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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 1  |  Page : 19-21

Initial data on clinical use of generic romiplostim for second-line and subsequent therapy of immune thrombocytopenia in India


Department of Clinical Hematology and Stem Cell Transplantation, Dayanand Medical College and Hospital, Ludhiana, Punjab, India

Date of Submission31-Aug-2020
Date of Acceptance10-Oct-2020
Date of Web Publication06-Jan-2021

Correspondence Address:
Dr. Suvir Singh
Department of Clinical Hematology and Stem Cell Transplantation, Dayanand Medical College and Hospital, Ludhiana - 141 001, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injms.injms_105_20

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  Abstract 


Introduction: Over 50% of adults with immune thrombocytopenia (ITP) require second-line therapy after steroids, but these options are plagued by low rates of response, which are often delayed by 2–3 months. Romiplostim is a thrombopoietin receptor agonist (TPO-RA) that has shown significant efficacy in this setting and is now available in a generic formulation. No data on the efficacy and safety of the same are available in the India context. Methodology: This study was conducted from August 2019 to July 2020. Romiplostim was used for patients with ITP that was (a) steroid or intravenous immunoglobulin (IvIg) refractory or (b) not responding to other second-line agents. Results: A total of 11 patients were included in the analysis (M:F = 6:5) with a median age of 44 years (range, 18–67). Initial therapy was corticosteroids for all patients of which nine (81%) had an initial response. Second-line therapy included azathioprine for six patients (54%) and IvIg for four (36%) patients. All patients were refractory to the second-line therapy and initiated on romiplostim at a median dose of 3.68 μg/kg/week (range, 2.7–6.2). A sustained response was observed in 10 patients (90.9%) after a median duration of 13 days (range, 2–32). At a median follow-up of 5.5 months, nine patients (81%) had stable platelet counts. Conclusion: Initial data suggest that generic romiplostim is an effective and safe second-line medication for ITP and can potentially avoid splenectomy in steroid and IvIg refractory patients. Prospective follow-up of more patients will provide a better perspective on efficacy and cost-effectiveness of TPO-RAs.

Keywords: Cost, immune thrombocytopenia, India, platelets, thrombocytopenia


How to cite this article:
Singh S, Kaur K. Initial data on clinical use of generic romiplostim for second-line and subsequent therapy of immune thrombocytopenia in India. Indian J Med Spec 2021;12:19-21

How to cite this URL:
Singh S, Kaur K. Initial data on clinical use of generic romiplostim for second-line and subsequent therapy of immune thrombocytopenia in India. Indian J Med Spec [serial online] 2021 [cited 2021 Apr 15];12:19-21. Available from: http://www.ijms.in/text.asp?2021/12/1/19/306244




  Introduction Top


Immune thrombocytopenia (ITP) is characterized by immune-mediated destruction of platelets, leading to isolated thrombocytopenia. Up to 70% of adult patients require second-line therapy after initial treatment with steroids, and the second-line and subsequent therapies for ITP are not well defined.[1] Description of newer mechanisms of platelet destruction in ITP have enabled the development of novel therapies, the most important being thrombopoietin receptor agonists (TPO-RAs).[2] Before the availability of TPO-RAs, splenectomy was the preferred second-line option for steroid or intravenous immuneglobulin (IvIg) refractory ITP.[3] Both TPO-RAs, eltrombopag and romiplostim have demonstrated response rates ranging from 74% to 90% in published data with a rapid onset of action.[4],[5] However, these agents were confined to a few select patients due to high costs and need of indefinite therapy. Introduction of generic romiplostim in 2019 provided a feasible second-line option for patients with refractory or chronic ITP. No prospective data are available on the efficacy of romiplostim in the Indian setting. We describe the first data on the clinical use of generic romiplostim as the second- or third-line therapy in steroid and IvIg refractory patients with ITP in the Indian scenario.


