| Abstract|| |
Context and Aims: To evaluate the efficacy and safety of biosimilar romiplostim in Indian patients with immune thrombocytopenic purpura (ITP). Settings and Design: Multicentre, retrospective observational study. Methods and Material: Patients with chronic ITP who received biosimilar romiplostim from July 2019 to March 2020 across 3 major hospitals in Guwahati, India, were included. The study outcomes were the platelet response (platelet count > 50 × 109/L), time to first response, number of dose-limiting events, and the median effective dose. Statistical Analysis Used: Descriptive. Results: Of 32 patients included in this analysis, majority (59.4%) were females. The mean (SD) age was 40.37 (15.79) years, and mean age at ITP diagnosis was 38.53 years. The median number of romiplostim doses were 27.5 (range: 10-42) over a period of 10 months; median romiplostim dose used was 4.2 μg/kg (range: 2.8-5 μg/kg). Platelet response was achieved as early as after one week in 9 (28.12%) patients, which continued to increase to 24 (75%) patients after the second, 30 (93.75%) patients after the third and all 32 (100%) patients after four weeks of romiplostim administration. The median platelet count was 161 × 109/L. Dose reduction was done in a total of 21 patients. Thrombocytosis (46.88%), elevated liver enzymes (15.63%) and myalgia (15.63%) were the most common adverse events. Conclusions: Biosimilar romiplostim was effective in achieving and maintaining platelet response without any new safety concerns in Indian adult patients with chronic ITP. The median effective dose of romiplostim required in our patients was lower as compared with the standard prescribed dose.
Keywords: Biosimilar, chronic, immune thrombocytopenia, refractory, romiplostim
|How to cite this article:|
Iqbal A, Sharma C, Bora RL, Phukan A. Efficacy and safety of biosimilar romiplostim in Indian patients with chronic immune thrombocytopenia: A multicentric retrospective study. Indian J Pathol Microbiol 2023;66:96-100
|How to cite this URL:|
Iqbal A, Sharma C, Bora RL, Phukan A. Efficacy and safety of biosimilar romiplostim in Indian patients with chronic immune thrombocytopenia: A multicentric retrospective study. Indian J Pathol Microbiol [serial online] 2023 [cited 2023 Feb 8];66:96-100. Available from: https://www.ijpmonline.org/text.asp?2023/66/1/96/367933
| Introduction|| |
Idiopathic thrombocytopenic purpura (ITP) is an acquired disease in children and adults resulting from antibody- and cell-mediated destruction of platelets and suppression of platelet production by the bone marrow (BM) megakaryocytes that may predispose to mucocutaneous bleeding.,,, It is characterized by low platelet counts < 100 × 109/L with normal morphology of red and white blood cells. Normal-to-large platelets can be seen with peripheral blood smears and bone marrow appears normal, with the absence of other causes., The incidence of ITP is estimated to be higher in adults (3.3/100,000/year) as compared with children (1.9 to 6.4/100,000/year). If the ITP lasts for >12 months, it is considered as chronic ITP - a serious and life threatening condition that affects women more than men at a rate of approximately 1.3:1 to 3:1., A low platelet count persisting after splenectomy and which requires treatment to maintain a 'safe' platelet count (range: ≤20 × 109/L to ≤50 × 109/L) is commonly referred as refractory ITP. These criteria are eventually met by <10% of patients initially diagnosed with ITP.
Current therapeutic armamentarium of chronic ITP includes corticosteroids, intravenous immunoglobulins, splenectomy, rituximab, danazol and cyclophosphamide, which primarily focus on reducing platelet destruction., In recent years, a novel non-immunologic therapeutic approach by stimulating platelet production has led to the development of several types of thrombopoiesis-stimulating agents (eg, thrombopoietin [TPO] receptor agonists). The American Society of Hematology (ASH) 2011 evidence-based guideline for ITP recommends TPO receptor agonists for patients at risk of bleeding who relapse after splenectomy or who have a contraindication to splenectomy and who have failed at least one other therapy.
