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DRUG REVIEW
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 105-110

Romiplostim – A narrative drug review


Department of Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Centre and Homi Bhabha Cancer Hospital, Tata Memorial Centre, Varanasi, Uttar Pradesh, India

Date of Submission10-Jan-2022
Date of Decision25-Feb-2022
Date of Acceptance11-Mar-2022
Date of Web Publication31-Mar-2022

Correspondence Address:
Anuj Gupta
Department of Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Center and Homi Bhabha Cancer Hospital (A Unit of Tata Memorial Center, Mumbai), Varanasi, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_17_22

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  Abstract 


Chemotherapy-induced thrombocytopenia (CIT) is a challenging condition that is routinely encountered in oncology practice. Currently, the sole therapeutic modality for CIT is the transfusion of platelets, especially when the platelet count is less than 20,000 per microliter. Chemotherapy dose reductions and dose delays result, which may lead to compromised outcomes. Drugs like oprelvekin and avatrombopag have been tried for CIT, but are not in routine use due to severe adverse effects. Romiplostim and eltrombopag are thrombopoietin receptor agonists that have been successfully used in benign conditions like idiopathic thrombocytopenic purpura (ITP), but are not approved for use in CIT. We searched PubMed for studies published in the last 5 years (2017–2021), using the key words “romiplostim,” “cancer,” and “malignancy”. We excluded articles that were related to benign causes of thrombocytopenia, articles for which the full text was not available, non-human studies, and articles in a language other than English. A total of 34 articles were included. In this narrative drug review, we have focused on romiplostim and the evidence supporting its use in both solid and hematologic malignancies.

Keywords: Chemotherapy-Induced Thrombocytopenia, hematologic malignancies, thrombocytopenia, solid tumors


How to cite this article:
Gupta A, Kapoor A, Choudhary A, Kumar S, Mishra BK. Romiplostim – A narrative drug review. Cancer Res Stat Treat 2022;5:105-10

How to cite this URL:
Gupta A, Kapoor A, Choudhary A, Kumar S, Mishra BK. Romiplostim – A narrative drug review. Cancer Res Stat Treat [serial online] 2022 [cited 2022 May 28];5:105-10. Available from: https://www.crstonline.com/text.asp?2022/5/1/105/341256




  Introduction Top


Thrombocytopenia is quite common in patients with cancer, occurring due to chemotherapy toxicity, infections, and/or bone marrow involvement by the tumor.[1] Chemotherapy regimens that include taxanes, nucleoside analogs like gemcitabine, and platinum compounds, especially carboplatin, account for up to 25% of cases of chemotherapy-induced thrombocytopenia (CIT).[2] CIT frequently leads to treatment interruptions, with resultant reduced dose intensity, which may compromise treatment efficacy and survival outcomes.[3],[4] Additionally, CIT necessitates chemotherapeutic dose reductions in subsequent cycles, which also detracts from the treatment outcomes. The only standard therapeutic option for severe CIT is platelet transfusion, which has its own limitations and logistic challenges.[3],[5]

In an observational study conducted in over 40,000 patients suffering from various non-hematologic malignancies (irrespective of the line of treatment), CIT was reported to occur in 52% cases. CIT was seen most commonly with gemcitabine-based regimens (64.2%), followed by taxane-based regimens (21.9%). When evaluated according to the primary disease site, colorectal (61.7%), non-small cell lung (50.5%), and ovarian cancer (45.6%) accounted for the majority of cases. Based on severity, grade 3 and 4 CIT most commonly developed in platinum and gemcitabine-based regimens (10.6%), followed by anthracycline-based regimens (5.2%).[2] CIT developed more frequently in later cycles of chemotherapy; 43.8% cases were seen in cycle 4, 37.8% in cycle 3, and only 0.6% in cycle 1.[5] The onset of CIT was usually within a week of the last chemotherapy dose, with the nadir platelet count reached at approximately day 14, followed by recovery to normal by the third to fourth week.[6]

