was investigated in prospective studies, yielding, surprisingly, a series of disappointing results. The principal end point in these studies was an increase in the hematologic response rate, which is a powerful surrogate for survival in SAA.5  The additions of mycophenolate and later, sirolimus to horse ATG/CsA were “negative” (that is, there was no increase in the response rates).6,7  A CsA taper course beyond 6 months did not increase the response or ultimately prevent relapses from occurring.8  The substitution of horse ATG for cyclophosphamide, rabbit ATG, and alemtuzumab was equally disappointing in prospective comparative studies due to increased toxicity and/or a lower hematologic response rate.9-15  In particular, results with rabbit ATG/CsA were unexpected and unanticipated given the activity of this regimen in relapsed and refractory SAA.16,17  This difference in efficacy does not seem to be related to rabbit ATG dosing.18,19  These studies led to the notion that a “ceiling” had been reached in regard to exploring more intense immunosuppressive regimens in SAA.20  Therefore, the standard immunosuppressive regimen still remains horse ATG/CsA in SAA.21 

The reasons for the lack of response to IST in SAA are not clearly understood, but prevailing notions included autoreactive T cells that may survive IST and/or significant destruction of the more primitive hematopoietic compartment, hindering the sprout of progenitor cells after the autoimmune insult was controlled. In a minority of cases, a cryptic underlying genetic defect could contribute to unresponsiveness to IST, and other approaches may be better suited in this selected group.22  The observation that the hematologic response rate did not improve despite more intense IST regimens argued against the existence of autoreactive cells not amenable to immunosuppression. Thus, the notion of an insufficient marrow unable to recover from a severe stem cell deficit became more preponderant. Unfortunately, efforts to stimulate this primitive compartment with growth factors, such as erythropoietin, granulocyte colony-stimulating factor (G-CSF), stem cell factor, and interleukins among others, have been to no avail.23-25  Approximately 10 years ago, agonists of the thrombopoietin (Tpo) receptor, which stimulated megakaryocytes to produce platelets, were approved for immune thrombocytopenia. These agents led to platelet count recovery in the majority of refractory cases of immune thrombocytopenia.26 

Apart from erythropoietin and G-CSF, Tpo has distinct properties that could be effective in stimulating hematopoietic stem cells (HSCs). This hormone, first cloned in 1994, was initially associated with megakaryocyte stimulation and platelet production.27-30  However, in vitro and experimental data implicated that Tpo also had an important role in stem cell proliferation and maintenance. First, unlike erythropoietin and G-CSF, the Tpo receptor is expressed in stem cells.31  Second, in Tpo receptor knockout models, aside from megakaryocytopenia and thrombocytopenia, significant reductions in HSCs were observed.32-35  Third, Tpo is commonly used along with other growth factors and interleukins in culture to stimulate stem cells in vitro.31  Fourth, in a rare form of marrow failure, amegakaryocytic thrombocytopenia, mutations in the Tpo receptor (c-MPL) resulted in multilineage cytopenias and significant HSC deficit in humans.36-39  Thus, a Tpo mimetic could in theory be active in ameliorating marrow function in aplastic anemia and associated disorders. The very elevated endogenous Tpo serum levels in SAA patients raised concerns of the ineffectiveness of this approach.40,41  Notwithstanding, a prospective dose escalation study was developed with eltrombopag in SAA patients with an insufficient response to initial IST. Later, due to the single-agent activity observed in these earlier studies, eltrombopag was combined with IST in front line.

Clinical development

Eltrombopag in refractory SAA

To overcome the high endogenous Tpo serum level and possible resistance to this approach, single-agent eltrombopag was developed in a phase 1/2 study, where 25 SAA patients unresponsive to initial IST received escalating doses starting at 50 mg up to 150 mg in 25-mg dose increment every 2 weeks (ramp-up study).42  The primary end point was hematologic response at 3 to 4 months. Overall, 11 (44%) achieved a hematologic response, of which 9 were in platelets, 9 were in neutrophil, and 6 were in the erythroid lineages (some patients had response in >1 lineage). In some responders, there was a corresponding increase in marrow cellularity, which along with the multilineage recoveries, suggested an HSC stimulation of eltrombopag. In an extension cohort of the ramp-up study (totaling 43 patients), the response rate remained at about 40%, and multilineage improvements continued to be seen.43  Clonal evolution was observed in 8 patients, including 5 with chromosome 7 loss or partial deletion. The cumulative incidence of clonal evolution in this refractory cohort was about 15% to 20%, which was similar to what has been reported historically.43  Of interest, most of the karyotype abnormalities occurred early—usually with the first 6 months of starting therapy. Eltrombopag was well tolerated, with principal toxicities being upper respiratory infection, fever, and musculoskeletal pain.42,43  There were no cases of significant increase in marrow reticulin deposition or thrombosis. In some patients who experienced a more robust hematologic response, drug discontinuation was possible after a quick taper, with most not relapsing.43  These studies led to the approval of eltrombopag as a single agent in SAA in patients with an insufficient response to initial IST.

In a follow-up phase 2 study by Winkler et al,44  39 patients with refractory SAA received a starting dose of eltrombopag of 150 mg (without the ramp up) for 6 months (fixed dose study). This design was chosen, because most responses in the ramp-up study occurred at 150 mg, suggesting it to be the more active dose. The duration of therapy was extended from 3 or 4 months (original ramp-up study) to 6 months (fixed dose study) to capture responses that may occur up to 6 months.44  These data were only presented in abstract form at the time of this writing. In total, 19 of 39 (49%) met criteria for hematologic response at 6 months. Compared with the ramp-up study, responses involving >1 lineage were more frequent in the fixed dose study by 6 months; they were observed in most responders and almost always equated to achieving transfusion independence. Of the 18 patients who met criteria for a robust response after a median follow-up of 12 months on drug, 13 had eltrombopag discontinued without a significant drop in blood counts. Of the remaining who relapsed, eltrombopag was successfully reinstituted with recovery of blood counts.

