Advertisement

Thrombopoietin Receptor Agonists: Characteristics, Adverse Effects, and Indications

  • Jenny Despotovic
  • Amanda Grimes
Chapter

Abstract

While the most commonly utilized first-line therapeutics for the treatment of immune thrombocytopenia (ITP) target the peripheral destruction of platelets, a preponderant second-line therapeutic agent targeting increased megakaryopoiesis and/or platelet production has now emerged, in the form of thrombopoietin receptor agonists (TPO-RAs). These TPO-RAs, eltrombopag and romiplostim, have been proven safe and effective in treating ITP in both children and adults and have also been approved for use in severe aplastic anemia and chronic hepatitis, with ongoing investigation in the treatment of other clinical entities as well, including myelodysplastic syndrome and acute myelogenous leukemia, chemotherapy-induced thrombocytopenia, congenital thrombocytopenia, and other diseases. This chapter will detail TPO-RA use in all of these different clinical settings.

18.1 Introduction

While the most commonly utilized first-line therapeutics for the treatment of immune thrombocytopenia (ITP) target the peripheral destruction of platelets, a preponderant second-line therapeutic agent targeting increased megakaryopoiesis and/or platelet production has now emerged, in the form of thrombopoietin receptor agonists (TPO-RAs). These TPO-RAs, eltrombopag and romiplostim, have been proven safe and effective in treating ITP in both children and adults and have also been approved for use in severe aplastic anemia and chronic hepatitis, with ongoing investigation in the treatment of other clinical entities as well, including myelodysplastic syndrome and acute myelogenous leukemia, chemotherapy-induced thrombocytopenia, congenital thrombocytopenia, and other diseases. This chapter will detail TPO-RA use in all of these different clinical settings.

18.2 Background

Thrombopoietin (TPO) is the major regulator of platelet production, acting largely via the JAK and STAT signaling pathways to stimulate megakaryocyte growth and platelet production (Kuter 2014). Shortly after identification and purification of TPO by five different groups in 1994 (de Sauvage et al. 1994; Lok et al. 1994; Bartley et al. 1994; Kuter et al. 1994; Kato et al. 1995), recombinant human TPO products were created and tested in immune thrombocytopenia (ITP) and other thrombocytopenic conditions. However, one of these agents resulted in the development of antibodies to the recombinant TPO protein, causing neutralization of both the recombinant TPO and endogenous TPO in some subjects, which resulted in severe thrombocytopenia (Li et al. 2001). This resulted in cessation of further development of recombinant TPO products. Development of less immunogenic second-generation TPO receptor agonists (RAs) ensued. These second-generation TPO mimetics bind to the TPO receptor at different sites, but both stimulate increased platelet production via the same mechanism as endogenous TPO. There are currently two TPO-RAs licensed for the treatment of ITP. Eltrombopag olamine is a non-peptide small-molecule TPO mimetic which activates the TPO receptor by binding to a transmembrane site on the receptor; and romiplostim is a peptide-antibody (Fc fragment) fusion protein which activates the TPO receptor by binding to its extra-cytoplasmic domain just as endogenous TPO does (Kuter 2014) (See Fig. 18.1) (Imbach and Crowther 2011). Both TPO-RAs have good efficacy and favorable safety profiles and were approved by the US Food and Drug Administration (FDA) for the treatment of chronic ITP in adults in 2008 (fda.gov 2017a, b). Eltrombopag received FDA approval for children with ITP in 2015 (fda.gov 2017a). These agents are common second-line treatment options for ITP and now have expanding roles in other thrombocytopenic conditions (Rodeghiero and Carli 2017).
Fig. 18.1

Structure of romiplostim and eltrombopag and the cellular mechanisms of action. Panel (a) shows the chemical structure of romiplostim, which is composed of the Fc portion of IgG1, to which two thrombopoietin peptides consisting of 14 amino acids are coupled through glycine bridges at the C-terminal of each γ heavy chain. Panel (b) shows the chemical structure of eltrombopag. Panel (c) shows the cellular mechanisms of action of romiplostim, which binds to the thrombopoietin receptor, and of eltrombopag, which binds to the thrombopoietin receptor’s transmembrane domain, thereby activating signaling that leads to increased platelet production. GRB2 denotes growth factor receptor-binding protein 2, JAK Janus kinase, MAPK mitogen-activated protein kinase, P phosphorylation, RAF rapidly accelerated fibrosarcoma kinase, RAS rat sarcoma GTPase, SHC Src homology collagen protein, and STAT signal transducer and activator of transcription. From The New England Journal of Medicine, Paul Imbach and Mark Crowther, Thrombopoietin-Receptor Agonists for Primary Immune Thrombocytopenia, Volume 365, Pages 734–741, Copyright © (2011) Massachusetts Medical Society. Reprinted with permission

18.3 Clinical Use and Pharmaceutical Considerations

Eltrombopag is approved for clinical use in children and adults with chronic ITP refractory to or recurrent after first-line therapies (including intravenous immunoglobulin [IVIG], anti-RhD immune globulin, glucocorticoids), adults with severe aplastic anemia (SAA) refractory to first-line therapies (immunosuppressive therapy) and ineligible for hematopoietic stem cell transplant (HSCT), and adults with chronic hepatitis secondary to hepatitis C virus (HCV) infection (to enable interferon therapy). Romiplostim is approved for clinical use in adults with chronic ITP refractory to or recurrent after first-line therapies.

