Evans syndrome: Disease awareness and clinical management in a nation-wide ITP-NET survey.

Evans syndrome (ES) is rare and mostly treated on a "case-by-case" basis and no guidelines are available. With the aim of assessing disease awareness and current management of adult ES, a structured survey was administered to 64 clinicians from 50 Italian participating centers. Clinicians had to be involved in the management of autoimmune cytopenias and were enrolled into the ITP-NET initiative. The survey included domains on epidemiology, diagnosis, and therapy of ES and was designed to capture current practice and suggested work-up and management. Thirty clinicians who had followed a median of 5 patients (1-45)/15 years responded. The combination of AIHA plus ITP was more common than the ITP/AIHA with neutropenia (p < .001) and 25% of patients had an associated condition, including lymphoproliferative syndromes, autoimmune diseases, or primary immunodeficiencies. The agreement of clinicians for each diagnostic test is depicted (i.e., 100% for blood count and DAT; only 40% for anti-platelets and anti-neutrophils; 77% for bone marrow evaluation). Most clinicians reported that ES requires a specific approach compared to isolated autoimmune cytopenias, due to either a more complex pathogenesis and a higher risk of relapse and thrombotic and infectious complications. The heterogeneity of treatment choices among different physicians suggests the need for broader harmonization.

Seroconversion to mRNA SARS-CoV-2 Vaccines in Hematologic Patients.

Hematologic patients show lower responses to SARS-CoV-2 vaccines, but predictors of seroconversion are lacking. In this prospective cohort study, hematologic patients undergoing SARS-CoV-2 mRNA vaccination at a single center in Milan, Italy, were sampled for anti-Spike and anti-Nucleocapsid IgG titer at 5 ± 1 weeks and at 3 months from the second vaccine dose. Patients (N = 393) received either BNT162b2 (Pfizer-BioNTech, 48%) or MRNA-1273 (Moderna, 52%), and 284 (72%) seroconverted and 100% persisted at 3 months. Non-response was higher in chronic lymphocytic leukemia (CLL) and lymphoma patients, and in those treated with small molecules and monoclonal antibodies. In myeloid neoplasms, lower responses were detected in patients with acute myeloid leukemia treated with venetoclax plus hypomethylating agents and in patients with myelofibrosis receiving ruxolitinib. Multivariable analysis showed that seroconversion was favorably associated with a diagnosis other than indolent lymphoma/CLL [OR 8.5 (95% CI 4.1-17.6)], lack of B-cell-depleting therapy [OR 3.15 (1.7-5.9)], and IgG levels within the normal range [OR 2.2 (1.2-4.2)]. We developed a simple algorithm according to these 3 risk factors [(A) diagnosis of indolent lymphoma/CLL, (B) B-cell-depleting treatment, and (C) low IgG] to predict non-response. IgG levels and treatment may be modifiable risk factors and should be considered for timing of vaccine administration.

Intravascular hemolysis and multitreatment predict thrombosis in patients with autoimmune hemolytic anemia.

BACKGROUND: Thrombosis may complicate autoimmune hemolytic anemia (AIHA), but its predictors are still lacking, and no clear-cut indications for anticoagulant prophylaxis are available. OBJECTIVES: To characterize frequency and severity of thromboses in AIHA patients and identify risk factors for thrombosis that may advise primary anticoagulant prophylaxis. PATIENTS/METHODS: A total of 287 consecutive AIHA patients diagnosed and followed from 1978 at a tertiary Italian center were retrospectively studied; 174 of them were prospectively evaluated from January 2020 until December 2021. AIHA relapse, thrombosis occurrence, and primary anticoagulant prophylaxis were evaluated. RESULTS: Thirty-three AIHA patients (11.4%) experienced thrombosis, 70% of whom hospitalized. The cumulative thrombosis incidence was higher in patients with lactate dehydrogenase (LDH) ≥ 1.5 (hazard ratio [HR] 3.22), in those experiencing infections (HR 3.57), receiving transfusions (HR 3.06), rituximab (HR 3.3), or cyclophosphamide (HR 2.67). By multivariable analysis, LDH, transfusions, rituximab, and cyclophosphamide treatment emerged as independent factors associated with thrombosis. Among 174 patients prospectively followed in the past 2 years, we observed 70 acute hemolytic episodes in 45 patients; 33/45 displayed LDH ≥1.5 × upper limit of normal, and 17 received anticoagulant prophylaxis with low molecular weight heparin for a median of 70 days (30-300). In those receiving prophylaxis no thrombotic complications occurred, whereas five thrombotic episodes were registered in the remaining 16 cases. CONCLUSIONS: Thrombosis was observed in about 11% of AIHA patients, mainly grade 3, and associated with intravascular hemolysis, need of transfusions, multitreatment, and infections, advising primary anticoagulant prophylaxis in these settings.

Seroconversion to mRNA SARS-CoV-2 vaccines in patients with autoimmune cytopenias and bone marrow failures.

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.

Efficacy and safety of cyclosporine A treatment in autoimmune cytopenias: the experience of two Italian reference centers.

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.

Low-Risk Myelodysplastic Syndrome Revisited: Morphological, Autoimmune, and Molecular Features as Predictors of Outcome in a Single Center Experience.