In this cohort, 6 of 39 developed cytogenetic abnormalities. Interestingly, all occurred early—within the first 6 months after the drug was initiated. These earlier cytogenetic abnormalities suggest that eltrombopag might be stimulating marrow preexistent clones, leading to their apparition in earlier evaluations within the first 6 months. Although the cumulative incidence of clonal evolution has not differed to date from historical experience, the earlier kinetics suggest a causal relation. Whole-exome sequencing performed at baseline has not correlated with important outcomes of hematologic response or clonal evolution.44-46  Full reporting of these data will provide additional insights into the activity of eltrombopag in refractory SAA.

In all, the hematologic response rate with eltrombopag in second-line SAA patients with an insufficient response to initial IST is about 40% to 50%. A starting dose of 150 mg for 6 months seems optimal given the quicker and more robust hematologic recovery, which has allowed successful discontinuation of eltrombopag in most responders. Abnormal cytogenetics identified in ∼15% to 20% to date is in accordance to date with the vast historical experience of IST regimens without eltrombopag in SAA.1  Notwithstanding, cytogenetic abnormalities have been observed in the historical cohort up to 10 years; thus, a longer follow-up in eltrombopag-treated patients will be important in defining this risk.

Eltrombopag combined with IST in first line

The next steps in development combined eltrombopag with the most active IST regimen in SAA, horse ATG/CsA, in patients not suitable for hematopoietic stem cell transplantation (HSCT) upfront (lack of donor, advanced age, comorbidities, and/or patient preference).47  This 3-drug regimen, which combined 2 immunosuppressants and a marrow stimulatory agent, was developed at the National Institutes of Health (NIH) to investigate its feasibility in terms of safety as well as address the limitations of horse ATG/CsA alone, which are namely a “ceiling” response rate of 60% to 70%, with only a minority being complete (about 10% historically); rates of relapse (in about 1/3 of responders); and clonal evolution (∼15%) long term.1  Thus, a primary end point of a complete response at 6 months of 30% or higher was chosen given its correlation with a better survival and fewer late events.1,5  Given the optimal dosing of the pilot trials, a starting dose of 150 mg was chosen to be combined with IST for a total of 6 months.47  Liver enzyme abnormalities are common with horse ATG/CsA, which is one of the toxicities with eltrombopag observed in 10% of patients.48  Thus, the initiation of eltrombopag was delayed by 2 weeks after IST until the liver enzymes had normalized or near normalized in the initial cohort of 30 patients (cohort 1). In this group, the overall hematologic response was 80%, of which 33% were complete. In a subsequent cohort of 31 patients (cohort 2), eltrombopag was also started on day 14, and duration was abbreviated to 3 months given concerns for clonal evolution with longer-term use of this agent. In this cohort 2, the response rates at 6 months were 87% overall and 26% complete. The small decline in the complete response and some loss of responses between 3 and 6 months led to the resumption of the 6-month course in a subsequent cohort of 31 patients (cohort 3). In this group, eltrombopag was started on day 1 along with the IST given the lightening of the concern for increase hepatotoxicity with the combination based on the experience of the prior 2 cohorts. In this group, the overall hematologic response rate was 95%, being complete in 58% at 6 months. The results of this latest cohort 3 represented a nearly 6 times increase in historical complete response rates (of about 10%) and a near doubling of the complete response rate compared with cohorts 1 and 2. The simultaneous initiation of all drugs on day 1 seemed to be optimal. In this study across all cohorts, there was a quality of life gain from the more rapid recovery of blood counts and the decreases in transfusion burden and hospital visits.47  Ancillary laboratory assays showed an increase in marrow progenitor cells in vitro after therapy compared with baseline samples, indicating recovery to a more normal functioning bone marrow.47  The overall hematologic response rate at 6 months for all cohorts (n = 92) was 87%, with 39% being complete, which achieved the primary end point of the protocol of a complete response rate of 30% or higher at 6 months.

Long-term events of relapse and clonal evolution have been reported in the upfront 3-drug regimen study; however, follow-up has been relatively short (median of 18 months). In cohort 1 and part of cohort 2, the CsA was discontinued at 6 months; this resulted in a relapse rate of 54%, which was higher than historically observed with IST alone.49  Thus, the protocol was amended in the latter part of cohort 2 to allow for a continued fixed low-dose CsA (2 mg/kg) after 6 months (for a total of 2 years), resulting in a decrease in the relapse rate to about 15%.47  The dose of 2 mg/kg was chosen based on prior experience that associated this dose with a decrease in relapse rate.8  To date, the 2-year cumulative incidence of clonal evolution rate is about 8%, which compares favorably with the historical data of IST without eltrombopag of ∼8% at this time point.47  Of note, most cytogenetic abnormalities have been detected early in the first 6 months (5 of 7), such as was observed in the initial pilot studies of eltrombopag in refractory SAA. In some cases, karyotype abnormalities did not correlate with poor counts or marrow dysplasia, at times being transient. Ancillary molecular analysis of marrow cells before treatment did not associate with hematologic response or risk of clonal evolution. This observation is in accordance with prior reports in which pretreatment mutational status was not universally associated with outcomes.45,50  After a median follow-up of 18 months, the overall survival was 97% (95% confidence interval, 94-100) in all cohorts and 99% (95% confidence interval, 97-100) when data were censored for stem cell transplantation.47 

The results with the use of eltrombopag in association with horse ATG/CsA are very encouraging, although some questions remain. First, the durability of response with the 3-drug regimen (without relapse and clonal evolution) will be of great relevance, and it will be defined with longer-term follow-up.51  Formal presentation of these results in the ∼150 patients treated with the 3-drug regimen by 2018 from the original NIH study is anticipated, which will better define the activity and safety of this regimen. Conversely, the role of the 3-drug regimen in pediatrics is yet unclear given the already higher overall and complete response rates with IST alone in this group and the small number of children included in the original reporting. Thus, a pediatric subset analysis of the NIH trial and dedicated studies in children will be important to establish its role in this patient population. Second, the duration of CsA beyond 2 years has not yet been defined. Currently in the NIH trial, CsA is administered up to 2 years, and its interruption at this time point is being investigated in a protocol comparing a CsA taper with its substitution for a tolerizing immunosuppressant (sirolimus; NCT02979873). Third, confirmation of these results in separate prospective cohorts will further strengthen the evidence and allow for incorporation of these novel regimens in routine clinical practice. The European Group for Blood and Marrow Transplantation (EBMT) is conducting a prospective, randomized, multicenter trial comparing horse ATG/CsA with and without eltrombopag (RACE study; NCT02099747), which will provide important confirmatory and comparative data on horse ATG/CsA alone. Of note, in the RACE study, eltrombopag is initiated on day 14 after IST, which was based on the initial cohorts of the American NIH experience. Given the substantial increase in complete responders when all 3 drugs were administered simultaneously on day 1 (cohort 3 of the NIH study), the European data may not reproduce the best results seen in the American trial. Nevertheless, preliminary results of the RACE study are anticipated in the next 1 to 2 years, as accrual completion of the 200-patient study is anticipated by the end of 2018. Importantly, this trial, given its direct comparison design, will more definitively define the clonal evolution risk between eltrombopag- and noneltrombopag-containing IST regimens as initial therapy in SAA.