  Methodology Top


Study design and setting

This study was a prospective, observational study conducted over 12 months from August 2019 to July 2020 in the department of Clinical hematology and stem cell transplantation. Patients who received second-line or subsequent therapy for ITP with romiplostim were included in the analysis. The International Working Group for ITP definitions were used to standardize terminology throughout the study.[6] Owing to lack of standardized guidelines for second-line therapy, the choice of therapy was based on the physician preference. Criteria for usage of romiplostim included were as follows: (a) as third line after failure of steroids or IvIg and (b) after lack of response to the second-line oral agents (danazol, dapsone, or azathioprine) after 6–8 weeks of treatment. Romiplostim was administered at a dosage of 5 μg/kg subcutaneously once a week, and concomitant immunosuppressive maintenance therapy was allowed to continue. Platelet counts were checked weekly, and doses were withheld if platelet counts were above 450,000/μl. Response to therapy was adapted from Phase 2 trials of romiplostim and defined as a platelet count of more than 50,000/μl on treatment.[7] For patients who achieved a stable platelet count, the duration between consecutive doses was gradually increased.


  Results Top


A total of 11 patients were included in the analysis over a 12-month period. This included six males and five females, with a median age of 44 years (range, 18–67). All patients had primary ITP and autoimmune markers were negative. All patients received steroids as the first-line therapy. The median dose of prednisolone as an initial therapy was 0.87 mg/kg/day (range, 0.67–25). In the entire cohort, nine patients achieved an initial response to steroids and two patients had steroid refractory disease. Baseline data of the patients are summarized in [Table 1]. Second-line therapy included azathioprine in six patients, IvIg in four patients, and romiplostim directly in one patient. The maximum median dose of azathioprine was 1.19 mg/kg/day (range, 0.74–1.54) and IvIg was 0.97 g/kg (range, 0.71–1.01). Romiplostim was used as a third-line option for all patients except one, who was directly initiated on romiplostim after failure of prednisolone. The indications for initiation of romiplostim were categorized as thrombocytopenia alone in seven patients, minor bleeding in three patients, and major bleeding in one patient. The median platelet count at starting romiplostim was 21,000/μl (range, 4000–30,000) and the median starting dose was 3.68 μg/kg/week (range, 2.7–6.2).
Table 1: Baseline characteristics of the patients

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The median time to any platelet response was 13 days (range, 2–32). The initial response rate was 100%, but clinically relevant durable response rate was 90.9%, owing to loss of response in one patient after 2 weeks of therapy. The median peak platelet count documented was 235,000/μl (range 74,000–837,000). Two patients developed thrombocytosis, which was asymptomatic and reversible on stopping romiplostim.

Due to COVID-19–related lockdown, many patients were unable to follow-up regularly and the telephonic follow-up was obtained from all patients after initial therapy. One patient, a 68-year-old woman with systemic hypertension was lost to follow-up and not contactable. All other patients were stable without any new symptoms. The median duration of follow-up was 166 days (range, 10–373), and no other adverse events were reported.


  Discussion Top


ITP is characterized a wide range of manifestations ranging from asymptomatic disease to life-threatening hemorrhage and has a negative impact on health-related quality of life.[8] Over 60%–70% of adult patients with ITP require second-line therapy for relapsed or refractory disease. Our experience with generic romiplostim demonstrates an overall response rate of 91% with rapid onset of action and minimal toxicity. Apart from one patient who was lost to follow-up, all other patients are stable after a median follow-up of 5.5 months.

Second-line therapy of ITP is contentious due to lack of head-to-head trials among various agents. Second-line agents include oral immunomodulators (azathioprine, dapsone, danazol, and cyclosporine), TPO-RAs (romiplostim and eltrombopag), low-dose chemotherapeutic agents (cyclophosphamide, vincristine), rituximab, or splenectomy.[9] Most data on efficacy and safety of second-line therapy is available from observational studies, and response rates of 40%–60% after a 4–6 week delay are typical.[10] Adult patients requiring second-line therapy of ITP can be refractory to steroids/IvIg (10%–15% patients) or achieve a response and then relapse (approximately 50%–60% patients).[11] TPO-RAs have demonstrated significant efficacy in both groups compared to other agents for second-line therapy. The most enduring impact of the same is visible in the ASH 2019 guidelines, which place TPO-RAs on equal footing with splenectomy and recommend them for patients who are not willing for surgery.[12] Our dataset reflects the same, and in the absence of TPO-RAs, most patients would have otherwise been advised splenectomy, which can now possibly be relegated as the “last” option in ITP.