Romiplostim and eltrombopag are thrombopoietic agents that stimulate platelet production, and have shown to increase platelet counts in both healthy adults, and patients with ITP., Romiplostim appeared to maintain platelet levels ≥50000/μL in durable responders from both splenectomised and non-splenectomised populations. Furthermore, the long-term safety results, and the ability to maintain platelet levels in durable responders over extended periods of time with romiplostim have been evidenced. Romiplostim has also demonstrated efficacy in patients with chronic ITP refractory to corticosteroids, immunoglobulins, or splenectomy. The current study aimed to evaluate the efficacy and safety of biosimilar romiplostim from Intas Pharmaceuticals Ltd. in Indian patients with chronic ITP.
| Subjects and Methods|| |
Study design and population
This retrospective observational study describes treatment with weekly romiplostim in adult patients with chronic ITP. Indian patients of either sex, diagnosed with ITP according to the ASH guidelines, who had received romiplostim were included in this analysis.
Platelet counts were performed weekly during the study. If the patient's platelet count was < 50000/μL, the dose was increased by 1 μg/kg; if >400000/μL, the drug was not administered. After the platelet count reduced to <200000/μL, romiplostim was resumed at a dose reduced by 1 μg/kg. Romiplostim doses are not altered during the 1st 4 weeks. Adverse event (AE) monitoring was performed weekly throughout the study.
Stable doses of corticosteroids, azathioprine or danazol were allowed and the doses could be reduced or discontinued after platelet counts reached 50000/μL. Rescue medications including platelet transfusions, steroids and anti-fibrinolytics could be administered when platelets counts were <10000/μL.
The efficacy outcome was the proportion of patients achieving platelet response defined as a platelet count at a scheduled weekly visit of ≥ 50000/μL. Other study outcomes were the median platelet count during the study, and the proportion of patients with at least one dose reduction. Safety and tolerability assessments included the incidence and type of AEs. The AEs leading to the romiplostim dose reduction were measured.
Demographic and baseline characteristics were summarized descriptively. Platelet response was summarized descriptively as both number and percentage for platelet response. Descriptive statistics for platelet count at a scheduled weekly visit were summarized. Proportion of patients who had rescue medication at each visit was presented as both number and percentage.
| Results|| |
Patient disposition and demographics
A total of 32 consecutive patients were included in this study. The study population was 100% Asian (all Indian) with (40.6%) males and (59.4%) females. The mean (SD) age of the population was 40.37 (15.79) years. The mean age at ITP diagnosis was 38.53 years [Table 1].
The patients were administered subcutaneous biosimilar romiplostim at a starting dose of 4-10 μg/kg every week. The median number of romiplostim doses used in this study was 27.5 (range: 10-42) over a period of 10 months. The mean romiplostim dose used was 4.51 μg/kg (range: 3.19-6.15 μg/kg), and the median romiplostim dose was 4.2 μg/kg (range: 2.8-5 μg/kg). A total of 5 patients were administered > 5 μg/kg mean romiplostim dose, of which 3 patients were initiated at 10 μg/kg dose; 1 patient also received platelet transfusion who had very low baseline platelet counts of 3000/μL.
Platelet response was achieved as early as after one week in 9 (28.12%) patients, which continued to increase to 24 (75%) patients after the second, 30 (93.75%) patients after the third and all 32 (100%) patients after four weeks of romiplostim administration [Figure 1]. The platelet counts decreased below 50 × 109/L in 2 patients by Week 5. After 1 month of romiplostim treatment, 3 patients had > 400 × 109/L platelet count.
|Figure 1: Platelet response post biosimilar romiplostim administration in patients (n = 32) with chronic ITP. ITP, immune thrombocytopenic purpura|
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The median platelet count was 161 × 109/L during the study. During the first month of romiplostim treatment, a marked improvement in the median platelet count was observed from baseline [Figure 2].
In 7 patients, standard doses of prednisolone were also used during the first month followed by rapid taper. Many patients (21/32) required dose reduction. The median effective dose of romiplostim was found to be 4.2 μg/kg (2.8-5 μg/kg).
