Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder characterized by a low platelet count. At the recently held 29th European Hematology Association (EHA) Annual Meeting, significant advancements were made in the field of ITP. "Oncology Frontier - Hematology Frontier" invited Professor Linhua Yang from the Second Hospital of Shanxi Medical University to select and detail some of the most impactful studies. This issue presents two studies: one on clonal hematopoiesis in ITP and its clinical significance, and the other on the safety and efficacy of avatrombopag for treating chronic ITP in children, with the aim of deepening understanding of ITP and providing new insights for future treatment strategies.

Clonal Hematopoiesis in Patients with Immune Thrombocytopenia: An International Multicenter Study

Abstract Number: S315

Abstract Type: Oral Presentation

Session Topic: Focus on Platelet Disorders: Clinical and Translational

Research Background

Immune thrombocytopenia (ITP) is caused by immune-mediated attacks on platelets and bone marrow progenitor cells. The diagnostic boundaries between ITP and clonal cytopenias (such as low-risk myelodysplastic syndromes) are not well defined. Somatic mutations can be found in individuals without myeloid malignancies through next-generation sequencing (NGS), indicating clonal hematopoiesis of indeterminate potential. The incidence and significance of clonal hematopoiesis in ITP remain unclear.

Research Objective

To investigate the incidence and clinical significance of clonal hematopoiesis in adult patients with primary immune thrombocytopenia (ITP).

Research Methods

From 2003 to December 2023, adult ITP patients from 13 centers in Italy, the UK, and the USA were followed, and NGS data (covering >50 genes in the bone marrow group) were obtained. Possible germline mutations with variant allele frequency (VAF) >40% were excluded. The incidence and types of detected mutations and their relationship with the clinical and laboratory characteristics of ITP were analyzed.

Research Results

A total of 173 ITP patients were included (see table), with 64 (37%) having at least one gene mutation and 35 (20%) having ≥2 gene mutations. The most frequent mutated genes were TET2 (37 cases), DNMT3A (19 cases), SRSF2 (12 cases), ASXL1 (10 cases), CBL (4 cases), BCOR (4 cases), SETBP1 (3 cases), SF3B1 (3 cases), NF1 (2 cases), TP53 (2 cases); EZH2 (3 cases), MPL (3 cases), EGLN1 (2 cases), IDH2 (2 cases), JAK2 (2 cases), PHF6 (2 cases), CEBPA (1 case), CBFB::MKL1 (1 case), RADS21 (1 case), STAG2 (1 case), and U2AF1 (1 case). The median VAF was 29% (2.6% – 39%). NGS-positive patients were significantly older [median age 70 (18-89) years] than NGS-negative patients [median age 61 (18-84) years] (P=0.05), while the platelet count at diagnosis, gender, prevalence of secondary ITP, and Evans syndrome were similar between the two groups.

82% of patients received treatment (median 2 lines of treatment, 1-7), mainly steroids (100%), thrombopoietin receptor agonists (TPO-RA) (75%), rituximab (23%), cytotoxic immunosuppressants (21%), and fostamatinib (14%, see table); NGS-positive patients had a higher proportion of relapse/refractory cases (≥3 lines) at 47% compared to 32% for NGS-negative patients (P=0.03). Among a few patients, NGS-positive patients had a higher efficacy rate for fostamatinib at 77% (10/13) compared to 9% (1/11) for NGS-negative patients (P=0.001). Throughout the study population, 18 patients (10%) experienced thrombotic complications unrelated to NGS mutations. No patients progressed to myeloid malignancies. During the median follow-up of 5 years (similar for NGS-positive/negative cases), 13 patients died, with more deaths in the NGS-positive group (14%) than the NGS-negative group (4%) (P=0.01). The causes of death were unrelated to ITP.

Research Conclusion

Preliminary data indicate that over one-third of ITP patients have clonal hematopoiesis, associated with older age, relapse, and refractory cases. This frequency is higher than expected in the population over 60 years old (Rossi et al., Blood, 2021), suggesting that disease-related autoimmune attacks may affect bone marrow progenitor cells, and treatment strategies may play a role in clonal selection.

Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of AVATROMBOPAG in Treating Chronic Immune Thrombocytopenia in Children (AVA-PED-301)

Abstract Number: S318

Abstract Type: Oral Presentation

Session Topic: Focus on Platelet Disorders: Clinical and Translational

Research Background

Avatrombopag (AVA) has been approved for treating chronic immune thrombocytopenia in adults (≥18 years). AVA is an oral thrombopoietin receptor agonist (TPO-RA) not restricted by food intake, making it particularly suitable for pediatric and adolescent ITP patients if its efficacy and safety are proven.

Research Objective

To evaluate the efficacy, safety, and pharmacokinetics of AVA in pediatric and adolescent ITP patients with a disease course of ≥6 months.

Research Methods

This phase 3b double-blind study (NCT04516967) included ITP patients aged >1 to <18 years with a disease duration of ≥6 months, with an average platelet count (PC) <30×10^9/L and no PC >35×10^9/L during screening. Patients were recruited from 34 sites in France, Germany, Hungary, Poland, Russia, Turkey, the UK, Ukraine, and the USA, stratified by age (1-6 years, 6-12 years, 12-18 years), and randomly assigned in a 3:1 ratio to receive AVA or placebo (PBO) for 12 weeks; the dose of the study drug was adjusted to maintain target PC of 50-150×10^9/L. During the 12-week core period, the study drug and placebo were administered in a double-blind manner. Patients who completed the 12-week core period, or those who did not achieve any platelet response at the maximum dose of the study drug under double-blind conditions, could enter an open-label extension (OLE) study for up to 2 years.

The preliminary analysis included all randomized patients; the safety analysis included all patients who received ≥1 dose of the study drug. The primary endpoint was sustained platelet response, defined as maintaining PC ≥50×10^9/L for ≥6 weeks during the last 8 weeks of the core period without rescue treatment. Secondary endpoints included PC ≥50×10^9/L on ≥2 consecutive occasions during the 12-week core period without rescue treatment, as well as platelet response on day 8 and the use of rescue treatment.

Research Results

Between March 5, 2021, and August 30, 2023, a total of 75 patients aged 1-17 years were enrolled, with 54 receiving AVA and 21 receiving PBO. The median time from ITP diagnosis to enrollment was 3.1 years (0.5-12.3 years) for the AVA group and 3.4 years (0.5-11.8 years) for the PBO group. Approximately 80% of patients had PC ≤15×10^9/L, 68% had previously received ≥3 types of ITP treatments, and 73% had previously received TPO-RAs. The mean enrollment age was 8.5 years for the AVA group and 10.0 years for the PBO group; 52% of all enrolled patients were male, and 84% were white.

44 (81.5%) AVA patients and 1 (4.8%) PBO patient completed the 12-week core period. Sustained platelet response was observed in 15 (28%) AVA patients and 0 PBO patients during weeks 5-12 (P=0.0077, 95% CI: 15.8-39.7). Continuous PC ≥50×10^9/L was observed in 44 (81.5%) AVA patients and 0 PBO patients (P≤0.0001, 95% CI: 71.1-91.8). Platelet response ≥50×10^9/L on day 8 was observed in 30 (56%) AVA patients and 0 PBO patients (P≤0.0001). Rescue treatment was used by 4 (7%) AVA patients and 9 (43%) PBO patients (P=0.0008).

Serious adverse events (SAEs) occurred in 5 (9%) AVA patients and 1 (5%) PBO patient. One (2%) AVA patient experienced 2 SAEs (headache; thrombocytosis) possibly related to treatment. Two (4%) AVA patients discontinued due to adverse events (leukocytosis on day 12; vomiting on day 63), and 1 (5%) PBO patient discontinued due to bruising on day 43. WHO grade ≥2 bleeding events occurred in 10 (19%) AVA patients and 8 (38%) PBO patients. No thrombotic events or deaths occurred during the core period. 73 patients (97%) entered the ongoing OLE study phase.

Research Conclusion

Avatrombopag (AVA) is an effective and well-tolerated oral TPO-RA suitable for patients aged >1 to <18 years with persistent and chronic ITP who have had inadequate responses to previous treatments.