Eltrombopag is an oral medication that is taken once daily. It should be administered on an empty stomach in order to maximize absorption. Additionally, eltrombopag binds strongly to divalent cations and cannot be taken in close proximity to a calcium-rich meal or the administration of multivitamin and/or mineral supplements (2 h before or 4 h after), as this cation binding would prevent absorption of the eltrombopag molecule. Dose should be titrated for a goal platelet count of 50,000/μL–200,000/μL, with desired platelet response typically achieved within an average of 7 weeks (Neunert et al. 2016). Eltrombopag is generally well tolerated and safe for long-term use. Romiplostim is administered via subcutaneous injection once weekly. Dosage is titrated for a goal platelet count of 50,000/μL–200,000/μL, with desired platelet response typically achieved within an average of 6 weeks (Neunert et al. 2016). Generally, romiplostim therapy is also well tolerated and safe for long-term use.

18.4 Adverse Effects and Theoretical Risks Associated with TPO-RA Use

Overall, TPO-RAs are very well tolerated; and clinical data over the past 10–15 years demonstrate that many of the theoretical risks potentially associated with TPO-RAs have not been seen in clinical practice. However, some adverse effects of TPO-RAs have been identified, and some theoretical risks require further investigation before definitive conclusions regarding actual risk associated with TPO-RA use can be made. Providers utilizing TPO-RAs in clinical practice should therefore be aware of these risks and adverse effects. Potential risks associated with TPO-RA use include thrombotic and/or thromboembolic complications, bone marrow fibrosis, rebound thrombocytopenia, cataracts, hepatic abnormalities, development of cross-reactive antibodies, and cytogenetic abnormalities/clonal evolution.

18.4.1 Adverse Effects and Risks Associated with both TPO-RA Agents (Eltrombopag and Romiplostim)

18.4.1.1 Risk of Thrombosis

Increased risk of thrombotic complications in patients receiving TPO-RA therapy has been a significant and closely monitored concern, with most studies confirming a slightly increased risk of thrombosis among ITP patients receiving both eltrombopag and romiplostim. However, the significance of this risk has remained uncertain, given the potential biases within these studies, the preexisting increased thrombotic risk among the ITP population, and the contribution of prior therapies (i.e., splenectomy) to thrombotic risk. A recent review of industry-sponsored eltrombopag and romiplostim investigations (Rodeghiero 2016) estimated the rate of thromboembolic events to be 2.5–3.2 per 100 patient-years with eltrombopag and 4.2–7.5 per 100 patient-years with romiplostim. The rate of thromboembolic events in ITP patients treated with TPO-RAs therefore appears to be higher than that in the general population, as well as that in ITP patients not receiving TPO-RA therapy, in which there is already ~two-fold increased risk of thromboembolism at baseline, compared to the general population (Rodeghiero 2016). Notably, occurrence of thromboembolic events was associated with advanced age and comorbid risk factors (hypertension, obesity, smoking, etc.), with the majority of data reported in adult patients. Pediatric ITP patients treated with both romiplostim (Tarantino et al. 2016; Bussel et al. 2015a) and eltrombopag (Bussel et al. 2015b) reported no occurrence of thromboembolic events in initial industry trials, although two thromboembolic events in pediatric ITP patients treated at ITP Consortium of North America (ICON) sites (2.5%), both receiving eltrombopag, were later reported (Neunert et al. 2016), with overall incidence of thrombosis among pediatric ITP patients receiving TPO-RA therapy remaining very low. Thrombotic risk in ITP patients treated with TPO-RAs does not appear to correlate linearly with the platelet count and also does not appear to correlate consistently with medication dose (Rodeghiero et al. 2013; Saleh et al. 2013). The extent of thrombotic risk associated with TPO-RA therapy is still being established, with ongoing investigation needed to verify true incidence rates and/or associations while controlling for confounding variables. As these data are further clarified, providers should be aware of this risk in clinical practice and evaluate individual risk factors on a case-by-case basis when considering initiation of TPO-RA therapy. Additionally, dosage should be titrated to achieve and maintain the minimum platelet count needed to reduce the risk of bleeding (≥50,000/μL), but attempt should not be made to normalize platelet count. Care should be taken to avoid thrombocytosis, as this could potentially contribute to the risk of thrombosis.