How eltrombopag is acting in SAA

The initial goal in using eltrombopag in SAA was to stimulate residual stem cells to proliferate and improve hematopoiesis and blood counts. Originally, a platelet response was sought given that frequent platelet transfusions (once or twice a week) tend to be more limiting for patients with persistent cytopenias and impact quality of life. The multilineage blood count recoveries, increase in marrow cellularity, and increase in CD34+ marrow cells in exploratory experiments indeed indicated that such an effect was taking place. The very high endogenous Tpo levels did not seem to hinder patient’s ability to recover, unlike what is observed in other marrow failure settings, such as in myelodysplastic syndrome, where exogenous erythropoietin therapy is largely ineffective when endogenous levels of erythropoietin are >200 to 500 mU/mL.52  Thus, other effects of eltrombopag could be at play in SAA, contributing to its activity.

Since its approval for immune thrombocytopenic purpura (ITP) and later SAA, important immunomodulatory properties have been reported with eltrombopag that may contribute to its positive net effect in immunologically mediated cytopenias. In SAA, there are important immune dysregulations that include a deficit of regulatory T cells; increased expression of proinflammatory cytokines and associated proteins (TH1 and TH17); increase in interleukin-2, interferon-γ, and tumor necrosis factor-α (TNFα) secretion; and expansion of oligoclonal CD8+ cytotoxic T cells among others.1,49,53-63  Eltrombopag could be addressing some of these abnormalities directly or indirectly by promoting a more tolerizing environment via an increase in regulatory T and B cells, secretion of transforming growth factor-β, impairment of dendritic cell differentiation, and a decreased release of interferon-γ and TNFα.64-66  These effects have been primarily described in immune thrombocytopenia, although it is plausible that similar actions are also occurring in SAA. Moreover, platelets in themselves may have immunomodulatory properties that contribute to the immune control in aplastic anemia (AA) and overall blood count recovery.66-68  Distinctly, a novel mechanism has been recently presented by Alvarado et al69  (in abstract form only at the time of this writing), showing that eltrombopag can evade the inhibitory effect of interferon-γ on HSCs and signal downstream of c-MPL to net a stimulatory effect. In contrast, in the same experimental design, native Tpo was inhibited by interferon-γ by forming a heterodimer-hindering signaling through c-MPL and subsequent target cell activation.69  The complete report of this observation is anticipated, which will shed additional insights into these mechanisms. Furthermore, eltrombopag has in its structure a chelator backbone that mobilizes intracellular iron, resulting in a decrease in total iron burden.70  Reports in pediatric ITP and AA have shown a progressive decline in ferritin levels with continued use of eltrombopag.71,72  Although there are reports suggesting a benefit of iron chelation in ameliorating cytopenias in AA, its direct benefit has yet to be established.73-76  Nevertheless, reducing total body iron burden in polytransfused patients is desirable to avoid long-term end organ complications and possibly, contribute to marrow recovery. Thus, the mechanisms by which eltrombopag improves marrow function in AA are likely to be multifactorial, and they are still being elucidated (Figure 1). These mechanisms, of course, may also be beneficial in other forms of marrow failure syndromes, myelodysplastic syndromes, poststem cell transplantation, cytopenias related to inflammatory and infectious conditions, and chemotherapy-induced thrombocytopenia among others. Indeed, several reports and clinical protocols are in development exploring this possibility. In AA, studies are ongoing exploring the use of eltrombopag and romiplostim in different forms of marrow failure in various doses either alone or in combination with different immunosuppressants (Table 1). Although data are more limited in SAA, romiplostim at higher weekly doses (10 μg/kg) seems effective, and even higher doses are currently under investigation.77,78 

Figure 1.

Different proposed mechanisms by which eltrombopag is improving hematopoiesis in aplastic anemia. IFNγ, interferon-γ; TGFβ, transforming growth factor-β.

Figure 1.

Different proposed mechanisms by which eltrombopag is improving hematopoiesis in aplastic anemia. IFNγ, interferon-γ; TGFβ, transforming growth factor-β.

Table 1.