The glycoprotein hormone, thrombopoietin, is synthesized primarily in the liver as a 353-amino acid precursor protein. Thrombopoietin is the primary growth factor for platelet production and is involved at virtually every step of platelet production from the stem cell stage through to the mature megakaryocyte (and possibly, platelet release).[7] Plasma thrombopoietin increases in response to a decline in platelet mass, especially if the number of megakaryocytes is reduced. In hematopoietic stem cells, stimulation of the thrombopoietin receptor results in signaling that influences quiescence, self-renewal, proliferation, and differentiation to megakaryocyte progenitors.[8] Drugs that have an agonistic effect on the thrombopoietin receptor lead to an increase in the platelet count and are thus effective in mediating transfusion independence in patients with immune thrombocytopenia.[8] The first-generation thrombopoietin receptor agonists provided suboptimal clinical benefit due to neutralizing antibodies against the host thrombopoietin.[8] Subsequently, second-generation thrombopoietin agonists were developed, such as eltrombopag and avatrombopag, which bypassed the neutralizing antibodies.[9] Romiplostim is one such second-generation thrombopoietin receptor agonist which has been used in chronic idiopathic thrombocytopenic purpura (ITP) for over a decade and has now been studied in CIT in solid and few hematologic malignancies.[10],[11]

In this review, we will outline the available evidence and discuss the clinical benefit achieved with romiplostim in patients with cancer.


  Methods Top


We performed an extensive PubMed search for full-text articles on romiplostim published in the last 5 years, that is, from 2017 to 2021, including meta-analyses, systematic reviews, randomized controlled trials, and case series, using the key words “romiplostim,” “cancer,” and “malignancy.” We excluded studies related to benign causes of thrombocytopenia, articles for which the full text was not available, non-human studies, and papers that were not in English. The methodology used is outlined in [Figure 1]. The United States Food and Drug Administration (FDA) website and the romiplostim package insert were reviewed to obtain the details regarding the chemical structure of the drug.
Figure 1: Flow diagram showing the detailed process whereby articles were selected for the drug review on romiplostim

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The key features of romiplostim are presented in [Table 1].
Table 1: Key features of romiplostim

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  Chemical Structure and Drug Class Top


Romiplostim is a peptibody molecule made from the fusion of two Fc peptides, each comprising 269 amino acids. The compound has a molecular weight of around 60 kDa.


  Mechanism of Action Top


Romiplostim interacts with the thrombopoietin receptor present on the megakaryocyte. It attaches to the thrombopoietin receptor at its distal domain and activates many downstream signal transduction pathways.[12] Romiplostim competitively binds to the thrombopoietin receptor, preventing the binding of the thrombopoietin ligand. Although romiplostim has a lower binding affinity for the thrombopoietin receptor, once bound, it rapidly leads to phosphorylation of the thrombopoietin receptor, resulting in activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, culminating in an increase in the platelet count via increased proliferation and decreased apoptosis of the megakaryocytes.[7]


  Dosing and Administration Top


Romiplostim is administered weekly by the subcutaneous route. It is initially dosed at 1 μg/kg/week subcutaneously. The dose can be increased in increments of 1 μg/kg to achieve the desired platelet count; the maximum dose should not exceed 10 μg/kg/week. Romiplostim should be stopped once the platelet count reaches 400 × 109/L.[13]

For patients with ITP, romiplostim should be slowly tapered (in steps of 2.5 μg/kg each month) if the platelet counts remain at 50°×109/L or higher and the patient is asymptomatic for at least 12 months. Stopping romiplostim suddenly may lead to rebound thrombocytopenia.[14]


  Metabolism and Clearance Top


Romiplostim has a half-life of 5–5.5 days and follows non-linear pharmacokinetics when given in the recommended dose range. The long half-life is the result of rapid internalization of romiplostim after it attaches to the neonatal Fc (FcRn) receptor. Subsequently, it is cleared by the reticuloendothelial system after being released by the cell into the systemic circulation. No dose adjustment is recommended in patients with hepatic or renal impairment.[12],[13]


  Toxicity Top


Overall, romiplostim is a well-tolerated drug. Adverse events that occur are usually mild to moderate and include post-injection headache (incidence ~35%), arthralgia (~26%), abdominal pain (11%), oropharyngeal pain (5%–15%), fatigue (~18%), and insomnia (16%).[15] Alarming adverse events include rebound severe thrombocytopenia (~38%), increased bone marrow reticulin (<1%), and increased proliferation of immunoblasts (3%).

