Adolescents and Young Adults with Secondary Chronic Immune Thrombocytopenia: A Switzerland/France Collaboration Project

Introduction

The main causes of secondary immune thrombocytopenia (sITP) in adults include lymphoproliferative disorders, systemic autoimmune disorders (SAD), chronic infections, such as HIV and HCV, primary immunodeficiency disorders (PID), and drugs. In children, sITP is rare and in the chronic phase mostly related to SAD or PID. However, studies on sITP in adolescents and young adults (AYAs) are scarce and do not definitively outline prevalence and causes. This study aimed to comprehensively describe chronic sITP in AYAs.

Methods

Data were extracted from the PARC-ITP, OBS’CEREVANCE and CARMEN-France registries, open since 2004, 2004, and 2013, respectively. PARC-ITP is an international registry from 32 countries collecting data prospectively of children and adults with newly diagnosed ITP, OBS’CEREVANCE is a French national prospective cohort of children aged <18 years with autoimmune cytopenia including chronic ITP and CARMEN-France enrols newly diagnosed ITP in adults ≥18 years from many French centres.

We included patients aged 12 to 25 years with a diagnosis of chronic ITP who were categorized "secondary" at ITP diagnosis or in the course of the disease (until last available follow-up (FU)). Pregnant women were excluded. Chronicity was defined as a platelet count <100 × 10⁹/L or ongoing treatment at 12 months, or as a documented relapse at later FU. In this study, definition of sITP was adapted from the criteria by Rodeghiero et al (Blood 2019). Underlying diseases were subclassified into 4 groups: 1. SAD, including also other autoimmune diseases known to be involved in the onset of sITP (e.g. inflammatory bowel syndrome), 2. Evans syndrome (with no causative disease) (ES), 3. PID, and 4. others, including cases of chronic infections and lymphoproliferative disease. The date determining the change from primary to secondary ITP was defined by the apparition of new specific laboratory or clinical manifestation, even if the concluding diagnosis may have been done later. Patients without a clear underlying condition but with some immunopathological manifestations (e.g. isolated decrease of IgG) were not considered to have sITP.

Results

A total of 960 AYAs were registered across all three registries until November 2021. Among them, 388 (64% female) were identified with chronic primary ITP, and 94 (68% female) with chronic sITP. FU information was available for 94 (100%), 94 (100%), and 80 (85%) sITP patients at 6, 12, and 24 months FU, respectively. The mean age at initial diagnosis was 14 years (SD 2.8), and the initial median platelet count was 14 x 10⁹/L (IQR 7;34).

The underlying cause of sITP was SAD in 54/94 (57%) patients, ES in 19 (20%), PID in 17 (18%), and other diseases in 4 (4%), which included 2 chronic infections (HIV and HCV) and 2 cases of Hodgkin lymphoma. Within the SAD group, the majority were female (87%), whereas the PID group had a higher percentage of males (82%). Seven patients presented with multiline cytopenia but were ultimately diagnosed with PID; one of these patients also developed Hodgkin lymphoma over the course of the disease. These 7 patients were categorized under the PID group, as it can be assumed that the immunodeficiency is the common cause for all the reported manifestations.

Secondary ITP was identified in 25 out of 94 (27%) AYAs at the time of ITP diagnosis (15 SAD, 3 ES, and 4 PID), either following the initial assessment or due to a known underlying disease. During the 6, 12, and 24-month FU periods, an additional 21, 10, and 10 patients were diagnosed with sITP, respectively. Consequently, the diagnosis of sITP was established within the first year of the disease for 56 AYAs (60%) and within two years for a total of 66 patients (70%). A very late diagnosis of sITP (>24 months) was reported in 28 cases (30%) (17 SAD, 6 ES, 5 PID). Patients with PID were more frequently diagnosed beyond 12 months (59%), in contrast SAD and ES mostly within the first year (>60%).

Discussion

This study reveals that sITP is identified in 20% of AYAs with chronic ITP. The underlying cause was diagnosed within the first year in 60% of cases only. These findings emphasize the importance of reevaluating the diagnosis over long-term FU in AYAs with chronic ITP, as new symptoms or laboratory findings may emerge many years after the initial onset of thrombocytopenia, potentially leading to a revised diagnosis.