Studies investigating Tpo receptor agonists in bone marrow failure syndromes

StudyPatient populationTrial identification*Start date
Upfront studies    
 Phase 2, single-arm, multicenter, open label study to investigate the efficacy and safety of eltrombopag and CsA as first-line therapy (SOAR). Sponsor Novartis (conducted worldwide) Severe and very severe AA NCT02998645 05/11/2017 
≥6 y 
 Phase 1/2, single-arm, open label, nonrandomized, prospective study of eltrombopag + horse ATG + CsA. Sponsor NHLBI. Conducted at the NIH Severe and very severe AA NCT01623167 06/12/2012 
≥2 y 
 Phase 2, multicenter, randomized study of eltrombopag combined with horse ATG + CsA vs horse ATG and CsA as first-line treatment in pediatric SAA. Sponsor Federal Research Institute of Pediatric Hematology, Oncology and Immunology. Conducted at the Russian Federation Severe and very severe AA NCT03413306 12/20/2016 
2-18 y of age 
 Randomized clinical trial of the use of eltrombopag in children with idiopathic aplastic anemia. Sponsor Assiut University. Conducted in Egypt Moderate and severe AA NCT03243656 12/2017 
1-18 y of age 
 Phase 2, eltrombopag; nonrandomized, single arm, open label, dose escalation to maximum 300 mg/d. Sponsor University of Utah and Novartis as collaborators. Conducted in Utah Moderate, severe, and very severe AA NCT01703169 11/2012 
≥18 y 
 Phase 2, eltrombopag; nonrandomized, single arm, open label. Sponsor NHLBI. Conducted at the NIH Moderate AA and unilineage bone marrow failure syndromes NCT01328587 04/01/2011 
≥18 y 
 Phase 3, horse ATG + CsA + eltrombopag; prospective, randomized, open label (RACE). Sponsor EBMT. Novartis and Pfizer as collaborators. Conducted in Europe Severe and very severe AA NCT02099747 03/2015 
≥15 y 
 Phase 2, eltrombopag + rabbit ATG + CsA; nonrandomized, single arm, open label. Sponsor Novartis. Conducted in Japan Moderate, severe, and very severe AA NCT02404025 03/2015 
≥18 to ≤75 y 
 Efficacy and safety of eltrombopag in combination with CsA in moderate aplastic anemia: prospective, randomized, multicenter study. Sponsor University of Ulm. Conducted in Germany Moderate AA NCT02773225 01/27/2015 
≥18 y 
Second-line studies    
 Phase 2, eltrombopag; nonrandomized, single arm, open label. Sponsor NHLBI. Conducted at the NIH AA refractory to standard IST NCT00922883 05/29/2009 
≥12 y 
 Phase 2, eltrombopag; nonrandomized, single arm, open label. Extended fixed dosing (150 mg) in SAA. Sponsor NHLBI. Conducted at the NIH Severe and very severe AA NCT01891994 06/28/2013 
≥2 to ≤100 y 
 Phase 2, eltrombopag; nonrandomized, open label. Sponsor Novartis. Conducted in Japan Refractory, moderate, or severe AA NCT02148133 06/23/2014 
≥18 to <80 y 
 Phase 2, open label, multicenter, intrapatient dose escalation study of eltrombopag + IST. Sponsor Novartis. Conducted in the United States, Hong Kong, the Russian Federation, and the United Kingdom Treatment-naïve, relapsed, or refractory SAA NCT03025698 09/30/2017 
1-18 y of age 
 Phase 2, romiplostim; nonrandomized, single arm, open label. Sponsor Kyowa Hakko Kirin Co., Ltd. Conducted in the Republic of Korea and Japan Refractory AA to at least on course of IST NCT02773290 05/2016 
≥20 y 
 Phase 2, randomized, open label, parallel, comparative, dose-finding study to evaluate the efficacy and safety of romiplostim in SAA. Sponsor Kyowa Hakko Kirin Co., Ltd. Conducted in the Republic of Korea Refractory SAA NCT02094417 04/14/2014 
≥19 y 
StudyPatient populationTrial identification*Start date
Upfront studies    
 Phase 2, single-arm, multicenter, open label study to investigate the efficacy and safety of eltrombopag and CsA as first-line therapy (SOAR). Sponsor Novartis (conducted worldwide) Severe and very severe AA NCT02998645 05/11/2017 
≥6 y 
 Phase 1/2, single-arm, open label, nonrandomized, prospective study of eltrombopag + horse ATG + CsA. Sponsor NHLBI. Conducted at the NIH Severe and very severe AA NCT01623167 06/12/2012 
≥2 y 
 Phase 2, multicenter, randomized study of eltrombopag combined with horse ATG + CsA vs horse ATG and CsA as first-line treatment in pediatric SAA. Sponsor Federal Research Institute of Pediatric Hematology, Oncology and Immunology. Conducted at the Russian Federation Severe and very severe AA NCT03413306 12/20/2016 
2-18 y of age 
 Randomized clinical trial of the use of eltrombopag in children with idiopathic aplastic anemia. Sponsor Assiut University. Conducted in Egypt Moderate and severe AA NCT03243656 12/2017 
1-18 y of age 
 Phase 2, eltrombopag; nonrandomized, single arm, open label, dose escalation to maximum 300 mg/d. Sponsor University of Utah and Novartis as collaborators. Conducted in Utah Moderate, severe, and very severe AA NCT01703169 11/2012 
≥18 y 
 Phase 2, eltrombopag; nonrandomized, single arm, open label. Sponsor NHLBI. Conducted at the NIH Moderate AA and unilineage bone marrow failure syndromes NCT01328587 04/01/2011 
≥18 y 
 Phase 3, horse ATG + CsA + eltrombopag; prospective, randomized, open label (RACE). Sponsor EBMT. Novartis and Pfizer as collaborators. Conducted in Europe Severe and very severe AA NCT02099747 03/2015 
≥15 y 
 Phase 2, eltrombopag + rabbit ATG + CsA; nonrandomized, single arm, open label. Sponsor Novartis. Conducted in Japan Moderate, severe, and very severe AA NCT02404025 03/2015 
≥18 to ≤75 y 
 Efficacy and safety of eltrombopag in combination with CsA in moderate aplastic anemia: prospective, randomized, multicenter study. Sponsor University of Ulm. Conducted in Germany Moderate AA NCT02773225 01/27/2015 
≥18 y 
Second-line studies    
 Phase 2, eltrombopag; nonrandomized, single arm, open label. Sponsor NHLBI. Conducted at the NIH AA refractory to standard IST NCT00922883 05/29/2009 
≥12 y 
 Phase 2, eltrombopag; nonrandomized, single arm, open label. Extended fixed dosing (150 mg) in SAA. Sponsor NHLBI. Conducted at the NIH Severe and very severe AA NCT01891994 06/28/2013 
≥2 to ≤100 y 
 Phase 2, eltrombopag; nonrandomized, open label. Sponsor Novartis. Conducted in Japan Refractory, moderate, or severe AA NCT02148133 06/23/2014 
≥18 to <80 y 
 Phase 2, open label, multicenter, intrapatient dose escalation study of eltrombopag + IST. Sponsor Novartis. Conducted in the United States, Hong Kong, the Russian Federation, and the United Kingdom Treatment-naïve, relapsed, or refractory SAA NCT03025698 09/30/2017 
1-18 y of age 
 Phase 2, romiplostim; nonrandomized, single arm, open label. Sponsor Kyowa Hakko Kirin Co., Ltd. Conducted in the Republic of Korea and Japan Refractory AA to at least on course of IST NCT02773290 05/2016 
≥20 y 
 Phase 2, randomized, open label, parallel, comparative, dose-finding study to evaluate the efficacy and safety of romiplostim in SAA. Sponsor Kyowa Hakko Kirin Co., Ltd. Conducted in the Republic of Korea Refractory SAA NCT02094417 04/14/2014 
≥19 y 

NHLBI, National Heart, Lung and Blood Institute.