One patient required temporary treatment cessation due to thrombosis. The most common AE was thrombocytosis (46.88%) followed by elevated liver enzymes (15.63%) and myalgia (15.63%) [Table 2]. None of the patients had breakthrough bleeding during treatment, and none required secondary management for thrombocytopenia.
| Discussion|| |
Romiplostim has been approved for the treatment of thrombocytopenia in adult patients with ITP or pediatric (≥1 years of age) patients with ITP for ≥6 months, inadequately responding to the corticosteroids, immunoglobulins, or splenectomy. Recently, romiplostim has also been approved by the US Food and Drug Administration (USFDA) for earlier use in newly diagnosed and persistent adult ITP. A review article of studies that evaluated the efficacy and safety in ITP patients reported significant platelet response in 75% of the patients receiving romiplostim (N = 303 from 4 studies) whereas 69% of the patients receiving eltrombopag (N = 448 from 5 studies). The safety profile of both the agents was generally well-tolerated.
This retrospective data collection study demonstrated the efficacy of biosimilar romiplostim once-weekly injection as determined by the primary efficacy measure, i.e., the proportion of patients achieving platelet response defined as a platelet count at a scheduled weekly visit of ≥50000/μL, in adult Indian patients with chronic ITP. Platelet response was achieved as early as one week in 9 (28.12%) patients, and all 32 (100%) patients after Week 4 of romiplostim administration. In a single arm, open label study, approximately 50% patients achieved platelet response at the end of 8 weeks with romiplostim administration. None of the patients in our study required the use of rescue medication for ITP, which shows good response of romiplostim in maintaining platelet counts. Though data for an active comparator or placebo group was not assessed in this study, the marked change from baseline for platelet response is noteworthy with the romiplostim treatment.
The efficacy results of this study are further substantiated with similar results from two pivotal, placebo-controlled, phase-3 trials, which were conducted in parallel at centers in the US and Europe in splenectomized (platelet responders: 16/42 [38%]) and non-splenectomized (25/41 [61%]) patients with chronic ITP, where platelet response was defined as platelet counts ≥50 × 109/L during six or more of the last 8 weeks of treatment. In Japanese patients, romiplostim (n = 22) at a dose of 3 μg/kg weekly for 12 weeks demonstrated platelet responses of ≥50 × 109/L in 95% of the patients. The median effective dose of romiplostim was 4.2 μg/kg (2.8-5 μg/kg) in our patients, which is lower than the standard prescribed dose (5-8 μg/kg).
In a 156-week long-term study by Bussel et al. in adult patients (n = 142) with chronic ITP, weekly subcutaneous administration of romiplostim resulted in a platelet response in 87% patients at one or more points during the study, comparable to all 100% patients achieving platelet response at least once during our study.
Thrombopoietin receptor agonists (romiplostim and eltrombopag) are recommended for patients at risk of bleeding who relapse after splenectomy or who have a contraindication to splenectomy and failed at least one other therapy. Effectiveness of romiplostim and eltrombopag for increasing platelet counts was compared in a meta-analysis. The indirect evidence suggests that romiplostim significantly improves overall platelet response compared with eltrombopag. There was no significant difference in durable platelet response in any of the analyses, although the direction of effect favored romiplostim (odds ratio [OR] = 0.15; 95% credible interval, 0.01-1.88); P values and Bayesian posterior probabilities ranged from 0.08 to 0.40 across analyses. Moreover, romiplostim has been shown to be effective in eltrombopag resistant/intolerant cases. In a retrospective evaluation of switching thrombopoietic receptor-agonists in ITP, out of 10 patients who failed to respond to the maximum eltrombopag dose and switched to romiplostim, complete response was seen in 50% patients where only 2 (20%) patients failed to respond to romiplostim given at its maximum dose (10 μg/kg/week). Overall, the above data favors romiplostim as an important therapeutic agent for adult Indian patients with chronic ITP.