Less common adverse events that occur in <10% of patients include dyspepsia (7%), paresthesia (6%), bronchitis (≥5%), cough (≥5%), peripheral edema (6%), and urticaria (5%). Few clinical trials have reported the occurrence of increased bone marrow fibrosis (<1%), which is reversible with drug discontinuation.[16],[17] Bone marrow fibrosis was more commonly seen in older patients with hematologic malignancies and immune-mediated pathology.[17]


  Romiplostim in Solid Malignancies Top


The efficacy of romiplostim in CIT has been reported in case reports,[18],[19],[20],[21] preclinical,[22] retrospective,[23],[24],[25] and clinical studies.[26],[27],[28] Some of the key studies are listed in [Table 2]. In one of the earliest studies by Entrena Ureña et al.[26] in 15 patients receiving chemotherapy, of whom 11 had non-hematologic malignancies, 13 (87%) achieved a response (defined as platelet counts >50 × 109/L) and 11 (73%) achieved platelet counts >100 × 109/L, allowing full-dose chemotherapy to continue. A multicenter study for the treatment of CIT in patients with solid tumors and lymphoid malignancies found that the median optimized dose was 3 μg/kg for the entire cohort, as well as for the sub-cohorts of solid and hematologic malignancies. Furthermore, romiplostim was found to be effective for the management of CIT in patients with solid tumors receiving a variety of chemotherapy regimens.[27]
Table 2: Various studies evaluating the efficacy of romiplostim in chemotherapy-induced thrombocytopenia

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  Romiplostim in Hematologic Disorders Top


Studies have shown that romiplostim is much more effective in CIT that develops in patients with solid tumors compared to hematologic malignancies.[23],[26] Safety and efficacy data were reported by Fenaux et al. in 60 patients with low risk myelodysplastic syndrome. Romiplostim therapy led to a platelet response in >80% of the patients that lasted for a median duration of 33 weeks with manageable toxicities; only 2 patients progressed to acute myeloid leukemia.[30] Greenberg et al. reported that in a double blind randomized trial of patients with low/intermediate risk myelodysplastic syndrome who had been treated with decitabine, romiplostim led to a lower platelet transfusion requirement and higher platelet counts compared to placebo.[31] Another study by Kantarjian et al. showed that romiplostim resulted in less transfusion dependency and fewer bleeding events compared to placebo.[32] Similarly, another randomized, double blind, placebo controlled Phase II study in patients with myelodysplastic syndrome showed a trend toward lower transfusion requirement with romiplostim in the low- and intermediate 1 (INT-1)-risk group treated with lenalidomide.[33] Giagounidis et al. reported that in patients with low/INT-1-risk myelodysplastic syndrome, romiplostim was associated with fewer bleeding complications and similar rates of progression to acute myeloid leukemia compared to placebo.[34]

Kantarjian et al.[32] conducted a Phase II, multicenter, double-blind trial to evaluate whether romiplostim potentially increased the risk of progression to acute myeloid leukemia. At 5 years of follow-up, the authors reported that the hazard ratio (HR) for transformation to acute myeloid leukemia and that for death did not differ between patients treated with romiplostim versus placebo, suggesting that the use of romiplostim was probably not associated with an increased risk of acute myeloid leukemia or death. Besides, high-dosage administration of granulocyte colony-stimulating factor (G-CSF) and romiplostim has been recommended for preventing severe acute radiation syndrome (ARS) in persons exposed to lethal total-body irradiation (TBI).[10] Some of the key studies related to the use of romiplostim in hematological malignancy are listed in [Table 3].
Table 3: Key trials of romiplostim in patients with hematologic disorders

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Additional large-scale prospective, randomized trials are needed to define the role of romiplostim in patients with hematologic malignancies.