18.4.1.2 Risk of Bone Marrow Fibrosis

Accelerated bone marrow fibrosis is another theoretical risk associated with TPO-RA therapy. Given that TPO-RAs work by stimulating megakaryopoiesis and increased platelet production, it is thought that profibrotic cytokines expressed by megakaryocytes and platelets will also be increased via the action of TPO-RAs on the TPO receptor (Kuter et al. 2007). Two large studies evaluating chronic ITP patients receiving long-term TPO-RA therapy showed a low incidence of bone marrow fibrosis—1.7% in patients receiving eltrombopag for up to 5.5 years (Brynes et al. 2015) and 2% in patients receiving romiplostim for up to 5 years (Rodeghiero et al. 2013). In these large adult trials, the majority of bone marrow fibrosis was restricted to reticulin fibrosis, with rarely identified collagen fibrosis (Rodeghiero et al. 2013; Saleh et al. 2013; Brynes et al. 2015). Reticulin fibers, best seen with a reticulin stain, can be seen normally in the bone marrow of healthy individuals, although increased levels of reticulin fibrosis may be associated with various disease processes and, in fact, have been demonstrated in adult ITP patients who are treatment naïve (present in 31% of ITP patients yet to receive therapy in one study) (Rizvi et al. 2015). Collagen fibrosis, conversely, is not present in healthy bone marrow and always reflects an underlying disease process—most often a myeloproliferative disorder. These fibers are composed of type I collagen and are best seen with a trichrome stain. The one ITP patient receiving romiplostim therapy in whom collagen fibrosis was identified also had known preexisting cytogenetic abnormalities associated with myelodysplastic syndrome (Rodeghiero et al. 2013). Also of note, identification of bone marrow fibrosis in chronic ITP patients receiving eltrombopag or romiplostim did not correlate with peripheral blood count abnormalities or other unexpected morphological or quantitative bone marrow abnormalities and also appeared to be reversible or stable once TPO-RA therapy was discontinued (Rodeghiero et al. 2013; Saleh et al. 2013; Brynes et al. 2015). Although smaller studies have shown more inconclusive results, the larger body of evidence regarding accelerated bone marrow fibrosis associated with TPO-RA therapy to date demonstrates no significant concern for this risk. Therefore, experts generally do not recommend routine bone marrow monitoring in patients receiving TPO-RA therapy, but continued monitoring of peripheral blood counts and smear should occur on a routine basis; and if cytopenias or morphological abnormalities develop, a bone marrow evaluation should be obtained.

18.4.1.3 Risk of Rebound Thrombocytopenia

Rebound thrombocytopenia following discontinuation of TPO-RA therapy is a well-documented risk, and many hematologists wean rather than abruptly discontinue these agents, with continued close follow-up for at least 2–4 weeks following discontinuation of therapy. The majority of ITP patients receiving TPO-RA therapy return to pre-therapy baseline platelet levels upon discontinuation of therapy, with a small subset of patients actually achieving sustained platelet responses following discontinuation of therapy (Ghadaki et al. 2013; Bussel et al. 2015c; Biagiotti et al. 2015). Up to 10% of patients experience significant rebound thrombocytopenia, with platelet counts decreasing below pretreatment levels and remaining low for 1–3 weeks before returning to prior baseline (Kuter et al. 2008). This is likely due to the fact that endogenous TPO activity is regulated by platelet mass, which may be suppressed while platelet levels are elevated on TPO-RA therapy and cannot quickly equilibrate when therapy is abruptly discontinued. This rebound thrombocytopenia can be associated with significant risk of bleeding. Therefore, although manufacturers of both agents recommend holding the dose if the platelet count exceeds 400,000/μL, experienced providers recommend close monitoring and dose reduction, as well as initiation of low-dose ASA if platelet count exceeds 800,000/μL, to avoid the risk of rebound thrombocytopenia, which in clinical practice likely poses higher risk to the patients than a transiently elevated platelet count (Kuter et al. 2010).

18.4.1.4 Risk of Clonal Evolution

Given prior knowledge of hematopoietic precursor cell expression of c-mpl (TPO receptor), the direct action of TPO on the hematopoietic stem cells was established shortly after its purification and successful cloning in 1994 (Zeigler et al. 1994). This direct stimulation of early hematopoietic stem cells by TPO is the basis for investigating the use of TPO-RAs in refractory and, now frontline, severe aplastic anemia (SAA). However, this is also the basis for the theoretical concern about clonal evolution with the use of TPO-RAs in both SAA and myelodysplastic syndromes (MDS)/acute myelogenous leukemia (AML). Recent studies evaluating the effects of eltrombopag therapy in SAA have shown new cytogenetic abnormalities/clonal evolution in 8–18% of SAA patients treated with eltrombopag (Desmond et al. 2014; Townsley et al. 2015; Gill et al. 2017; Townsley et al. 2017), which appears consistent with the incidence of clonal evolution in historical cohorts of SAA patients treated with immunosuppressive therapy alone. This likely represents a risk associated with the disease and not eltrombopag therapy, but further investigation is needed to clarify the potential risks of clonal evolution in the treatment of SAA and MDS/AML with TPO-RAs.

18.4.2 Adverse Effects and Risks Associated with Eltrombopag

18.4.2.1 Risk of Cataract Formation

There was initial concern for increased risk of cataract formation related to eltrombopag therapy, due to preliminary findings in animal studies. However, no clinical investigation has shown an increased risk of cataracts with eltrombopag use (Bussel et al. 2009; Cheng et al. 2011). There have been cataracts reported in patients treated with both eltrombopag and romiplostim, but these patients were also exposed to significant steroid doses. There does not appear to be an increased risk of cataract in children. Some experts continue to recommend baseline ophthalmologic evaluation prior to initiation of eltrombopag therapy and annually while continuing therapy, as further clinical data accumulates.

