Posted on 4 April 202412 April 2024

During the 65^th ASH meeting that took place in San Diego in December 2023, many interesting abstracts concerning immune thrombocytopenia have been presented, covering different topics from the pathogenesis to treatments, from diagnosis to bleeding and thrombotic risk.

Here you can find a summary of the most relevant presentations; for the complete list of the abstracts, please visit the American Society of Hematology official website.

Treatment of primary ITP.

In the last years we have become accustomed to seeing many advances in the treatment of ITP, and the latest ASH meeting did not disappoint us. Besides TPO-mimetics, which are widely used as second-line therapy, advances in other treatment modalities have been highlighted. They include the BTK inhibitor rilzabrutinib, the FcRn inhibitor efgartigimod, an anti-CD38 antibody, a JAK 1/2 kinase inhibitor, and even the preclinical data of an anti-CD19 CAR-T cell and in vitro data of an anti-GPIbα chimeric auto-antibody receptor T cell.

The efficacy and safety of TPO-mimetics when used early in the course of the disease was explored by Virk Z et al., comparing the outcomes of patients treated with avatrombopag before (23) or during chronic phase (55).  No differences were observed in terms of efficacy (considering both platelet response and bleeding events) and safety, with special focus on the occurrence of thrombocytosis and thromboembolic events with only one patient in the chronic group who developed a VTE.

TPO-mimetics are widely used as second-line therapy. Kuter D et al. reported on 375 patients with primary ITP lasting ≥3 months who were started with either TPO-RAs (51%) or rituximab (49%). A higher proportion of patients switched from rituximab to TPO-RAs (23.6%) than vice versa (9%). In both groups, the rate of bleeding events was 288 per 1000 person-years, thromboembolic events were 129 and infections 70 per 1000 person-years.

The use of high dose romiplostim (10mcg/kg) in patients with severe bleeding to rapidly increase platelet counts is quite common in clinical practice. However, King E et al. found that this practice significantly increased thrombotic events without affecting platelet response or time to response.

Yin J et al. and Fu H et al. explored the safety and efficacy of the combination of rhTPO plus either hetrombopag or eltrombopag. The first study enrolled 30 patients with severe ITP, mostly newly diagnosed. Platelet response was quick (a median of 4.5 days to reach a platelet count > 30×10⁹/L), and no thrombotic events were reported. Similar results were reported by Fu H et al. with the combination of eltrombopag and rhTPO.

Beyond TPO-mimetics, promising results emerged from trials involving BTK inhibitors and efgartigimod. Cooper N et al. reported the results of part B phase 1/2 study with rilzabrutinib. 26 patients with relapsed/refractory ITP received rilzabrutinib 400 mg bid. The primary endpoint of durable platelet response was achieved by 9 patients (35%). Notably, 25% of patients achieved platelet counts ≥50×10⁹/L by day 15 of treatment. Common AEs included diarrhea, headache and nausea. Tarantino M et al. reported on the effects of rilzabrutinib on bleeding and health-related quality of life (HRQoL).

Broome C et al. highlighted the rapid platelet count increase, within the first 7 days after treatment with efgartigimod in the phase 3 ADVANCE IV study.

New therapeutic approaches include cellular therapy, anti-CD38 antibodies and kinase inhibitors.

Wang Y et al. demonstrated the efficacy of CD19 CAR-T cells in a murine model of ITP, showing a significant increase in platelet count, and a decrease in the percentage of CD19+ B cells, CD138+ plasma cells, and antiplatelet antibodies.

Zhou J et al. developed anti-GPIbα chimeric auto-antibody receptor (CAAR) T cells that identify and eliminate autoreactive B cells, with promising results in vitro.

Chen Y et al. conducted a phase I study to explore the safety and efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) in 18 patients with R/R ITP, reporting a 44.4% response rate, with an acceptable safety profile.

Chen Y et al. reported encouraging results from a phase II trial with CM313, an anti-CD38 antibody administered weekly for 8 weeks: the primary endpoint of a platelet count ≥50×10 ⁹/L within 8 weeks after the first dose was achieved by all seven evaluable patients.

Zhao P et al. evaluated the efficacy of baricitinib, a JAK 1/2 kinase inhibitor, in a randomized phase II trial, as first-line treatment in combination with high-dose dexamethasone, demonstrating a higher sustained response rate at 6 months, compared to dexamethasone alone.

Posted on 25 March 20249 April 2024

During the 65^th ASH meeting that took place in San Diego in December 2023, many interesting abstracts concerning immune thrombocytopenia have been presented, covering different topics from the pathogenesis to treatments, from diagnosis to bleeding and thrombotic risk.

