What data are available to support switching between thrombopoietin receptor agonists in patients with immune thrombocytopenia?

Introduction
Immune thrombocytopenia (ITP) is an acquired thrombocytopenia caused by antibodies that target platelet antigens, resulting in platelet destruction with or without impairment of platelet production.¹ The goal of treatment of ITP is to reach a sustained increase in platelet count that is considered hemostatic for a given patient while also avoiding adverse effects.² In 2019, the American Society of Hematology (ASH) and an international expert panel issued recommendations regarding the treatment of this condition.^2,3 Short-courses of oral corticosteroids are typically the first-line treatment for newly diagnosed ITP to halt the destruction of platelets.² Second-line options for treatment of ITP are generally reserved for patients with severe bleeding or those with recurrent thrombocytopenia following corticosteroid treatment, and include thrombopoietin receptor agonists (TPO-RAs), rituximab, and splenectomy. The ASH guideline recommends the use of second-line agents in patients with ITP for at least 3 months or who are corticosteroid-dependent or unresponsive to corticosteroids. Decisions regarding second-line treatment are highly patient-specific and must consider the comparative risks and benefits of available approaches, including their mechanism, efficacy, and adverse effects. Furthermore, the ASH guideline suggests that TPO-RAs may be preferred in patients who place a high value on achieving a durable response, as TPO-RAs are associated with higher rates of durable response compared to rituximab.

Pharmacology
Thrombopoietin (TPO), a glycoprotein produced primarily in the liver but also in the kidneys and bone marrow, is the primary regulator of platelet production.⁴ Upon binding to TPO receptors on megakaryocytes, hematopoietic stem cells, and platelets themselves, TPO stimulates the proliferation and differentiation of megakaryocytes, resulting in increased platelet production. The TPO-RAs mimic the function of TPO, albeit these agents are functional rather than structural TPO mimetics, because they lack sequence homology to endogenous TPO. It has been proposed that since these agents do not bear any structural similarity to native TPO, they should not trigger autoimmune, anti-TPO antibodies, which have occurred with previous TPO mimetics leading to their discontinuation.

Table 1 provides a comparison of TPO-RAs approved for use in patients with ITP.^4,5,6,7 TPO-RAs differ in their molecular structure, pharmacokinetic profile, and the manner in which they stimulate the TPO receptor.⁴ Avatrombopag and eltrombopag are orally administered non-peptide agents derived from small molecule screening techniques. Romiplostim is an injectable peptide TPO-RA; this agent is composed of immunoglobulin heavy chains that contribute to the agent’s longer duration of action. Romiplostim is also the only TPO-RA that binds at the same site as endogenous TPO; the other agents bind at alternative sites on the TPO receptor. Pharmacokinetic analyses have demonstrated that peak platelet counts with maximal doses of romiplostim were 8 to 10 times higher versus those achieved with eltrombopag, and peak platelet counts with maximal doses of avatrombopag were 3 to 5 times higher versus those achieved with eltrombopag. Furthermore, lower endogenous TPO levels (≤100 pg/ mL) have been shown to predict an increased response to eltrombopag and romiplostim, as compared with higher TPO levels (>200 pg/mL).

Switch Data
Pharmacologic differences amongst the TPO-RAs appear to have clinically relevant effects, and patients with ITP who experience toxicity or lack of efficacy with one TPO-RA may benefit from switching to an alternate TPO-RA.⁴ While the ASH guidelines do not discuss switching between TPO-RAs, a 2019 international expert panel states that switching from one TPO-RA to another and sequential therapy have been shown to have a positive effect on efficacy and safety outcomes.³

In a 2019 systematic review, 18 retrospective cohort studies (N=401) that reported on platelet response after switching from eltrombopag to romiplostim and vice versa were identified and data were descriptively described.⁸ The primary reason for switching was lack of efficacy (58%). Non-efficacy-related reasons for switching included adverse events (AEs), patient preference, and platelet count fluctuations. After switching, 77.5% of patients achieved or maintained a platelet response, and 93% of patients who switched due to reasons other than lack of efficacy maintained their response after switching. Although the rate of switching due to safety and tolerability was comparable between agents, switching due to platelet count fluctuations was reported exclusively in patients who received romiplostim.