*

Trial identification, sponsor, collaborator(s), and sites were accessed at www.clinicaltrials.gov on September 1, 2018.

Practical considerations

With all eltrombopag-containing regimens (upfront and in refractory settings), continued follow-up will provide safety and efficacy data and define longer-term risks of relapse and clonal evolution.51  “Real world” data thus far have confirmed the results reported in the earlier clinical trials in SAA.77,79,80  Several practical considerations will also emerge from these observations. For example, eltrombopag was developed as a single agent in refractory SAA; however, its combination with CsA is common in the “real world.” Given the good tolerability of this combination reported to date, it is rational to use such a combination with the expectation of complementary or even synergistic mechanisms of action. However, the proven benefit of the combination of eltrombopag plus CsA vs eltrombopag alone in the refractory setting has not yet been established. In East Asian patients, eltrombopag should be administered at lower doses (75–100 mg) given known population pharmacokinetic dynamics. However, some reports recently have proposed that higher doses (up to 300 mg) are tolerated and efficacious in East Asians, requiring additional studies for confirmation.77,80  Liver enzymes should be monitored in all patients, and dosage should adjusted according to published protocols.42,43,47  Mild to moderate indirect bilirubin increase is common and usually of no consequence to the patient.

Frequency of bone marrow sampling in clinical trials included baseline; 3, 6, and 12 months; and yearly thereafter given concerns for clonal evolution. This practice of more frequent sampling early on in therapy permits detection of cytogenetic abnormalities while patients are on therapy during the first 6 months. If no response is observed at 6 months on the optimal dose (150 mg), eltrombopag should be discontinued given risks/benefits and the possible promotion of clonal evolution with its continued use long term. Among responders, attempt to discontinue eltrombopag should be sought especially if blood count recovery is robust and/or counts have been stable for at least 6 months. It is very important to follow dietary restrictions strictly associated with eltrombopag to derive optimal drug activity, because drug levels cannot be monitored.

The adoption of eltrombopag with standard horse ATG/CsA upfront is evolving, and its role should be better defined in ongoing studies (Table 1). The efficacy of combining eltrombopag with rabbit ATG/CsA or CsA alone (ATG-free regimen) is also being elucidated in these trials. Reducing the refractory pool of patients to initial IST and achieving transfusion independence quicker are desirable with the 3-drug combination (horse ATG/CsA/eltrombopag). Its benefit as it relates to standard IST alone and HSCT (in certain age groups; for example, 20-40 years) is of interest, and it is being elucidated with ongoing studies, the results of which are anticipated in coming months and years. Also, the use of the 3-drug combination as a second salvage course of therapy in relapse and refractory patients treated initially with IST alone is intuitive, although it has not yet been defined in this setting. Another question still open is if patients unresponsive to the initial 3-drug regimen benefit from a second course of IST.

Conclusion

Eltrombopag represents an important addition to the armamentarium in AA that, for several decades, lacked approval of new therapies. Eltrombopag is currently approved as a single agent in patients with an insufficient response to initial immunosuppression. Regulatory approval of the combination with horse ATG/CsA is anticipated in the United States given the high overall and complete response rates with this regimen. The immune and nonimmune properties of eltrombopag may be complementary or synergize with those of immunosuppressive therapies, contributing to a more rapid and robust recovery of blood counts when given in combination in SAA. Thus, combining therapies with different modes of action in improving hematopoiesis is proving to be beneficial in SAA. The addition of androgens and possibly, other growth factors (G-CSF and erythropoietin) to the 3-drug regimen may further improve marrow function and blood count recovery, and these possibilities are likely to be investigated in clinical research protocols. In coming years, more will be learned from these trials, and real word evidence (in unselected patients) will further solidify the role of the Tpo receptor agonists in marrow failure syndromes and other cytopenic scenarios.

Correspondence

Phillip Scheinberg, Division of Hematology, Hospital A Beneficência Portuguesa, Rua Martiniano de Carvalho, 951, Sao Paulo, SP 01321-001, Brazil; e-mail: scheinbp@bp.org.br.

