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T. Pincez et al.
remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IM increased with age: at the age of 20 years, 74% had at least one clinical IM (cIM). A wide range of cIM occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IM. The number of cIM was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio 1.4, 95% Confidence Interval: 1.15–1.60, P=0.0002, Cox proportional haz- ards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 years (range, 1.7–31.5 years), and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, long-term outcomes of pES showed remission of cytopenias but frequent IM linked to high second-line treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.
Introduction
The presence of both immune thrombocytopenic pur- pura (ITP) and autoimmune hemolytic anemia (AIHA) defines Evans syndrome (ES). Pediatric-onset ES (pES) is a rare disease, and approximately ten new cases are diag- nosed every year in France, which has a population of 66 million.1 Since its first description in 1951 by Robert Evans,2 our understanding of pES has been based on small retrospective cohorts with limited follow-up.3-7 In 2004, the French Rare Disease Center CEREVANCE set up the prospective national cohort OBS’CEREVANCE, which includes children with AIHA, chronic ITP persisting for more than 12 months (cITP), and pES.8
Preliminary reports from this cohort and previously published studies showed that pES is a chronic disease with a high rate of relapse for both types of cytope- nias.1,3,4,7,9 Mortality rates across studies have ranged from 7–36%.1,3-7 In addition to cytopenias, immunopathologi- cal manifestations (IM) such as autoimmune/autoinflam- matory organ diseases, lymphoproliferation, and hypogammaglobulinemia have been reported in 70–80% of patients with pES.4,5,8,10 In an undetermined number of cases, pES is thought to be “secondary” and caused by an underlying disease, classically systemic lupus erythe- matosus (SLE) or autoimmune lymphoproliferative syn- drome (ALPS).1,11,12 Recently, genetic analyses found a heterogeneous genetic background in up to 65% of a sub- set of 80 patients from the OBS’CEREVANCE cohort. These patients carried variants in genes that are linked to primary immunodeficiencies (PID) or involved in immune responses.13
Overall, outcomes and the long-term course of pES are poorly understood. There have been no comprehensive longitudinal studies including both cytopenia and IM. In addition, the transition to adulthood is often particularly challenging for patients with chronic pediatric diseases.14 Adolescents–young adults (AYA) outcomes have not been investigated in patients with pES, and whether the disease improves with age is unknown. In a clinical set- ting, the possibility to identify high-risk patients would be extremely helpful in the management of this complex disease. Here, we describe the long-term course of hema- tological IM and treatments received throughout child- hood into adulthood in patients with pES from the OBS’CEREVANCE cohort. We aimed to identify clinical- ly relevant factors associated to the occurrence of IM, the number of second-line treatments received and mortali- ty. Particularly, we investigated the impact of the number second-line treatment received and splenectomy on mor- tality.
Methods
OBS’CEREVANCE prospective national cohort
Inclusion and exclusion criteria are shown in the Online Supplementary Table S1.1,8,15 Data collected have been previously detailed.1,8 Patients were included if <18 years old at first cytope- nia diagnosis. The coordinating center gathered and analyzed all data from the medical team in charge in real time, enabling prospective follow-up even after the pediatric-to-adult transition. The CEREVANCE group recommends scheduling clinical and bio- logical follow-up at least every 6-12 months. Some patients under- went genetic analyses, as previously described.13 Written informed consent was obtained from parents and eligible patients. The cohort study was approved by the Institutional Ethics Committee (CPPRB-A; Bordeaux, France) and the database was registered with the national data protection authority (CNIL, 1396823V0).
Patient selection
Patients with pES, defined as the simultaneous (within 1 month) or sequential association of ITP and AIHA, were included if at least 5 years of follow-up data were available after the first cytope- nia diagnosis. In order to provide a complete mortality report, all patients, including those with less than 5 years of follow-up data, were included in the survival analyses. The data were extracted on 21 June 2019.
Definitions
Initial cytopenia refers to the onset of ITP or AIHA (whichever occurred first) and does not take autoimmune neutropenia (AIN) into account. The IM categories were separated in clinical (cIM) and biological (bIM). pES was defined as secondary if a diagnosis of SLE or PID was made during the follow-up period. SLE diagno- sis was made according to the Systemic Lupus International Collaborating Clinics Classification criteria (SLICC).16 ALPS diag- nosis was based on international criteria.17 Second-line treatments were all immunomodulatory or immunosuppressive treatments, including splenectomy but excluding steroids and therapeutic intravenous immunoglobulins (IVIG). Sustained complete remis- sion (CR) was defined as remission persisting until final follow-up, regardless of ongoing treatments.
For analyses by age, patients were assessed annually from birth (for IM and treatments) or from cytopenia onset (for AIHA and ITP), until final follow-up. Occasional treatments (e.g., splenecto- my and rituximab) were considered as ongoing if these occurred during the previous year. Further details are stated in the Online Supplementary Table S1.
Statistical analyses
Continuous and categorical variables were compared using Wilcoxon–Mann–Whitney non-parametric test and Fisher’s exact test, respectively. Correlations were tested using the Pearson cor-
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haematologica | 2022; 107(2)