Immunomodulation and Romiplostim − What Does the Recently Published iROM Study Say?
Primary immune thrombocytopenia (ITP) is caused by an immunity disorder, involving not only the production of antibodies but also changes in cytokine levels, predominance of Th1 lymphocytes over Th2, increase in Th17 cells, and conversely a decrease in T-regulatory lymphocytes (Tregs). One treatment option is the use of thrombopoietin receptor agonists (TPO-RA), which primarily increase platelet production. Recently, attention has also been focused on their potential immunomodulatory effects and protolerogenic effect associated with Tregs activation, which was the subject of the Swiss iROM study.
Methodology and Study Course
Adult patients with a platelet count < 30 × 109/l, or at risk of dropping below this value, who had failed first-line treatment or experienced relapse or significant adverse effects were included in the study. Patients who had already undergone second-line treatment, suspected secondary ITP, history of thromboembolic disease (TEN), or were using immunomodulatory medications were excluded.
Romiplostim from the TPO-RA group was administered subcutaneously for 22 weeks with an initial dose of 1 μg/kg per week, adjusted according to treatment response. Rescue medication (corticosteroids, intravenous immunoglobulins, tranexamic acid) was allowed for the first 3 weeks, after which only corticosteroids were permitted.
After 22 weeks, patients were monitored for an additional 30 weeks, during which 5 follow-up visits occurred in weeks 24, 30, 35, 40, and 52. Immunological testing was conducted 5 times, in weeks 1, 6, 12, 22, and 52. The immunological profile was assessed using flow cytometry with fluorescence-activated cell sorting (FACS), cytokine level measurements, and expression of selected genes.
Findings
A total of 13 patients were included in the study, consisting of 3 women and 6 men with newly diagnosed ITP and 4 women with chronic ITP. The median age was 31 years, and the median platelet count at study entry was 29 × 109/l. By the end of the study, 6 patients achieved sustained remission off-treatment (SROT) in weeks 22−52, all with newly diagnosed ITP. No sustained remission was achieved in patients with chronic ITP. The disease relapsed in the remaining 7 patients. The romiplostim dose was lower, and platelet increase was faster in the SROT group. In the entire study population, the number of Tregs significantly increased between weeks 6 and 52 (p = 0.017).
Immunologically, the study revealed the following findings:
- Levels of interleukins IL-4, IL-9, and IL-17F significantly decreased in the first 6 weeks for all patients; initial levels were higher in the relapsed group.
- Levels of TGF-β and IL-35 increased within the first 6 weeks, initially higher in the SROT group. Only 1 patient with relapse showed a significant increase in TGF-β levels.
- Platelet counts increased by approximately 0.5 with each unit Increase in TGF-β levels (p < 0.001).
In patients who achieved SROT, FOXP3 (Treg) expression gradually increased, peaking in week 22, with no changes seen in patients with relapse in weeks 22 or 52. GATA3 (Th2) expression increased in SROT patients, while it decreased or remained unchanged in the relapsed group. TBX21 (Th1) expression did not change significantly. RORC (Th17) expression slightly increased in weeks 22 and 52 for all patients.
Conclusion and Discussion
The iROM study demonstrated that romiplostim has immunomodulatory effects and can favorably influence the prognosis of immune thrombocytopenia. The study authors propose two mechanisms for this effect: induction of immune tolerance by exposure to a large number of antigens and the intrinsic immune activity of platelets producing transforming growth factor beta (TGF-β), which positively affects Tregs. The rapid increase in platelet count is thus associated with the induction of immune tolerance. Early administration of romiplostim may also play a role, though more data is needed for this conclusion.
(jala)
Source: Schifferli A., Rüfer A., Rovo A. et al. Immunomodulation with romiplostim as a second-line strategy in primary immune thrombocytopenia: the iROM study. Br J Haematol 2023 Oct; 203 (1): 119−130, doi: 10.1111/bjh.19074.
Did you like this article? Would you like to comment on it? Write to us. We are interested in your opinion. We will not publish it, but we will gladly answer you.
