Juri Alessandro Giannotta

Diagnostic boundaries between immune thrombocytopenia (ITP) and other thrombocytopenic states, such as thrombocytopenic myelodysplastic syndromes, may be difficult to establish, and the detection of somatic mutations by next-generation sequencing (NGS) may be of aid. Here, we aimed at characterizing the prevalence and clinical significance of clonal hematopoiesis in ITP. In this multicentric retrospective observational study, we enrolled 167 adult patients with ITP, followed at 13 centers in Italy, United Kingdom, and the United States. Patients underwent NGS evaluation after a median of 3.6 years from ITP onset, and 83% had received at least 1 therapy line, for a median of 2 lines (range, 0-9); 51 of 167 patients (30%) had at least 1 mutation. After exclusion of germ line variants and polymorphisms, 31 of 167 (18.5%) were defined as having clonal hemopoiesis. Most commonly mutated genes were TET2, DNMT3A, SRSF2, and ASXL1 (median variant allele frequency, 29%); 19 of 31 patients (68%) had high-risk variants, and 8 had multiple mutations. Mutated patients were more frequently older males and showed a shorter time from first to second-line therapy, particularly with thrombopoietin receptor agonist (TPO-RA). Additionally, clonal hematopoiesis was associated with increased thrombotic risk (26% vs 8% in NGS-negative cases; P = .01), independently from TPO-RA exposure, though with an age effect. These data demonstrated the prevalence of clonal hematopoiesis in 18% of adult patients with ITP, which is associated with older age, relapsed/refractory disease, and high risk of thrombotic complications.

Data concerning the efficacy of SARS-CoV-2 vaccines in patients with non-oncological hematologic conditions are lacking. These include autoimmune cytopenias (autoimmune hemolytic anemia AIHA, immune thrombocytopenia ITP, and autoimmune neutropenia), and bone marrow failure syndromes (aplastic anemia, low risk myelodysplastic syndromes, and paroxysmal nocturnal hemoglobinuria). These conditions may relapse/reactivate after COVID-19 infection and vaccine. Moreover, they are mainly handled with immunosuppressive drugs that may hamper the response to vaccine. In this study, we prospectively evaluated the rate of seroconversion after mRNA SARS-CoV-2 vaccines in patients with autoimmune cytopenias or bone marrow failure syndrome after 2 ± 1 months from the last vaccine dose. Overall, 149 patients were tested and 135 (91%) seroconverted. The highest proportion of non-responders was observed in Evans syndrome (association of ITP and AIHA) and warm AIHA patients (p = 0.001), in those with lower levels of baseline serum IgG (p = 0.008), and in patients on active therapy with steroids (p = 0.03) who also had lower anti-Spike titers. The latter were inversely related with age, and a positively with lymphocyte counts. Additionally, patients who had received rituximab within 12 months from vaccination showed higher rates of non-response (p = 0.03) as compared to those treated before. Contrarily, cyclosporine alone, complement inhibitors, and bone marrow stimulating agents had no detrimental effect on seroconversion. These data suggest maintaining high vigilance and adherence to preventive/protective measures in this population since a proportion of cases may not respond or exhibit low anti-Spike titers.

Summary: We describe the clinical/haematological characteristics of 446 patients with hereditary spherocytosis diagnosed in the last 40 years in a reference centre. The frequency of splenectomy decreased over time (44% before 1990 to 7% in 2011–2020), notwithstanding a confirmed good efficacy. Age at splenectomy progressively increased (63% in children before 1990 to 88% in patients aged ≥20 years in 2011–2020). Our real‐life experience showed that even a fraction of patients in the trait/mild categories (19/92, 21%) were splenectomised, whilst 30/78 (38%) in the moderate/severe groups were not. Overall, these data pinpoint to the increasing awareness about post‐splenectomy thromboses and infections.

Background: Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) show good responses to frontline steroids. About two-third of cases relapse and require second-line treatment, including rituximab, mainly effective in AIHA, and thrombopoietin-receptor agonists (TPO-RAs) in ITP, while the use of splenectomy progressively decreased due to concerns for infectious/thrombotic complications. For those failing second line, immunosuppressants may be considered. Objectives: The aim of this study was to evaluate the efficacy of cyclosporine treatment in patients with ITP and AIHA. Design: In this retrospective study, we evaluated the efficacy and safety of cyclosporine A (CyA) in ITP ( N = 29) and AIHA ( N = 10) patients followed at two reference centers in Milan, Italy. Methods: Responses were classified as partial [Hb > 10 or at least 2 g/dl increase from baseline, platelets (PLT) > 30 × 10⁹/l with at least doubling from baseline] and complete (Hb > 12 g/dl or PLT > 100 × 10⁹/l) and evaluated at 3, 6, and 12 months. Treatment emergent adverse events were also registered. Results: The median time from diagnosis to CyA was 35 months (3–293), and patients had required a median of 4 (1–8) previous therapy lines. Median duration of CyA was 28 (2–140) months and responses were achieved in 86% of ITP and 50% of AIHA subjects. Responders could reduce or discontinue concomitant treatment and resolved PLT fluctuations on TPO-RA. CyA was generally well tolerated, and only two serious infectious complications in elderly patients on concomitant steroids suggesting caution in this patient population. Conclusion: CyA may be advisable in ITP, which is not well controlled under TPO-RA, and in AIHA failing rituximab, particularly if ineligible in clinical trial.

Evans syndrome (ES) is a rare condition, defined as the presence of 2 autoimmune cytopenias, most frequently autoimmune hemolytic anemia and immune thrombocytopenia (ITP) and rarely autoimmune neutropenia. ES can be classified as primary or secondary to various conditions, including lymphoproliferative disorders, other systemic autoimmune diseases, and primary immunodeficiencies, particularly in children. In adult ES, little is known about clinical features, disease associations, and outcomes. In this retrospective international study, we analyzed 116 adult patients followed at 13 European tertiary centers, focusing on treatment requirements, occurrence of complications, and death. ES was secondary to or associated with underlying conditions in 24 cases (21%), mainly other autoimmune diseases and hematologic neoplasms. Bleeding occurred in 42% of patients, mainly low grade and at ITP onset. Almost all patients received first-line treatment (steroids with or without intravenous immunoglobulin), and 23% needed early additional therapy for primary refractoriness. Additional therapy lines included rituximab, splenectomy, immunosuppressants, thrombopoietin receptor agonists, and others, with response rates >80%. However, a remarkable number of relapses occurred, requiring ≥3 therapy lines in 54% of cases. Infections and thrombotic complications occurred in 33% and 21% of patients, respectively, mainly grade ≥3, and correlated with the number of therapy lines. In addition to age, other factors negatively affecting survival were severe anemia at onset and occurrence of relapse, infection, and thrombosis. These data show that adult ES is often severe and marked by a relapsing clinical course and potentially fatal complications, pinpointing the need for high clinical awareness, prompt therapy, and anti-infectious/anti-thrombotic prophylaxis.