18.4.2.2 Risk of Liver Function Abnormalities

Hepatic abnormalities have been noted with eltrombopag therapy. Elevations in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin occurred in 4–6% of patients receiving eltrombopag therapy (Novartis 2016). Although these hepatobiliary laboratory abnormalities are generally asymptomatic and appear to resolve with disruption or discontinuation of therapy, certain monitoring parameters and corresponding dose titration or discontinuation actions are recommended to prevent drug-induced liver injury. Large trials reporting the safety of eltrombopag therapy in ITP patients generally recommend discontinuing drug when the following parameters are met: ALT ≥ 5× the upper limit of normal and/or ALT ≥ 3× the upper limit of normal with accompanying hepatitis symptoms or rash and bilirubin ≥1.5× the upper limit of normal (with >35% direct fraction) (Saleh et al. 2013). Additionally, providers utilizing eltrombopag in the setting of thrombocytopenia related to chronic HCV-associated hepatitis, specifically in combination with ribavirin- and interferon-based therapies, need to be aware of the increased risk for acute hepatic decompensation in this setting (fda.gov 2017a).

18.4.2.3 Other Adverse Effects Associated with Eltrombopag

Milder side effects noted most commonly in patients receiving eltrombopag therapy include headache, nasopharyngitis, upper respiratory tract infection, and fatigue (Saleh et al. 2013). However, eltrombopag therapy is generally well tolerated.

18.4.3 Adverse Effects and Risks Associated with Romiplostim

18.4.3.1 Risk of Antibody Development

Previous experience with the first-generation recombinant TPO proteins and resultant development of cross-reactive antibodies with the use of the pegylated recombinant product generated persistent concern for the development of similar antibodies with the use of second-generation TPO-RAs as well. Eltrombopag carries no relevant risk for cross-reactive or neutralizing antibody formation though, as it is a small-molecule therapeutic and also shares no structural or epitope homology with endogenous TPO; and in clinical practice, no antibody formation has been noted. Conversely, romiplostim does carry a theoretical risk of cross-reactive antibody formation, as it acts on the same TPO receptor extra-cytoplasmic binding domain as endogenous TPO acts upon, albeit without any structural similarity to endogenous TPO. However, no cross-reactive antibody formation has occurred in 10–15 years of clinical romiplostim use. Romiplostim therapy does result in formation of neutralizing anti-romiplostim antibodies in a small subset of patients, which results in a decrease or cessation of treatment response. This phenomenon should therefore be considered and further investigated in patients previously responsive to romiplostim therapy, with subsequent loss of response (Neunert et al. 2016; Rodeghiero et al. 2013; Carpenedo et al. 2016).

18.4.3.2 Other Adverse Effects Associated with Romiplostim

The most commonly noted side effects in patients receiving romiplostim therapy are headache, fatigue, and nasopharyngitis (Rodeghiero et al. 2013), although as previously noted, romiplostim is well tolerated overall.

18.5 Use of Thrombopoietin Receptor Agonists in Immune Thrombocytopenia (ITP)

TPO-RA therapy is most extensively studied and widely utilized in the treatment of patients with ITP. Early clinical trials investigating the use of both eltrombopag and romiplostim in adults with chronic ITP resulted in an FDA indication for both agents in adult patients with chronic ITP refractory to first-line therapies (IVIG, anti-D immune globulin, and glucocorticoids) (fda.gov 2017a, b). Eltrombopag and romiplostim response rates in treatment-refractory chronic ITP patients, generally defined by achievement of platelet count ≥50,000/μL, averaged ~80% (compared to an average of 20% or less in placebo groups), also with decreased bleeding events, improved health-related quality of life scores, and no increased incidence of severe adverse effects noted in eltrombopag (Saleh et al. 2013; Bussel et al. 2009; Cheng et al. 2011; Bussel et al. 2007; Bussel et al. 2013) and romiplostim (Rodeghiero et al. 2013; Kuter et al. 2008; Kuter et al. 2010) treatment groups. Additionally, follow-up studies demonstrated maintenance of sustained treatment response and continued safety in chronic ITP patients receiving long-term eltrombopag (Saleh et al. 2013) or romiplostim (Rodeghiero et al. 2013) therapy for up to 3–5 years. Similarly, studies in pediatric ITP patients (≥1 year of age) have demonstrated the safety and efficacy of eltrombopag in this population (Bussel et al. 2013; Grainger et al. 2015), with an FDA indication for the use of eltrombopag in pediatric chronic ITP patients refractory to first-line therapies. Likewise, ongoing studies show excellent safety and efficacy profiles for romiplostim use in the treatment of pediatric ITP (Tarantino et al. 2016; Bussel et al. 2011), and this therapy is also widely utilized clinically for the treatment of childhood ITP.

In clinical practice, the role of TPO-RA therapy in ITP continues to expand significantly as further data proving the safety and efficacy of these agents is compiled. For example, TPO-RA therapy is occasionally implemented earlier in the treatment of symptomatic ITP, in an attempt to avoid splenectomy or extensive glucocorticoid exposure, prior to possible disease resolution over the first 12 months. These agents may be easily weaned during the persistent phase, as spontaneous recovery occurs. Alternatively, therapy may be continued or reinitiated as indicated, if chronic disease develops. Studies have shown that response is maintained with intermittent use (i.e., response is again achieved at similar levels when TPO-RA therapy is resumed) and extended use (Rodeghiero et al. 2013; Bussel et al. 2013) and that therapy can be discontinued with no irreversible or long-term complications once ITP resolves (Ghadaki et al. 2013). Moreover, studies show that up to 30% of ITP patients treated with TPO-RAs maintain an extended response (up to 6 months and longer) once therapy is discontinued (Ghadaki et al. 2013; Bussel et al. 2015c; Biagiotti et al. 2015), with the implication that TPO-RA therapy may be capable of inducing a sustained platelet response. More long-term follow-up data is needed to define this possibility.