References

References
1.
Scheinberg
P
,
Young
NS
.
How I treat acquired aplastic anemia
.
Blood
.
2012
;
120
(
6
):
1185
-
1196
.
2.
Frickhofen
N
,
Heimpel
H
,
Kaltwasser
JP
,
Schrezenmeier
H
;
German Aplastic Anemia Study Group
.
Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia
.
Blood
.
2003
;
101
(
4
):
1236
-
1242
.
3.
Frickhofen
N
,
Kaltwasser
JP
,
Schrezenmeier
H
, et al
;
The German Aplastic Anemia Study Group
.
Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine
.
N Engl J Med
.
1991
;
324
(
19
):
1297
-
1304
.
4.
de Planque
MM
,
Bacigalupo
A
,
Würsch
A
, et al
;
Severe Aplastic Anaemia Working Party of the European Cooperative Group for Bone Marrow Transplantation (EBMT)
.
Long-term follow-up of severe aplastic anaemia patients treated with antithymocyte globulin
.
Br J Haematol
.
1989
;
73
(
1
):
121
-
126
.
5.
Rosenfeld
S
,
Follmann
D
,
Nunez
O
,
Young
NS
.
Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome
.
JAMA
.
2003
;
289
(
9
):
1130
-
1135
.
6.
Scheinberg
P
,
Wu
CO
,
Nunez
O
, et al
.
Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study
.
Haematologica
.
2009
;
94
(
3
):
348
-
354
.
7.
Scheinberg
P
,
Nunez
O
,
Wu
C
,
Young
NS
.
Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil
.
Br J Haematol
.
2006
;
133
(
6
):
606
-
611
.
8.
Scheinberg
P
,
Rios
O
,
Scheinberg
P
,
Weinstein
B
,
Wu
CO
,
Young
NS
.
Prolonged cyclosporine administration after antithymocyte globulin delays but does not prevent relapse in severe aplastic anemia
.
Am J Hematol
.
2014
;
89
(
6
):
571
-
574
.
9.
Scheinberg
P
,
Townsley
D
,
Dumitriu
B
, et al
.
Moderate-dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution
.
Blood
.
2014
;
124
(
18
):
2820
-
2823
.
10.
Scheinberg
P
,
Nunez
O
,
Weinstein
B
,
Scheinberg
P
,
Wu
CO
,
Young
NS
.
Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia
.
Blood
.
2012
;
119
(
2
):
345
-
354
.
11.
Scheinberg
P
,
Nunez
O
,
Weinstein
B
, et al
.
Horse versus rabbit antithymocyte globulin in acquired aplastic anemia
.
N Engl J Med
.
2011
;
365
(
5
):
430
-
438
.
12.
Tisdale
JF
,
Dunn
DE
,
Geller
N
, et al
.
High-dose cyclophosphamide in severe aplastic anaemia: a randomised trial
.
Lancet
.
2000
;
356
(
9241
):
1554
-
1559
.
13.
Marsh
JC
,
Bacigalupo
A
,
Schrezenmeier
H
, et al
;
European Blood and Marrow Transplant Group Severe Aplastic Anaemia Working Party
.
Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party [published correction appears in Blood. 2013;121(25):5104]
.
Blood
.
2012
;
119
(
23
):
5391
-
5396
.
14.
Zheng
Y
,
Liu
Y
,
Chu
Y
.
Immunosuppressive therapy for acquired severe aplastic anemia (SAA): a prospective comparison of four different regimens
.
Exp Hematol
.
2006
;
34
(
7
):
826
-
831
.
15.
Tisdale
JF
,
Maciejewski
JP
,
Nuñez
O
,
Rosenfeld
SJ
,
Young
NS
.
Late complications following treatment for severe aplastic anemia (SAA) with high-dose cyclophosphamide (Cy): follow-up of a randomized trial
.
Blood
.
2002
;
100
(
13
):
4668
-
4670
.
16.
Di Bona
E
,
Rodeghiero
F
,
Bruno
B
, et al
.
Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO) [published correction appears in Br J Haematol. 2000;108(2):461]
.
Br J Haematol
.
1999
;
107
(
2
):
330
-
334
.
17.
Scheinberg
P
,
Nunez
O
,
Young
NS
.
Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia
.
Br J Haematol
.
2006
;
133
(
6
):
622
-
627
.
18.
Lin
SF
,
Liu
S
,
Xue
HM
, et al
.
Comparison of two dosages of rabbit antithymocyte globulin (r-ATG) in treating children with severe aplastic anemia
.
Pharmazie
.
2018
;
73
(
5
):
264
-
268
.
19.
Clé
DV
,
Atta
EH
,
Dias
DSP
, et al
.
Rabbit antithymocyte globulin dose does not affect response or survival as first-line therapy for acquired aplastic anemia: a multicenter retrospective study [published online ahead of print 5 July 2018]
.
Ann Hematol
. doi:10.1007/s00277-018-3416-4.
20.
Passweg
JR
,
Tichelli
A
.
Immunosuppressive treatment for aplastic anemia: are we hitting the ceiling?
Haematologica
.
2009
;
94
(
3
):
310
-
312
.
21.
Hayakawa
J
,
Kanda
J
,
Akahoshi
Y
, et al
.
Meta-analysis of treatment with rabbit and horse antithymocyte globulin for aplastic anemia
.
Int J Hematol
.
2017
;
105
(
5
):
578
-
586
.
22.
Townsley
DM
,
Dumitriu
B
,
Young
NS
.
Danazol treatment for telomere diseases
.
N Engl J Med
.
2016
;
375
(
11
):
1095
-
1096
.
23.
Marsh
JC
,
Ganser
A
,
Stadler
M
.
Hematopoietic growth factors in the treatment of acquired bone marrow failure states
.
Semin Hematol
.
2007
;
44
(
3
):
138
-
147
.
24.
Marsh
JC
.
Hematopoietic growth factors in the pathogenesis and for the treatment of aplastic anemia
.
Semin Hematol
.
2000
;
37
(
1
):
81
-
90
.
25.
Füreder
W
,
Valent
P
.
Treatment of refractory or relapsed acquired aplastic anemia: review of established and experimental approaches
.
Leuk Lymphoma
.
2011
;
52
(
8
):
1435
-
1445
.
26.
Imbach
P
,
Crowther
M
.
Thrombopoietin-receptor agonists for primary immune thrombocytopenia
.
N Engl J Med
.
2011
;
365
(
8
):
734
-
741
.
27.
Kuter
DJ
,
Beeler
DL
,
Rosenberg
RD
.
The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production
.
Proc Natl Acad Sci USA
.
