Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder with thrombocytopenia as the main clinical manifestation. At the recent 29th Annual Meeting of the European Blood Association (EHA), several research advances were made in the field of ITP. Professor Yang Linhua from the Second Hospital of Shanxi Medical University was invited to introduce the blockbuster studies in detail, and the two articles brought in this issue are about the occurrence and clinical significance of clonal hematopoiesis in ITP, as well as the safety and efficacy of avatrombopag for the treatment of chronic ITP in children, in order to deepen everyone's understanding of ITP and provide new ideas for future treatment strategies.
1
Clonal hematopoiesis in patients with immune thrombocytopenia: an international multicenter study
Abstract Number: S315
Abstract Type: Oral presentation
Session: Focus on Platelet Disorders: Clinical and Translational
Background:
Immune thrombocytopenia (ITP) is caused by immune-mediated attacks on platelets and bone marrow precursor cells. The diagnostic boundaries between ITP and clonal cytopenia (e.g., low-risk myelodysplastic syndrome) are not well defined. Somatic mutations, i.e., clonal hematopoiesis with uncertain potential, may also be found in individuals without myeloid tumors by Next generation sequencing (NGS). The incidence and significance of clonal hematopoiesis in ITP are unknown.
Objectives:
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 patients with ITP were followed in 13 centers in Italy, United Kingdom, and United States, and available NGS data (bone marrow group > 50 genes). Among the possible germline mutations, 40% of the variant allele frequency (VAF>) mutations were excluded. Analyze the incidence and type of mutations detected and their relationship to the clinical and laboratory features of ITP.
Findings:
A total of 173 patients with ITP (see table below) were enrolled, of whom 64 (37%) had at least one gene mutation and 35 (20%) had ≥ two gene mutations. The mutant 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), and 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 and U2AF1 cases each The median VAF was 29% (2.6%~39%). The age of NGS-positive patients [median age 70 (18~89) years] was significantly greater than that of NGS-negative patients [median age 61 (18~84) years] (P=0.05), while the prevalence of platelet value, gender, secondary ITP, and Evans's syndrome at diagnosis were similar between the two groups.
82% of patients were treated (median 2nd line therapy, 1~7), mainly steroid hormones (100%), thrombopoietin receptor agonists (TPO-RA) (75%), rituximab (23%), cytotoxic immunosuppressants (21%), and fostamatinib (14%, see table below); The proportion of relapsed/refractory patients was higher in NGS-positive patients (47% >3-line) and 32% in NGS-negative patients (P=0.03). In a small number of patients, the response rate of formatinib was 77% (10/13) in NGS-positive patients compared with 9% (1/11) in NGS-negative patients (P=0.001). Eighteen patients (10%) of the entire study population developed thrombotic complications unrelated to NGS mutations during the course of the disease. None of the patients progressed to myeloid tumors. During the 5-year median follow-up period (NGS-positive/negative cases were similar), 13 patients died, more common in the NGS-positive group (14 percent) and 4 percent in the NGS-negative group (P = 0.01). The cause of death was not related to ITP.
Conclusions of the study
Preliminary data suggest that more than one-third of patients with ITP have clonal hematopoiesis, which is associated with advanced age, relapse, and refractory. This frequency is higher than expected in the 60-year-old population (Rossi et al., Blood, 2021), suggesting that disease-related autoimmune attacks may have an impact on bone marrow precursor cells, and that treatments may play a role in clonal selection.
2
A phase 3 randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of AVATROMBOPAG in the treatment of children with chronic immune thrombocytopenia (AVA-PED-301).
Abstract Number: S318
Abstract Type: Oral Report
Session: Focus on Platelet Disorders: Clinical and Translational
Background:
Avatrombopag (AVA) is approved for the treatment of chronic immune thrombocytopenia in adults (≥ 18 years of age). AVA is a food-unrestricted oral thrombopoietin receptor agonist (TPO-RA) that would be particularly appropriate for pediatric and adolescent patients with ITP if demonstrated efficacy and safety.
Objectives:
To assess the efficacy, safety, and pharmacokinetics of AVA in pediatric and adolescent patients with ITP ≥ 6 months of disease.
Research Methods:
The subjects included in this phase 3b double-blind study (NCT04516967) were ITP patients aged >1~<18 years old, with a disease duration of ≥ 6 months, and the average platelet count (PC) during the screening period was < 30×109/L and no PC >35×109/L。 Subjects were recruited from 34 sites in France, Germany, Hungary, Poland, Russia, Turkey, United Kingdom, Ukraine and United States, stratified by age into 1~6 years, 6~12 years old, and 12~18 years old, and randomly assigned to receive AVA or placebo (PBO) for 12 weeks according to 3:1; Adjust the dose of the study drug to make the target PC reach 50~150×109/L. During this 12-week core period, subjects and investigators were double-blinded. Subjects who complete a 12-week core phase trial, or who do not have any platelet response at the maximum dose of study drug in a double-blind setting, may enter an open-label extension (OLE) trial for up to 2 years.
