Background: Tubulin β-1 (TUBB1) is a major β-tubulin isotype expressed in megakaryocytes (MK) and platelets. TUBB1 mediates pro-platelet formation and transport of cytoplasmic contents to pro-platelet. Studies have shown that TUBB1 genetic variations or polymorphisms can lead to thrombocytopenia, or are associated with treatment failures in immune thrombocytopenia.

Aims: Recently, thrombopoietin-receptor agonists (TPO-Ras) have been used in the treatment of thrombocytopenia. Whether TUBB1 variants impact the efficacy of eltrombopag therapy still need to be investigated.

Methods: Based on NGS method, we detected 81 cases with TUBB1 genetic variants out of 310 patients who failed to respond to a 4-week conventional corticosteroids therapy. Patients with severe thrombocytopenia among them received eltrombopag treatment. The clinical manifestations and treatment effects of these patients were analyzed retrospectively.

Results: 81 cases of TUBB1 genetic variants included common variants (MAF >1%) R307H and Q43P, rare variants (MAF < 1%) R318W, T107P, R241T and newly detected variant G38R and T149I. Among these cases, 39 patients had moderate thrombocytopenia, the other 42 patients had severe thrombocytopenia (< 30 × 10⁹/L). 31 of these patients were treated with eltrombopag for 4 – 6 weeks, of which only 5 achieved major responses, 7 transiently responded, and the remaining 19 were ineffective. Eltrombopag is effective mainly in R307H carriers, while patients with other variants responded significantly lower to eltrombopag than the reported average effectiveness (Table 1). Four patients with rare variants were treated with cyclosporine after ineffective eltrombopag therapy, and two of them partly responded (platelets > 50 × 10⁹/L).

Conclusions: R307H is the most common TUBB1 variant in patients with refractory thrombocytopenia. Eltrombopag was partly effective in increasing platelet counts in patients with R307H. But patients with other TUBB1 variants, especially those with rare variants, do not respond well to eltrombopag. For these patients, immune modulatory therapies or other therapeutic options should be considered.

[Genetic features and response to eltrombopag treatment of TUBB1 variant carriers.]

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/refractory-thrombocytopenia-with-tubb1-variants-clinical-features-and-responses-to-eltrombopag-treatment/