Table 2 summarizes more recently published studies, all of which further support the findings of the systematic review.^9-11 The first study was a small (N=44) retrospective cohort of adults with ITP at 4 sites in the United States and reported outcomes in patients who switched from eltrombopag or romiplostim to avatrombopag.⁹ Platelet response (platelet count ≥50,000/μl) was achieved in 41 of 44 patients (93%) who switched to avatrombopag and a complete platelet response (platelet count ≥100,000/μl) was achieved in 38 of 44 patients (86%) who switched to avatrombopag. Furthermore, of 28 patients receiving concomitant ITP medications prior to switching to avatrombopag, 16 patients (57%) were able to discontinue one or more concomitant medications after initiating avatrombopag. Authors of this study also reported outcomes by reason for switch. First, of the 23 patients who switched for improved convenience, response was achieved in all 23 patients and complete response was achieved in 22 of 23 patients (96%). Next, of the 14 patients who switched due to ineffectiveness of the prior TPO-RA, 12 patients (86%) achieved response and 10 patients (71%) achieved complete response with avatrombopag. Lastly, of the 7 patients who switched due to AEs with prior therapy, 6 patients (86%) achieved a complete response with avatrombopag and one patient did not respond.

The second study retrospectively compared switching between eltrombopag and romiplostim in older adults (≥60 years of age) with ITP and took place at 21 sites in Italy.¹⁰ Of the 72 patients who were resistant to or relapsed after the first TPO-RA, switching to the alternate TPO-RA achieved a platelet response (defined in this study as a platelet count ≥30,000/μl or doubling from baseline) in 60 patients (83.3%) and a complete platelet response in 47 (65.3%) patients. No cross-toxicity was observed in 32 patients who experienced AEs during treatment with the first TPO-RA.

A third study retrospectively compared switching between eltrombopag and romiplostim in 23 children with ITP.¹¹ After switching to eltrombopag, 8 (80%) patients achieved a platelet response. After switching to romiplostim, 8 (62%) patients achieved a platelet response.

Conclusion
In patients with ITP who do not achieve or sustain an adequate response with initial TPO-RA therapy, switching to an alternate TPO-RA is supported by a 2019 international consensus report and several newer retrospective studies.^4,8-11 Published studies have demonstrated that the majority of patients who switch to an alternate TPO-RA achieve a platelet response with the new treatment, including heavily pretreated patients. The safety profiles of the available TPO-RAs do not completely overlap, therefore, switching between TPO-RAs may be helpful in mitigating adverse effects and tolerability issues.⁴

References:

1. Cooper N, Ghanima W. Immune thrombocytopenia. N Engl J Med. 2019;381(10):945-955. doi:10.1056/NEJMcp1810479
2. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866. doi:10.1182/bloodadvances.2019000966
3. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817. doi:10.1182/bloodadvances.2019000812
4. Gilreath J, Lo M, Bubalo J. Thrombopoietin receptor agonists (TPO-RAs): drug class considerations for pharmacists. Drugs. 2021;81(11):1285-1305. doi:10.1007/s40265-021-01553-7
5. Package insert. AkaRx, Inc; 2021.
6. Package insert. Novartis Pharmaceuticals Corporation; 2021.
7. Package insert. Amgen, Inc.; 2022.
8. González-Porras JR, Godeau B, Carpenedo M. Switching thrombopoietin receptor agonist treatments in patients with primary immune thrombocytopenia. Ther Adv Hematol. 2019;10:2040620719837906. doi:10.1177/2040620719837906
9. Al-Samkari H, Jiang D, Gernsheimer T, et al. Adults with immune thrombocytopenia who switched to avatrombopag following prior treatment with eltrombopag or romiplostim: A multicentre US study. Br J Haematol. 2022;197(3):359-366. doi:10.1111/bjh.18081
10. Palandri F, Rossi E, Bartoletti D, et al. Real-world use of thrombopoietin receptor agonists in older patients with primary immune thrombocytopenia. 2021;138(7):571-583. doi:10.1182/blood.2021010735
11. Suntsova EV, Maschan AA, Baydildina DD, et al. Thrombopoietin receptor agonist switch in children with persistent and chronic severe immune thrombocytopenia: A retrospective analysis in a large tertiary center. Pediatr Blood Cancer. 2019;66(6):e27704. doi:10.1002/pbc.27704

Prepared by:
Katherine Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

September 2022

The information presented is current as of August 22, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.