Figure 1. Median platelet count (IQR) without rescue therapy in the core phase - full analysis set
The primary analysis included all randomized subjects; The safety analysis included all subjects who received ≥1 dose of study drug. The primary endpoint is durable platelet response, defined as the maintenance of PC≥50×109/L for ≥ 6 weeks in the last 8 weeks of the core phase without rescue therapy. The secondary endpoint was 2 consecutive ≥ of PC ≥50×109/L in the 12-week core phase without rescue therapy. Other secondary endpoints included platelet response on day 8 and the use of rescue therapy.
Findings:
From March 5, 2021 to August 30, 2023, a total of 75 subjects aged 1~17 years were included, 54 were assigned to AVA treatment, and 21 were enrolled in the PBO group. The median time from ITP diagnosis to enrollment was 3.1 years (0.5~12.3 years) in the AVA group and 3.4 years (0.5~11.8 years) in the PBO group. Approximately 80% of participants had PCs ≤ 15×109/L, 68% had received ≥ 3 ITP drugs, and 73% had received TPO-RAs. The mean age of enrollment was 8.5 years in the AVA group and 10.0 years in the PBO group, and 52% of all enrolled participants were male and 84% white.
Forty-four (81.5%) participants with AVA and one (4.8%) participant with PBO completed the 12-week core phase trial. Durable platelet reactions were observed in 15 (28%) AVA subjects and 0 PBO subjects at 5~12 weeks (P=0.0077, 95%CI: 15.8~39.7). In 44 (81.5%) AVA subjects and 0 PBO subjects, two consecutive PC≥ of 50×109/L were observed (P≤0.0001, 95%CI: 71.1~91.8). Platelet response ≥of 50×109/L was observed on day 8 in 30 (56%) AVA subjects and 0 PBO subjects (P≤0.0001), and rescue treatment was used in 4 (7%) AVA subjects and 9 (43%) PBO subjects (P=0.0008).
Serious adverse events occurred in five (9%) participants with AVA and one (5%) participant with PBO. One (2%) participant with AVA experienced two serious adverse reactions (SAEs) (headache; thrombocytosis), which may be related to treatment. Two participants (4%) in the AVA group were affected by adverse events (polyleukocytosis at day 12; Day 63 vomiting) without, and 1 (5%) in the PBO group withdrew due to day 43 contusion. Ten (19%) participants in the AVA group and eight (38%) participants in the PBO group experienced WHO≥2 grade 2 bleeding events. No participants had thrombotic events or deaths during the core phase. Seventy-three participants (97%) entered the ongoing OLE study phase.
Conclusions of the study
Avatrombopag (AVA) is a potent and well-tolerated oral TPO-RA for patients aged > 1~<18 years, persistent and chronic ITP with poor prior efficacy.
Prof. Linhua Yang
Director of the Hematology Research Center of Shanxi Medical University, Department of Hematology, Second Hospital of Shanxi Medical University
Second-level professor, doctoral supervisor, expert with special allowance from the State Council
Member of the Standing Committee of the Hematology Society of the Chinese Medical Association
Vice Chairman of China Hematology Alliance
Vice Chairman of the Hematology Committee of the Chinese Medical Education Association
Vice Chairman of the Hematology Rehabilitation Professional Committee of the Chinese Association of Rehabilitation Medicine
Vice Chairman of the Precision Diagnosis and Treatment Committee of Hematology of the China Research Hospital Association
Member of the Standing Committee of the CSCO Leukemia Lymphoma Expert Committee
Member of the Standing Committee of the Hematology Committee of the Cross-Strait Medical and Health Exchange Association
Member of the Standing Committee of the Hematology and Immunology Branch of the Chinese Society of Pathophysiology
Member of the Standing Committee of the Hematology and Oncology Professional Committee of the Chinese Women Physicians Association
President of the Hematology Branch of Shanxi Medical Doctor Association
Chairman of the Leukemia Lymphoma Professional Committee of Shanxi Anti-Cancer Association
He is a member of the editorial board of the Chinese edition of "Hemophilia" and "Blood", and the editorial board member of "Chinese Journal of Hematology", "Chinese Journal of Internal Medicine", "Chinese Journal of General Practice", "Chinese Journal of Cell and Stem Cell" and so on