Here you can find a summary of the most relevant presentations; for the complete list of the abstracts, please visit the American Society of Hematology official website.

Pathogenesis and diagnosis.

The pathogenesis of ITP is not fully understood, likely involving a complex interplay of multiple mechanisms that cooperate to increase platelet clearance and impair megakaryocyte activity. These mechanisms are probably initiated by antiplatelet antibodies and perpetuated by an abnormal activation of cytotoxic T cells, T helper cells, plasma cells and other immune effectors. Below you will read more about advances in understanding B and T-cell activity in ITP.

The occurrence of a moderate, isolated thrombocytopenia is rather frequent in everyday clinical practice, and it can be the manifestation of several diseases or conditions. The lack of a diagnostic test, or a diagnostic score for ITP complicates the diagnostic process, which frequently requires a panel of tests to rule out secondary causes or other diseases. Below you will read about a new diagnostic tool for differential diagnosis of primary versus secondary ITP. But clearly this issue is demanding further studies.

Pathogenesis

The role of antiplatelet antibodies in the pathogenesis of ITP is continuously under investigation. Han F et al. observed that patients with anti-GPIb antibodies respond less well to TPO-RA treatment, with impaired MK maturation in vitro. This finding was confirmed in animal model, where mice with GPIb alfa deficiency exhibited reduced responsiveness to TPO-RA treatment, inhibited MKpoiesis and platelet production, even in the presence of TPO.

Among cytokines, TGF-β1 seems to play a key role in ITP pathogenesis. Xu M et al. explored TGF-β1 in ITP patients treated with TPO-RAs, showing lower plasma activated TGF-β1 levels and regulatory T cells in non-responders and in those unable to achieve a sustained response. Lower levels of activated TGF-β1 in the bone marrow were associated with higher numbers of MKs, but impaired MKpoiesis. Knockout mice for TGF-β1 displayed reduced Treg cells, elevated M1 macrophages, and reduced response to TPO-RAs, which was restored by adding integrin αvβ8, which enhances TGF-β1 activation and promotes the formation of Tregs.

Iguratimod inhibits the production of several inflammatory cytokines by enhancing mitophagy, a process that eliminates damaged mitochondria. Chen Y et al. explored its effect in ITP. ITP patients’ CD4+ T cells exhibited compromised mitophagy and mitochondrial function, restored after Iguratimod treatment, along with rebalancing of Th1/Th2 lymphocytes, restoring Tregs and improving mitophagy and mitochondria function.

Diagnosis

The diagnosis of ITP may be challenging, and definite diagnostic criteria are still lacking. A new diagnostic tool proposed by the Japanese group (Kashiwagi H. et al.) integrates clinical features and laboratory markers into a scoring system designed to differentiate between hyporegenerative and consumption thrombocytopenia. Notably, this scoring system requires a normal or slightly increased plasma thrombopoietin (TPO) level and elevated percentage of immature platelets (IPF%) for the diagnosis of ITP. Validated on 112 thrombocytopenic patients, it showed a sensitivity of 53% and a specificity of 96%.

The occurrence of a mild-to-moderate isolated thrombocytopenia in asymptomatic patients is common in clinical practice. However, should this finding raise concern? Rudbeck Jule A. et al. explored whether such subjects carry a higher risk of hematological diseases and death. Their study, involving over 300.000 UK individuals aged 40-70 years and a validation cohort of over 100.000 Danish individuals, revealed an increased relative risk of hematologic disease and death, both from hematologic causes and overall, in individuals with thrombocytopenia with or without anemia. The  10-year absolute risk of death from hematologic disease remained below 5% for most combinations of sex, age, platelet count and hemoglobin, but was notably higher for men aged 60-70 years with mild anemia combined with moderate-severe thrombocytopenia, underscoring the need for special attention in this group.

ITP and other autoimmune cytopenias (AIC) can occur in the context of overt lymphoproliferative diseases requiring chemotherapy or be associated with indolent B-cell clones (IBC) that do not necessitate specific treatment. Zadro Y. et al. retrospectively reported on 187 adult patients with an AIC (ITP, AIHA or ES) associated with IBC, managed in France. Most of them (72%) were treated without chemotherapy, receiving corticosteroids, IVIg and rituximab, while the remaining (28%) received a chemotherapy-based treatment including cyclophosphamide, bendamustine and others. Interestingly, there was no difference in efficacy and safety between the two groups.