1994
;
91
(
23
):
11104
-
11108
.
28.
Sohma
Y
,
Akahori
H
,
Seki
N
, et al
.
Molecular cloning and chromosomal localization of the human thrombopoietin gene
.
FEBS Lett
.
1994
;
353
(
1
):
57
-
61
.
29.
Bartley
TD
,
Bogenberger
J
,
Hunt
P
, et al
.
Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl
.
Cell
.
1994
;
77
(
7
):
1117
-
1124
.
30.
de Sauvage
FJ
,
Hass
PE
,
Spencer
SD
, et al
.
Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand
.
Nature
.
1994
;
369
(
6481
):
533
-
538
.
31.
Yoshihara
H
,
Arai
F
,
Hosokawa
K
, et al
.
Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche
.
Cell Stem Cell
.
2007
;
1
(
6
):
685
-
697
.
32.
Alexander
WS
,
Roberts
AW
,
Nicola
NA
,
Li
R
,
Metcalf
D
.
Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl
.
Blood
.
1996
;
87
(
6
):
2162
-
2170
.
33.
Qian
H
,
Buza-Vidas
N
,
Hyland
CD
, et al
.
Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells
.
Cell Stem Cell
.
2007
;
1
(
6
):
671
-
684
.
34.
Fox
N
,
Priestley
G
,
Papayannopoulou
T
,
Kaushansky
K
.
Thrombopoietin expands hematopoietic stem cells after transplantation
.
J Clin Invest
.
2002
;
110
(
3
):
389
-
394
.
35.
Solar
GP
,
Kerr
WG
,
Zeigler
FC
, et al
.
Role of c-mpl in early hematopoiesis
.
Blood
.
1998
;
92
(
1
):
4
-
10
.
36.
Ballmaier
M
,
Germeshausen
M
,
Krukemeier
S
,
Welte
K
.
Thrombopoietin is essential for the maintenance of normal hematopoiesis in humans: development of aplastic anemia in patients with congenital amegakaryocytic thrombocytopenia
.
Ann N Y Acad Sci
.
2003
;
996
(
1
):
17
-
25
.
37.
Ihara
K
,
Ishii
E
,
Eguchi
M
, et al
.
Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia
.
Proc Natl Acad Sci USA
.
1999
;
96
(
6
):
3132
-
3136
.
38.
Tonelli
R
,
Scardovi
AL
,
Pession
A
, et al
.
Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT)
.
Hum Genet
.
2000
;
107
(
3
):
225
-
233
.
39.
Ballmaier
M
,
Germeshausen
M
,
Schulze
H
, et al
.
c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia
.
Blood
.
2001
;
97
(
1
):
139
-
146
.
40.
Kosugi
S
,
Kurata
Y
,
Tomiyama
Y
, et al
.
Circulating thrombopoietin level in chronic immune thrombocytopenic purpura
.
Br J Haematol
.
1996
;
93
(
3
):
704
-
706
.
41.
Feng
X
,
Scheinberg
P
,
Wu
CO
, et al
.
Cytokine signature profiles in acquired aplastic anemia and myelodysplastic syndromes
.
Haematologica
.
2011
;
96
(
4
):
602
-
606
.
42.
Olnes
MJ
,
Scheinberg
P
,
Calvo
KR
, et al
.
Eltrombopag and improved hematopoiesis in refractory aplastic anemia
.
N Engl J Med
.
2012
;
367
(
1
):
11
-
19
.
43.
Desmond
R
,
Townsley
DM
,
Dumitriu
B
, et al
.
Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug
.
Blood
.
2014
;
123
(
12
):
1818
-
1825
.
44.
Winkler
T
,
Cooper
JN
,
Townsley
DM
, et al
.
Eltrombopag for refractory severe aplastic anemia: dosing regimens, long-term follow-up, clonal evolution and somatic mutation profiling [abstract]
.
Blood
.
2017
;
130
(
suppl 1
):
777
.
45.
Yoshizato
T
,
Dumitriu
B
,
Hosokawa
K
, et al
.
Somatic mutations and clonal hematopoiesis in aplastic anemia
.
N Engl J Med
.
2015
;
373
(
1
):
35
-
47
.
46.
Cooper
JN
,
Young
NS
.
Clonality in context: hematopoietic clones in their marrow environment
.
Blood
.
2017
;
130
(
22
):
2363
-
2372
.
47.
Townsley
DM
,
Scheinberg
P
,
Winkler
T
, et al
.
Eltrombopag added to standard immunosuppression for aplastic anemia
.
N Engl J Med
.
2017
;
376
(
16
):
1540
-
1550
.
48.
Wong
RSM
,
Saleh
MN
,
Khelif
A
, et al
.
Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study
.
Blood
.
2017
;
130
(
23
):
2527
-
2536
.
49.
Young
NS
,
Calado
RT
,
Scheinberg
P
.
Current concepts in the pathophysiology and treatment of aplastic anemia
.
Blood
.
2006
;
108
(
8
):
2509
-
2519
.
50.
Kulasekararaj
AG
,
Jiang
J
,
Smith
AE
, et al
.
Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome
.
Blood
.
2014
;
124
(
17
):
2698
-
2704
.
51.
Scheinberg
P
.
Recent advances and long-term results of medical treatment of acquired aplastic anemia: are patients cured?
Hematol Oncol Clin North Am
.
2018
;
32
(
4
):
609
-
618
.
52.
Hellström-Lindberg
E
.
Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies
.
Br J Haematol
.
1995
;
89
(
1
):
67
-
71
.
53.
Niu
Q
,
Zhou
Q
,
Liu
Y
,
Jiang
H
.
Expression of CXCR4 on T-cell subsets and plasma IL-17 concentrations in patients with aplastic anaemia
.
Sci Rep
.
2017
;
7
(
1
):
9075
.
54.
Arieta Kuksin
C
,
Gonzalez-Perez
G
,
Minter
LM
.
CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia
.
Blood
.
2015
;
125
(
13
):
2087
-
2094
.
55.
Shi
J
,
Ge
M
,
Lu
S
, et al
.
Intrinsic impairment of CD4(+)CD25(+) regulatory T cells in acquired aplastic anemia
.
Blood
.
2012
;
120
(
8
):
1624
-
1632
.
56.
Minter
LM
.
NOTCH signaling in immune-mediated bone marrow failure of aplastic anemia
.
Rare Dis
.
2013
;
1
(
1
):
e26764
.
57.
Solomou
EE
,
Wong
S
,
Visconte
V
,
Gibellini
F
,
Young
NS
.
Decreased TCR zeta-chain expression in T cells from patients with acquired aplastic anaemia
.
Br J Haematol
.
2007
;
138
(
1
):
72
-
76
.
58.
Solomou
EE
,
Rezvani
K
,
Mielke
S
, et al
.
Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia
.
Blood
.
2007