Rapidity of platelet responses with TPO-RAs is a unique feature and is described to occur at a median of about 2 weeks.[7] We note a similar timeframe, with a median time to response of 13 days.[13] Due to fixed strength of the available vials, overdosing or underdosing may inadvertently occur due to variable patient weight. The median dose used in our study (3.68 μg/kg/week) was lower than the recommended dose (5 μg/kg/week). This warrants further investigation as it may help bring down costs of treatment.

This is the first study from India documenting the clinical use of generic romiplostim in patients with refractory or chronic ITP. The small size of the initial cohort and single-center nature of data are possible limitations.

This observational study allows for two pertinent conclusions. First, generic romiplostim emerges as an effective treatment option for second-line or subsequent treatment of ITP, with high response rates, minimal toxicity, and a short time to response. Second, on a more pensive note, the lack of published Indian data on the second-line treatment of ITP is conspicuous. As cost is a significant determinant of treatment choice in India, the evaluation of “older” agents such as azathioprine, dapsone, and danazol is a significant unmet need. The cost of these agents is markedly lower than even the generic version of romiplostim, and their true efficacy should not stay obscured due to lack of prospective data. Generic romiplostim may be recommended for steroid or IvIg refractory patients as an effective rescue medication.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Stasi R, Stipa E, Masi M, Cecconi M, Scimò MT, Oliva F, et al. Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med 1995;98:436-42.  Back to cited text no. 1
    
2.
Grodzielski M, Goette NP, Glembotsky AC, Pietto MC, Méndez-Huergo SP, Pierdominici MS, et al. Multiple concomitant mechanisms contribute to low platelet count in patients with immune thrombocytopenia. Sci Rep 2019;9:2208.  Back to cited text no. 2
    
3.
Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr., Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011;117:4190-207.  Back to cited text no. 3
    
4.
Kuter DJ, Bussel JB, Newland A, Baker RI, Lyons RM, Wasser J, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: Safety and efficacy. Br J Haematol 2013;161:411-23.  Back to cited text no. 4
    
5.
Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): A 6-month, randomised, phase 3 study. Lancet 2011;377:393-402.  Back to cited text no. 5
    
6.
Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: Report from an international working group. Blood 2009;113:2386-93.  Back to cited text no. 6
    
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Newland A, Godeau B, Priego V, Viallard JF, Fernández MF, Orejudos A, et al. Remission and platelet responses with romiplostim in primary immune thrombocytopenia: Final results from a phase 2 study. Br J Haematol 2016;172:262-73.  Back to cited text no. 7
    
8.
Sestøl HG, Trangbæk SM, Bussel JB, Frederiksen H. Health-related quality of life in adult primary immune thrombocytopenia. Expert Rev Hematol 2018;11:975-85.  Back to cited text no. 8
    
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Depré F, Aboud N, Mayer B, Salama A. Efficacy and tolerability of old and new drugs used in the treatment of immune thrombocytopenia: Results from a long-term observation in clinical practice. PLoS One 2018;13:e0198184.  Back to cited text no. 9
    
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Grace RF, Neunert C. Second-line therapies in immune thrombocytopenia. Hematology Am Soc Hematol Educ Program 2016;2016:698-706.  Back to cited text no. 10
    
11.
Godeau B, Caulier MT, Decuypere L, Rose C, Schaeffer A, Bierling P. Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: Results of a randomized trial comparing 0.5 and 1 g/kg b.w. Br J Haematol 1999;107:716-9.  Back to cited text no. 11
    
12.
Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv 2019;3:3829-66.  Back to cited text no. 12
    
13.
Kuter DJ, Rummel M, Boccia R, Macik BG, Pabinger I, Selleslag D, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010;363:1889-99.  Back to cited text no. 13
    



 
 
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