  Special Populations Top


Pregnancy:

There is a lack of data on the safety and efficacy of romiplostim in pregnant women. Animal studies have shown that romiplostim crosses the placental barrier and causes adverse effects on the fetus, like an abnormal rise in the platelet count and embryotoxicity. There is no clear US FDA recommendation for the use of romiplostim in pregnancy. Patients who become pregnant while on romiplostim treatment are encouraged to enroll in patient surveillance programs. The FDA label states that the drug should not be used during pregnancy unless the benefit outweighs the risk to the fetus. US FDA pregnancy category: Not assigned

Lactation:

It is unclear whether romiplostim is secreted in the breast milk. Hence, the decision regarding the use of romiplostim in lactating women should be taken carefully, after weighing the risks and the benefits. There is no clear-cut FDA recommendation for its use in lactating women. The decision to discontinue breastfeeding or the drug should be made after taking into account the importance of the drug for the mother.

Pediatric use:

The FDA has approved the use of romiplostim in patients who are 1 year of age and older and have been diagnosed with ITP for at least 6 months and have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Geriatric population:

Overall, there is no difference in the safety and efficacy of romiplostim when used in older and younger patients. In general, dose adjustment for an older patient should be cautiously evaluated, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.[10]


  Limitations Top


Currently, the literature on the use of romiplostim for thrombocytopenia in patients with cancer is limited to case reports or small single-center studies.[18],[19],[20],[21] The available evidence suggests that romiplostim can effectively increase the platelet count in patients with cancer. However, robust multicenter studies to support such use are lacking, which precludes its approval for use in CIT by the regulatory authorities. Predictors of non-response to romiplostim, the optimal dosing regimen, and its utilization in non-myeloid hematologic malignancies like lymphoma and myeloma are yet to be studied.

Further studies should evaluate and report more relevant outcome measures beyond a mere increase in the platelet count, like treatment resumption without further reduction in the dose of chemotherapy or treatment delay. Data on the safety profile, especially bleeding or thrombosis, are scant. The possible association of romiplostim with an increased risk of venous thrombosis, which could be significant in patients with cancer who are already at an increased risk due to the malignancy and therapy, needs to be explored in detail.


  Conclusions Top


Romiplostim effectively increases the platelet count in patients with cancer, although the data are limited. The management of thrombocytopenia in patients with cancer remains an off-label use of romiplostim. However, there is a role for the use of romiplostim in desperate situations where overcoming CIT is essential for optimal treatment outcomes. The risks and benefits of the treatment should be weighed in each patient before prescribing romiplostim.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.[36]



 
  References Top

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Kuter DJ, Tarantino MD, Lawrence T. Clinical overview and practical considerations for optimizing romiplostim therapy in patients with immune thrombocytopenia. Blood Rev 2021;49:100811.  Back to cited text no. 14
    
15.
Leader A, Hofstetter L, Spectre G. Challenges and advances in managing thrombocytopenic cancer patients. J Clin Med 2021;10:1169.  Back to cited text no. 15
    
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Wun T, White RH. Epidemiology of cancer-related venous thromboembolism. Best Pract Res Clin Haematol 2009;22:9-23.  Back to cited text no. 16
    
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Khorana AA, Dalal M, Lin J, Connolly GC. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer 2013;119:648-55.  Back to cited text no. 17
    
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Hassan BA, Yusoff ZB, Hassali MA, Bin Othman S. Treatment patterns and outcomes in management of solid cancer patients suffering from thrombocytopenia in Penang hospital. Asian Pac J Cancer Prev 2011;12:2841-5.  Back to cited text no. 19
    
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Demeter J, Istenes I, Fodor A, Paksi M, Dombi P, Valasinyószki E, et al. Efficacy of romiplostim in the treatment of chemotherapy induced thrombocytopenia (CIT) in a patient with mantle cell lymphoma. Pathol Oncol Res 2011;17:141-3.  Back to cited text no. 20
    
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23.
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30.
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