The advent of TPO-RA therapies has broadened the therapeutic landscape in ITP. TPO-RAs induce reliable platelet responses in the majority of patients and are also associated with decreased bleeding events, improved health-related quality of life, and an overall favorable safety profile, including the lack of immunosuppression associated with other second-line therapies. When one TPO-RA is ineffective or not tolerated, response or tolerability could be achieved by switching to an alternate TPO-RA, with no cross-resistance noted between the two available drugs in this class.

In summary, abundant data supports consideration of treatment with TPO-RA therapies in both adults and children with chronic ITP. Treated patients often have reduced bleeding complications, fewer activity restrictions, and potentially improved quality of life (Tarantino et al. 2016; Bussel et al. 2013; Rodeghiero et al. 2013; Saleh et al. 2013; Kuter et al. 2008; Kuter et al. 2010; Bussel et al. 2009; Cheng et al. 2011; Bussel et al. 2007; Bussel et al. 2013; Grainger et al. 2015; Bussel et al. 2011). Additionally, patients may be able to avoid splenectomies or adverse effects of prolonged immunosuppression. Occasional sustained platelet responses have occurred after TPO-RA therapy is discontinued, but these agents should not be considered curative.

18.6 Use of Thrombopoietin Receptor Agonists in Severe Aplastic Anemia (SAA)

Outside of therapy for chronic ITP, eltrombopag has a clinical indication for the treatment of patients with SAA who are refractory to first-line immunosuppressive therapies and are ineligible for hematopoietic stem cell transplant (HSCT). In its original use, eltrombopag was intended to ameliorate the complications of thrombocytopenia which are associated with SAA. However, during initial trials, trilineage effects of eltrombopag were noted, with improved red blood cell (RBC) and white blood cell (WBC) parameters in addition to the improved megakaryopoiesis and platelet production which was expected (Desmond et al. 2014). As discussed previously, this is likely due to the direct action of the TPO-RAs on early hematopoietic precursors via the same mechanism as endogenous TPO (Zeigler et al. 1994), creating expansion of all hematopoietic stem cells and thereby all cell lines. This finding prompted further investigation of eltrombopag as therapy for SAA, with ongoing trials now investigating this medication as a frontline therapeutic option (in combination with immunosuppressive therapy) for SAA. Early results are promising, with a recently published trial enrolling 92 SAA patients to receive eltrombopag in combination with immunosuppressive therapy as frontline therapy (starting at either Day 1 or Day 14) showing average complete response rates of 39% at 6 months and overall response rates of 87% at 6 months, compared to complete response rates of 10% and overall response rates of 66% in historical SAA cohorts treated with immunosuppressive therapy alone (Townsley et al. 2017). Incidentally, greatest response rates were noted in the patient cohort beginning eltrombopag therapy at Day 1. In all patients receiving frontline eltrombopag, marked increases in bone marrow cellularity, CD34+ stem cells, and early hematopoietic progenitors were noted. Hematopoietic progenitor stimulation does raise the concern for potential development of new cytogenetic abnormalities or clonal evolution in SAA, given that up to 1/3 of AA/SAA patients have genetic mutations typically associated with myeloid neoplasms (Yoshizato et al. 2015). However, rates of clonal evolution in this study of 92 SAA patients treated with frontline eltrombopag therapy were similar to those in historical cohorts treated with immunosuppressive therapy alone (~8%) (Townsley et al. 2017). Further investigation of TPO-RAs in the treatment of SAA is needed at this point; however, preliminary findings portend a possible paradigm shift in the management of SAA, with the introduction of eltrombopag as a frontline treatment option.

18.7 Use of Thrombopoietin Receptor Agonists in Chronic Hepatitis

A third clinical indication for the use of eltrombopag is in the treatment of chronic hepatitis C virus (HCV)-associated hepatitis. The premise of this indication is based on the frequent need for peginterferon-based therapy in patients with chronic HCV infection, which cannot be effectively completed in the setting of comorbid thrombocytopenia. Eltrombopag has proven effective in raising platelet counts in this population, leading to decreased bleeding complications and, most importantly, to successful completion of peginterferon therapy without interruptions, dose reductions, or discontinuations. This has led to an increased rate of sustained virological response during peginterferon-based antiviral therapy in this population of patients (Fried et al. 2002). As peginterferon therapy becomes less utilized in the advent of newer antiviral therapies for HCV infection, this indication for eltrombopag therapy may change. However, both eltrombopag and peginterferon therapy will likely continue to play a significant role in HCV-associated hepatitis therapy for an extended period of time, until these newer antiviral agents become more widely available and accessible throughout the world.

18.8 Off-Label Uses of Thrombopoietin Receptor Agonists, Currently Under Investigation

18.8.1 First-Line Treatment for Aplastic Anemia

Investigation of eltrombopag as first-line treatment in SAA is discussed in detail above (Use of TPO-RAs in SAA). Early results are promising, likely owing to generalized stimulation of early hematopoietic precursor cells by eltrombopag, ultimately resulting in multi-lineage effects.