;
110
(
5
):
1603
-
1606
.
59.
Solomou
EE
,
Keyvanfar
K
,
Young
NS
.
T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia
.
Blood
.
2006
;
107
(
10
):
3983
-
3991
.
60.
de Latour
RP
,
Visconte
V
,
Takaku
T
, et al
.
Th17 immune responses contribute to the pathophysiology of aplastic anemia
.
Blood
.
2010
;
116
(
20
):
4175
-
4184
.
61.
Scheinberg
P
,
Chen
J
.
Aplastic anemia: what have we learned from animal models and from the clinic
.
Semin Hematol
.
2013
;
50
(
2
):
156
-
164
.
62.
Risitano
AM
,
Maciejewski
JP
,
Green
S
,
Plasilova
M
,
Zeng
W
,
Young
NS
.
In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing
.
Lancet
.
2004
;
364
(
9431
):
355
-
364
.
63.
Kordasti
S
,
Costantini
B
,
Seidl
T
, et al
.
Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment
.
Blood
.
2016
;
128
(
9
):
1193
-
1205
.
64.
Bao
W
,
Bussel
JB
,
Heck
S
, et al
.
Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents
.
Blood
.
2010
;
116
(
22
):
4639
-
4645
.
65.
Nishimoto
T
,
Numajiri
M
,
Nakazaki
H
,
Okazaki
Y
,
Kuwana
M
.
Induction of immune tolerance to platelet antigen by short-term thrombopoietin treatment in a mouse model of immune thrombocytopenia
.
Int J Hematol
.
2014
;
100
(
4
):
341
-
344
.
66.
Schifferli
A
,
Kühne
T
.
Thrombopoietin receptor agonists: a new immune modulatory strategy in immune thrombocytopenia?
Semin Hematol
.
2016
;
53
(
suppl 1
):
S31
-
S34
.
67.
Sadallah
S
,
Amicarella
F
,
Eken
C
,
Iezzi
G
,
Schifferli
JA
.
Ectosomes released by platelets induce differentiation of CD4+T cells into T regulatory cells
.
Thromb Haemost
.
2014
;
112
(
6
):
1219
-
1229
.
68.
Sadallah
S
,
Eken
C
,
Martin
PJ
,
Schifferli
JA
.
Microparticles (ectosomes) shed by stored human platelets downregulate macrophages and modify the development of dendritic cells
.
J Immunol
.
2011
;
186
(
11
):
6543
-
6552
.
69.
Alvarado
LJ
,
Andreoni
A
,
Huntsman
HD
,
Cheng
H
,
Knutson
JR
,
Larochelle
A
.
Heterodimerization of TPO and IFNγ impairs human hematopoietic stem/progenitor cell signaling and survival in chronic inflammation [abstract]
.
Blood
.
2017
;
130
(
suppl 1
):
4
.
70.
Vlachodimitropoulou
E
,
Chen
YL
,
Garbowski
M
, et al
.
Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator
.
Blood
.
2017
;
130
(
17
):
1923
-
1933
.
71.
Lambert
MP
,
Witmer
CM
,
Kwiatkowski
JL
.
Therapy induced iron deficiency in children treated with eltrombopag for immune thrombocytopenia
.
Am J Hematol
.
2017
;
92
(
6
):
E88
-
E91
.
72.
Zhao
Z
,
Sun
Q
,
Sokoll
LJ
, et al
.
Eltrombopag mobilizes iron in patients with aplastic anemia
.
Blood
.
2018
;
131
(
21
):
2399
-
2402
.
73.
Banerjee
A
,
Mifsud
NA
,
Bird
R
, et al
.
The oral iron chelator deferasirox inhibits NF-κB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia
.
Br J Haematol
.
2015
;
168
(
4
):
576
-
582
.
74.
Cheong
JW
,
Kim
HJ
,
Lee
KH
, et al
;
Korean Society of Hematology Acute Myeloid Leukemia/Myelodysplastic Syndrome Working Party
.
Deferasirox improves hematologic and hepatic function with effective reduction of serum ferritin and liver iron concentration in transfusional iron overload patients with myelodysplastic syndrome or aplastic anemia
.
Transfusion
.
2014
;
54
(
6
):
1542
-
1551
.
75.
Lee
SE
,
Yahng
SA
,
Cho
BS
, et al
.
Improvement in hematopoiesis after iron chelation therapy with deferasirox in patients with aplastic anemia
.
Acta Haematol
.
2013
;
129
(
2
):
72
-
77
.
76.
Lee
JW
,
Yoon
SS
,
Shen
ZX
, et al
.
Hematologic responses in patients with aplastic anemia treated with deferasirox: a post hoc analysis from the EPIC study
.
Haematologica
.
2013
;
98
(
7
):
1045
-
1048
.
77.
Gill
H
,
Leung
GM
,
Lopes
D
,
Kwong
YL
.
The thrombopoietin mimetics eltrombopag and romiplostim in the treatment of refractory aplastic anaemia
.
Br J Haematol
.
2017
;
176
(
6
):
991
-
994
.
78.
Lee
JW
,
Jang
JH
,
Lee
S-E
,
Jung
CW
,
Park
S
,
Oh
I-H
.
Efficacy and safety of romiplostim in patients with aplastic anemia refractory to immunosuppressive therapy: 1-year interim analysis of phase 2 clinical trial
.
Blood
.
2016
;
128
(
22
):
3910
.
79.
Lengline
E
,
Drenou
B
,
Peterlin
P
, et al
.
Nationwide survey on the use of eltrombopag in patients with severe aplastic anemia: a report on behalf of the French Reference Center for Aplastic Anemia
.
Haematologica
.
2018
;
103
(
2
):
212
-
220
.
80.
Hwang
YY
,
Gill
H
,
Chan
TSY
,
Leung
GMK
,
Cheung
CYM
,
Kwong
YL
.
Eltrombopag in the management of aplastic anaemia: real-world experience in a non-trial setting
.
Hematology
.
2018
;
23
(
7
):
399
-
404
.

Author notes

This article was selected by the Blood Advances and Hematology 2018 American Society of Hematology Education Program editors for concurrent submission to Blood Advances and Hematology 2018. It is reprinted from Blood Advances 2018, Volume 2.

Competing Interests

Conflict-of-interest disclosure: P.S. is on the Board of Directors or an advisory committee for Novartis and has been affiliated with the Speaker’s Bureau for Pfizer and Novartis.

Off-label drug use: Off-label use of eltrombopag in combination with immunosuppressive therapy will be discussed.