ICIS Report: Potential of TPO-RA as Early Immunomodulatory Treatment of Immune Thrombocytopenia

Early Treatment of ITP

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased destruction of platelets and their decreased production. The cause of the immune system's loss of tolerance to its own platelets is not clear. The main pathogenic mechanism in ITP is circulating antibodies against platelets leading to phagocytosis, but other pathogenic changes are also involved. In chronic ITP, immune disturbances likely accumulate over time, significantly decreasing the chances of cure. Early and high therapeutic response can ensure the prevention of thrombocytopenia relapses and disease chronicity. Early immunomodulation is also a way to prevent the development of refractory ITP.

Achieving Sustained Remission Off Treatment (SROT)

Recent studies have examined the hypothesis that intensive multimodal therapy administered in the early phase of the disease can even lead to the cure of ITP. The therapy combines products targeting both innate and acquired immunity, specifically:

1. B lymphocytes and plasma cells and the effect of antibodies (e.g., rituximab, belimumab, high-dose dexamethasone /HD-DXM/ and i.v. immunoglobulins)
2. T lymphocytes (cyclosporin and mycophenolate mofetil)
3. inflammatory reactions (corticosteroids)
4. platelet production (TPO-RA)

The term SROT (sustained remission off treatment) is currently used to describe patients who can stop ITP treatment without risk and maintain remission. Achieving SROT is possible, but it is necessary to identify which ITP patients are the best candidates for early immunomodulation strategies. A recent review summarizes the results of 6 previous studies evaluating early treatment in ITP patients and reporting the achievement of SROT after ≥ 6 months.

An Overview of Studies Evaluating the Achievement of SROT in ITP

• In a 2014 study, treatment with HD-DXM and eltrombopag (days 5–32) in 12 newly diagnosed ITP patients led to platelet counts of ≥ 100 × 10⁹/l after 6 months in 50% of the participants.
• A 2016 study with romiplostim administered for ≤ 12 months in 75 patients with newly diagnosed ITP reported achieving platelet counts of ≥ 50 × 10⁹/l after > 6 months in 32% of those treated.
• A randomized study from 2020 evaluated the addition of recombinant thrombopoietin (for 14 days) to HD-DXM in 174 newly diagnosed ITP patients. Platelet counts of ≥ 100 × 10⁹/l were achieved after 6 months in 46% of those treated compared to 32% with HD-DXM alone (p < 0.05), and after 12 months in 42% vs. 26%.
• In another 2020 study involving 46 newly diagnosed ITP patients, eltrombopag (administered for 12 weeks) + HD-DXM resulted in platelet counts of ≥ 50 × 10⁹/l in 57% of cases after 6 months.
• In the 2021 ESTIT study, eltrombopag administered for 24 weeks in 51 second-line treatment patients resulted in platelet counts of ≥ 30 × 10⁹/l in 25% of those treated.
• The latest iROM study, published in 2023, showed that platelet counts of ≥ 100 × 10⁹/l were achieved after 12 months in 67% of 9 newly diagnosed ITP patients receiving romiplostim.

None of these studies identified predictors of long-term treatment response, except for the 2016 study, where platelet count during the first 2 months (139 vs. 87 × 10⁹/l) correlated with achieving remission.

Reasons for Early Use of TPO-RA in ITP

SROT as a therapeutic goal appears to be achievable with various drugs or their combinations. TPO-RA have shown the highest potential to reverse immune changes occurring in ITP, although there are no direct comparisons. TPO-RA exhibit immunomodulatory effects and properties that induce immune tolerance and increase not only platelet counts but also concentrations of transforming growth factor-beta (TGF-β) and stimulate regulatory T and B lymphocytes.

According to the ICIS report, the rationale for early use of TPO-RA to achieve early remission of ITP can be summarized as follows:

1. In newly diagnosed ITP, immune system dysregulation is lower, so the chance for an immunomodulatory effect of TPO-RA is considered higher. Studies show more frequent achievement of SROT when treating ITP in early stages compared to later stages, especially when using TPO-RA.
2. TPO-RA can achieve higher response rates when administered to newly diagnosed ITP patients.
3. TPO-RA are typical steroid-sparing drugs. When used in the early phase of ITP, unwanted systemic immunosuppression from corticosteroids, which may affect the immunomodulatory effect, can be avoided.

Conclusion

Early immunomodulation with TPO-RA may effectively prevent refractory ITP. However, further studies are needed to account for the proportion of spontaneous remissions in newly diagnosed ITP and provide more precise data on potentially reversible molecular changes in the pathogenesis of ITP.

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Source: González-López T. J., Schifferli A. Early immunomodulation in immune thrombocytopenia – a report of the ICIS meeting in Lenzerheide, Switzerland 2022. Br J Haematol 2023 Oct; 203 (1): 101–111, doi: 10.1111/bjh.19082.