18.8.2 Myelodysplastic Syndrome (MDS)/Acute Myelogenous Leukemia (AML)

The premise for investigation of TPO-RAs in the treatment of MDS and AML is similar to that in SAA. Thrombocytopenia is a major problem in these patients, occurring in 40–65% (Kantarjian et al. 2007) and contributing significantly to bleeding complications and morbidity/mortality in this population of patients. Eltrombopag and romiplostim are expected to ameliorate the thrombocytopenic complications associated with MDS and AML if found to be safe and effective. There are currently many ongoing trials among pediatric and adult patients with MDS/AML, mostly in advanced or refractory patients (with eltrombopag) but also in lower-risk patients (with romiplostim). Generally, treatment with both TPO-RAs has been demonstrated to be safe, although there was early concern for increased progression to AML in patients treated with romiplostim (with updated findings less clear that there is any increased risk of AML progression associated with romiplostim therapy (Kantarjian et al. 2015)).

Eltrombopag has been studied in 98 relapsed or refractory adult patients with intermediate-2- or high-risk MDS or AML, with good results. Rates of platelet and red blood cell transfusion independence were improved in the eltrombopag-treated patients vs patients receiving placebo therapy (38% vs 21% and 20% vs 6%, respectively) (Platzbecker et al. 2015). In another trial investigating the efficacy and safety of eltrombopag in intermediate-2- or high-risk MDS or AML patients, the frequency of clinically relevant thrombocytopenic events and severe bleeding was also decreased in the eltrombopag treatment group (Mittelman et al. 2016). In both of these trials, there was no increased frequency of disease progression in the eltrombopag-treated patients; and in fact, in the latter trial (Mittelman et al. 2016), there was a reduced trend of disease progression in the eltrombopag-treated arm vs placebo (42% vs 60%, respectively). Another ongoing study investigating eltrombopag therapy in adult patients with relapsed or refractory low- and intermediate-1-risk MDS has shown promising results as well, with 54% of patients receiving eltrombopag therapy having achieved a platelet response at 24 weeks, compared to 27% of patients receiving placebo therapy. Again, the incidence of AML evolution or MDS disease progression was not increased in eltrombopag-treated patients; and of note, six patients treated with eltrombopag had gone into complete remission at 24 weeks (Oliva et al. 2015).

Romiplostim therapy in MDS has been studied largely in lower-risk patients. In one year-long study in low- and intermediate-1-risk MDS patients receiving supportive care only with platelet counts ≤50,000/μL, a durable platelet response was achieved in 46% of romiplostim-treated patients. Notably, progression to AML was observed in ~5% of patients (two patients) (Kantarjian et al. 2010a). Additional smaller studies investigating the safety and efficacy of romiplostim in combination with azacitidine (Kantarjian et al. 2010b), lenalidomide (Wang et al. 2012), and decitabine (Greenberg et al. 2013) in lower-risk MDS patients all demonstrated improved thrombocytopenic events and decreased bleeding events in romiplostim-treated patients. Numbers of patients included in each study were too small to determine romiplostim effects on disease progression. At this time, further studies are needed to clarify whether romiplostim therapy in MDS or AML poses a risk for accelerated disease progression. Eltrombopag, however, appears not to be associated with risk for disease progression in MDS and AML patients (Platzbecker et al. 2015; Mittelman et al. 2016; Oliva et al. 2015). This may be due to eltrombopag’s ancillary property as a divalent ion chelator—specifically as an iron chelator in this instance (Roth et al. 2012). Again, further investigations regarding potential antitumor properties of eltrombopag are yet to be completed in the clinical setting and will need further exploration before definitive associations are made.

18.8.3 Chemotherapy-Induced Thrombocytopenia

TPO-RAs have not yet been extensively studied in the setting of chemotherapy-induced or radiation-induced thrombocytopenia and/or bone marrow failure. However, small studies investigating both eltrombopag and romiplostim use among patients receiving chemotherapy for solid tumors have shown favorable results. For both TPO-RA agents, treatment resulted in decreased platelet count nadirs and fewer dose modifications and/or interruption of chemotherapy (Winer et al. 2015; Kellum et al. 2010; Parameswaran et al. 2014). Larger randomized trials are needed to determine safety and to better identify optimal treatment groups for TPO-RA therapy in chemotherapy-induced thrombocytopenia prior to recommending TPO-RA therapy in this clinical setting.

18.8.4 Thrombocytopenia Following Hematopoietic Stem Cell Transplant (HSCT)

Delayed platelet recovery following HSCT is a common problem associated with HSCT in both children and adults. No extensive investigation regarding the use of TPO-RA therapy in the setting of post-HSCT thrombocytopenia has been done. However, early and ongoing studies are promising, confirming both safety and efficacy of TPO-RAs in this setting. An ongoing phase 2 randomized controlled trial evaluating the safety and efficacy of eltrombopag in the treatment of delayed platelet recovery (≥35 days after HSCT) in adult patients undergoing HSCT demonstrated platelet response (≥50,000/μL) in 21% of eltrombopag-treated patients at 8 weeks, vs 0% of patients receiving placebo. Additionally, there was no increased morbidity/mortality or incidence of adverse effects in the group of patients receiving eltrombopag therapy (Popat et al. 2015). Similarly, two case series evaluating the use of romiplostim in delayed platelet recovery post-HSCT showed no increased adverse effects in romiplostim-treated patients and demonstrated realization of platelet response (≥50,000/μL) in all patients treated within 2–12 weeks (Calmettes et al. 2011; Poon et al. 2013). Further data is needed to determine safety and efficacy of TPO-RA approach for management of thrombocytopenia following HSCT, but early results are promising.