To our knowledge, innovator romiplostim has not been launched in India, and a biosimilar romiplostim (ROMY of Intas Pharmaceuticals Limited) has been approved by the Indian drug regulators for ITP management. The biosimilar romiplostim was developed with an intent to provide access to Indian patients, with a cost-effective alternative. Romiplostim had an acceptable safety profile consistent with that observed in the long-term, open-label, single-arm study. The study limitations included the retrospective nature and a lack of comparator group to better assess the efficacy and minimize the possible confounding variables. Also, the platelet counts were not available for all patients at all timepoints. The details of platelet count at each visit is provided in the [Figure 2] for median platelet counts in this study.
In conclusion, our study suggests that subcutaneous administration of biosimilar romiplostim was effective in increasing the platelet counts and well-tolerated in adult Indian patients with chronic immune thrombocytopenic purpura and can be considered as an important therapeutic option in this group of patients.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 2009;113:2161-71.
Chalmers S, Tarantino MD. Romiplostim as a treatment for immune thrombocytopenia: A review. J Blood Med 2015;6:37-44.
Provan D, Newland AC. Current management of primary immune thrombocytopenia. Adv Ther 2015;32:875-87.
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.
Terrell DR, Beebe LA, Vesely SK, Neas BR, Segal JB, George JN. The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports. Am J Hematol 2010;85:174-80.
Frederiksen H, Schmidt K. The incidence of idiopathic thrombocytopenic purpura in adults increases with age. Blood 1999;94:909-13.
Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Taylor PR. Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: A prospective study of a population-based cohort of 245 patients. Br J Haematol 2003;122:966-74.
Ruggeri M, Fortuna S, Rodeghiero F. Heterogeneity of terminology and clinical definitions in adult idiopathic thrombocytopenic purpura: A critical appraisal from a systematic review of the literature. Haematologica 2008;93:98-103.
Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001;97:2549-54.
Patel H, Patel N, Vyas A, Patel M, Pandey S. Romiplostim: A novel c-Mpl/CD110 receptor ligand for the management of idiopathic thrombocytopenic purpura. J Clin Diagn Res 2009;3:1690-6.
Palau J, Jarque I, Sanz MA. Long-term management of chronic immune thrombocytopenic purpura in adults. Int J Gen Med 2010;3:305-11.
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.
Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther 2004;76:628-38.
Jenkins JM, Williams D, Deng Y, Uhl J, Kitchen V, Collins D, et al
. Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist. Blood 2007;109:4739-41.
Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, et al
. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007;357:2237-47.
Bussel JB, Kuter DJ, George JN, McMillan R, Aledort LM, Conklin GT, et al
. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 2006;355:1672-81.
Shirasugi Y, Ando K, Miyazaki K, Tomiyama Y, Okamoto S, Kurokawa M, et al
. Romiplostim for the treatment of chronic immune thrombocytopenia in adult Japanese patients: A double-blind, randomized phase III clinical trial. Int J Hematol 2011;94:71-80.
Nplate (romiplostim). Now Approved for Earlier Use in Adults with Immune Thrombocytopenia. Thousand Oaks, CA: Amgen; 2019.
Bidika E, Fayyaz H, Salib M, Memon AN, Gowda AS, Rallabhandi B, et al
. Romiplostim and eltrombopag in immune thrombocytopenia as a second-line treatment. Cureus 2020;12:e9920.
Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, et al
. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: A double-blind randomised controlled trial. Lancet 2008;371:395-403.
Cooper N, Terrinoni I, Newland A. The efficacy and safety of romiplostim in adult patients with chronic immune thrombocytopenia. Ther Adv Hematol 2012;3:291-8.
Khellaf M, Viallard JF, Hamidou M, Cheze S, Roudot-Thoraval F, Lefrere F, et al
. A retrospective pilot evaluation of switching thrombopoietic receptor-agonists in immune thrombocytopenia. Haematologica 2013;98:881-7.
Department of Medical Oncology, Dr. Bhubaneswar Barooah Cancer Institute, Gopinath Nagar, Guwahati, Assam
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2]