18.8.5 Congenital Thrombocytopenias

Very little investigation regarding the role of TPO-RAs in the setting of hereditary thrombocytopenias has been completed. However, we know that this is a rapidly expanding category of diseases given the ongoing advances in genetic diagnostic tools, with potential utility of TPO-RA therapy. Small studies have shown some benefit of eltrombopag therapy in both Wiskott-Aldrich syndrome and myosin heavy chain 9 (MYH-9)-related thrombocytopenias; but more studies are needed to delineate the safety and efficacy of TPO-RA therapy in this clinical setting.

References

  1. 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;77:1117–24.CrossRefPubMedGoogle Scholar
  2. Biagiotti C, Carrai V, Bacchiarri F, et al. Persistent remission of chronic immune thrombocytopenia after thrombopoietin mimetics discontinuation. Haematologica. Conference Publication: (var.pagings). 2015;100:124.CrossRefGoogle Scholar
  3. Brynes RK, Orazi A, Theodore D, et al. Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: data from the EXTEND study. Am J Hematol. 2015;90:598–601.CrossRefPubMedGoogle Scholar
  4. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357:2237–47.CrossRefPubMedGoogle Scholar
  5. Bussel JB, Provan D, Shamsi T, et al. Effect of Eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:641–8.CrossRefPubMedGoogle Scholar
  6. Bussel JB, Buchanan GR, Nugent DJ, et al. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. Blood. 2011;118:28–36.CrossRefPubMedGoogle Scholar
  7. Bussel JB, Saleh MN, Vasey SY, et al. Repeated short-term use of eltrombopag in patients with chronic immune thrombocytopenia (ITP). Br J Haematol. 2013;160:538–46.CrossRefPubMedGoogle Scholar
  8. Bussel JB, de Miguel PG, Despotovic JM, et al. Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol. 2015a;2(8):e315–25.CrossRefPubMedGoogle Scholar
  9. Bussel JB, Hsieh L, Buchanan GR, et al. Long-term use of the thrombopoietin-mimetic romiplostim in children with severe chronic immune thrombocytopenia (ITP). Pediatr Blood Cancer. 2015b;62:208–13.CrossRefPubMedGoogle Scholar
  10. Bussel J, Shah KM, Brigstocke S, et al. Tapering eltrombopag in patients with chronic ITP: how successful is this and in whom does it work? Blood. 2015c;126:1054.Google Scholar
  11. Calmettes C, Vigouroux S, Tabrizi R, et al. Romiplostim (AMG531, Nplate) for secondary failure of platelet recovery after allo-SCT. Bone Marrow Transplant. 2011;46:1587–9.CrossRefPubMedGoogle Scholar
  12. Carpenedo M, Cantoni S, Coccini V, et al. Response loss and development of neutralizing antibodies during long-term treatment with romiplostim in patients with immune thrombocytopenia: a case series. Eur J Haematol. 2016;97(1):101–3.CrossRefPubMedGoogle Scholar
  13. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377:393–402.CrossRefPubMedGoogle Scholar
  14. de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994;369:533–8.CrossRefPubMedGoogle Scholar
  15. Desmond R, Townsley D, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818–25.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.CrossRefPubMedGoogle Scholar
  17. Ghadaki B, Nazi I, Kelton JG, et al. Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists. Transfusion. 2013;53:2807–12.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Gill H, Leung G, Lopes D, et al. The thrombopoietin mimetics eltrombopag and romiplostim in the treatment of refractory aplastic anaemia. Br J Haematol. 2017;176(6):991–4.CrossRefPubMedGoogle Scholar
  19. Grainger JD, Locatelli F, Chotsampancharoen T, et al. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015;386(10004):1649–58.CrossRefPubMedGoogle Scholar
  20. Greenberg PL, Garcia-Manero G, Moore M, et al. A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine. Leuk Lymphoma. 2013;54:321–8.CrossRefPubMedGoogle Scholar
  21. Imbach P, Crowther M. Thrombopoietin-receptor agonists for primary immune thrombocytopenia. N Engl J Med. 2011;365:734–41. (Figure 1. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission.)CrossRefPubMedGoogle Scholar
  22. Kantarjian H, Giles F, List A, et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007;109:170–1714.CrossRefGoogle Scholar
  23. Kantarjian H, Fenaux P, Sekeres MA, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2010a;28:437–44.CrossRefPubMedGoogle Scholar
  24. Kantarjian HM, Giles FJ, Greenberg PL, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010b;116:3163–70.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Kantarjian HM, Mufti G, Fenaux P, et al. Romiplostim in thrombocytopenic patients with low-risk or intermediate-1-risk myelodysplastic syndrome results in reduced bleeding without impacting leukemic progression: updated follow-up results from a randomized, double-blind, placebo-controlled study. ASH Annu Meet Abstr Blood. 2015;126(23).Google Scholar
  26. Kato T, Ogami K, Shimada Y, et al. Purification and characterization of thrombopoietin. J Biochem (Tokyo). 1995;118:229–36.CrossRefGoogle Scholar
  27. Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, et al. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin. 2010;26(10):2339–46.CrossRefPubMedGoogle Scholar
  28. Kuter DJ. Milestones in understanding platelet production: a historical overview. Br J Haematol. 2014;165(2):248–58.CrossRefPubMedGoogle Scholar
  29. Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci U S A. 1994;9(1):11104–8.CrossRefGoogle Scholar
  30. Kuter DJ, Bain B, Mufti G, et al. Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol. 2007;139(3):351–62.CrossRefPubMedGoogle Scholar
  31. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371:395–403.CrossRefPubMedGoogle Scholar
  32. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010;363(20):1889–99.CrossRefPubMedGoogle Scholar
  33. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241–8.CrossRefPubMedGoogle Scholar
  34. Lok S, Kaushansky K, Holly RD, et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature. 1994;369:565–8.CrossRefPubMedGoogle Scholar
  35. Mittelman M, Platzbecker U, Afanasyev B, et al. Thrombopoietin receptor agonist eltrombopag for advanced MDS or AML and severe thrombocytopenia: 12-week, randomized, placebo-controlled, phase 2 ASPIRE study. Haematologica. 2016;101(s1):15–6.Google Scholar
  36. Neunert C, Despotovic J, Haley K, et al. Thrombopoietin receptor agonist use in children: data from the pediatric ITP consortium of North America ICON2 study. Pediatr Blood Cancer. 2016;63(8):1407–13.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Novartis PROMACTA [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2016.Google Scholar
  38. Oliva EN, Santini V, Alati C, et al. Eltrombopag for the treatment of low and intermediate-1 IPSS risk myelodysplastic syndromes: interim results on efficacy, safety and quality of life of an international, multicenter prospective, randomized, trial. ASH Annu Meet Abstr Blood. 2015;91.Google Scholar
  39. Parameswaran R, Lunning M, Mantha S, et al. Romiplostim for management of chemotherapy-induced thrombocytopenia. Support Care Cancer. 2014;22(5):1217–22.CrossRefPubMedGoogle Scholar
  40. Platzbecker U, Wong RS, Verma A, et al. Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial. Lancet Haematol. 2015;2(10):e417–26.CrossRefPubMedGoogle Scholar
  41. Poon LM, Di Stasi A, Popat U, et al. Romiplostim for delayed platelet recovery and secondary thrombocytopenia following allogeneic stem cell transplantation. Am J Blood Res. 2013;3:260–4.PubMedPubMedCentralGoogle Scholar
  42. Popat U, Ray G, Basset R et al. Eltrombopag for post-transplant thrombocytopenia: results of phase II randomized double blind placebo controlled trial. ASH Annu Meet Abstr Blood 2015;738.Google Scholar
  43. Rizvi H, Butler T, Calaminici M, et al. United Kingdom immune thrombocytopenia registry: retrospective evaluation of bone marrow fibrosis in adult patients with primary immune thrombocytopenia and correlation with clinical findings. Br J Haematol. 2015;169(4):590–4.CrossRefPubMedGoogle Scholar
  44. Rodeghiero F. Is ITP a thrombophilic disorder? Am J Hematol. 2016;91:423–36.CrossRefGoogle Scholar
  45. Rodeghiero F, Carli G. Beyond immune thrombocytopenia: the evolving role of thrombopoietin receptor agonists. Ann Hematol. 2017;96(9):1421–34.  https://doi.org/10.1007/s00277-017-2953-6.CrossRefPubMedGoogle Scholar
  46. Rodeghiero F, Stasi R, Giagounidis A, et al. Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia: a pooled analysis of 13 clinical trials. Eur J Haematol. 2013;91:423–36.CrossRefPubMedGoogle Scholar
  47. Roth M, Will B, Simkin G, et al. Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation. Blood. 2012;120:386–94.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121:537–45.CrossRefPubMedGoogle Scholar
  49. Tarantino MD, Bussel JB, Blanchette VS, et al. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10039):45–54.CrossRefPubMedGoogle Scholar
  50. Townsley D, Dumitriu B, Scheinberg P, et al. Eltrombopag added to standard immunosuppression for aplastic anemia accelerates count recovery and increases response rates. Blood. 2015;126:LBA-2.CrossRefGoogle Scholar
  51. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376(16):1540–50.CrossRefPubMedPubMedCentralGoogle Scholar
  52. U.S. Food and Drug Administration. Eltrombopag. Available from www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=022291. Accessed 22 May 2017a.
  53. U.S. Food and Drug Administration. Romiplostim. Available from www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=125268. Accessed 22 May 2017b.
  54. Wang ES, Lyons RM, Larson RA, et al. A randomized, double-blind, placebo-controlled phase 2 study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate-1 risk myelodysplastic syndrome receiving lenalidomide. J Hematol Oncol. 2012;5:71.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Winer ES, Safran H, Karaszewska B, et al. Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study. Cancer Med. 2015;4(1):16–26.CrossRefPubMedGoogle Scholar
  56. Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373:35–47.CrossRefPubMedGoogle Scholar
  57. Zeigler FC, de Sauvage F, Widmer HR, et al. In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells. Blood. 1994;84(12):4045–52.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Pediatric Hematology/Oncology, Baylor College of Medicine/Texas Children’s HospitalHoustonUSA

Personalised recommendations