Low-risk myelodysplastic syndromes (LR-MDS) are a very heterogeneous disease, with extremely variable clinical features and outcome. Therapeutic strategies are still limited and mainly consist of erythropoiesis-stimulating agents (ESAs) and transfusion support. The contribution of molecular lesions and of autoimmune phenomena to pathogenesis and clinical course, including leukemic evolution, is a field of open investigation. We analyzed data from a cohort of 226 patients with LR-MDS followed at our center in the last 20 years, focusing on morphological, immunological (antiplatelets and anti-erythrocyte autoantibodies, anti-erythroblast antibodies), and molecular features. Hypoplastic bone marrow was found in 7% of the cases correlating with younger age, deeper cytopenia, lower dysplasia, and worse response to ESAs. A marker of autoimmunity was observed in 46% of the tested cases, who were younger, were less frequent dysplastic changes, and responded better to ESAs and steroids. Finally, 68% of the tested cases displayed at least one somatic mutation, most commonly SF3B1, TET2, ASXL1, and SRSF2, associated with older age, presence of neutropenia, and lower response to ESAs. Leukemic evolution (2.2%) was associated with presence of somatic mutations, and survival was favorably related to response to ESAs and transfusion independence. Overall, granular evaluation and re-evaluation are pivotal in LR-MDS patients to optimize clinical management.

Changing trends of splenectomy in hereditary spherocytosis: The experience of a reference Centre in the last 40 years.

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.

Clinical exome sequencing for diagnosing severe cryptogenic liver disease in adults: A case series.

Liver diseases remain unexplained in up to 30% of adult patients; genetic analysis could help establish the correct diagnosis. In six adult patients with cryptogenic liver disease, we performed whole-exome sequencing (WES) and evaluated the individual predisposition to progressive fatty liver disease by polygenic risk scores (PRS). In one patient, WES was allowed to diagnose the Hermansky-Pudlak syndrome. In the other two patients, genetic variants in LDLRAP1/MSH6 and ALDOB genes were identified, contributing to explaining the clinical presentation and disease pathogenesis (50% diagnostic uptake). In the other three patients, rare variants with a high likelihood of disrupting protein function in APOB, ATP7B, ABCB4 and ATP8B1 were identified. One patient who developed hepatocellular carcinoma during the follow-up had a high PRS value. The study supports the role of WES, combined with risk stratification by PRS and accurate clinical assessment in improving the diagnosis and informed management in patients with cryptogenic liver disease, a positive family history or severe fatty liver not fully accounted for by environmental triggers.

Paroxysmal Nocturnal Hemoglobinuria in the Context of a Myeloproliferative Neoplasm: A Case Report and Review of the Literature.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolytic anemia and thrombosis and is notoriously associated with aplastic anemia and myelodysplastic syndromes. Rarer associations include myeloproliferative neoplasms (MPNs), which are also burdened by increased thrombotic tendency. The therapeutic management of this rare combination has not been defined so far. Here, we describe a 62-year-old man who developed a highly hemolytic PNH more than 10 years after the diagnosis of MPN. The patient started eculizumab, obtaining good control of intravascular hemolysis but without amelioration of transfusion-dependent anemia. Moreover, we performed a review of the literature regarding the clinical and pathogenetic significance of the association of PNH and MPN. The prevalence of PNH clones in MPN patients is about 10%, mostly in association with JAK2V617F-positive myelofibrosis. Thrombotic events were a common clinical presentation (35% of subjects), sometimes refractory to combined treatment with cytoreductive agents, anticoagulants, and complement inhibitors. The latter showed only partial effectiveness in controlling hemolytic anemia and, due to the paucity of data, should be taken in consideration after a careful risk/benefit evaluation in this peculiar setting.

Co-Occurrence of Myeloid and Lymphoid Neoplasms: Clinical Characterization and Impact on Outcome. A Single-Center Cohort Study.

The co-occurrence of myeloid neoplasms and lymphoproliferative diseases (LPDs) has been epidemiologically described, particularly in myeloproliferative neoplasms (MPNs). However, the clinical features of these patients are poorly known. In this study, we evaluated a single-center cohort of 44 patients with a diagnosis of myeloid and LPD focusing on clinical features, therapy requirement, and outcome. The two diagnoses were concomitant in 32% of patients, while myeloid disease preceded LPD in 52% of cases (after a median of 37 months, 6-318), and LPD preceded myeloid neoplasm in 16% (after a median of 41 months, 5-242). The most prevalent LPD was non-Hodgkin lymphoma (50%), particularly lymphoplasmacytic lymphoma (54.5%), followed by chronic lymphocytic leukemia (27%), plasma cell dyscrasias (18.2%), and rarer associations such as Hodgkin lymphoma and Erdheim-Chester disease. Overall, 80% of BCR-ABL1-negative MPN patients required a myeloid-specific treatment and LPD received therapy in 45.5% of cases. Seven subjects experienced vascular events, 13 a grade >/= 3 infectious episode (9 pneumonias, 3 urinary tract infection, and 1 sepsis), and 9 developed a solid tumor. Finally, nine patients died due to solid tumor (four), leukemic progression (two), infectious complications (two), and brain bleeding (one). Longer survival was observed in younger patients (p = 0.001), with better performance status (p = 0.02) and in the presence of driver mutations (p = 0.003). Contrarily, a worse survival was significantly associated with the occurrence of infections (p < 0.0001). These data suggest that in subjects with co-occurrence of myeloid and lymphoid neoplasms, high medical surveillance for infectious complications is needed, along with patient education, since they may negatively impact outcome.

Bortezomib in autoimmune hemolytic anemia and beyond.

Bortezomib is a first-in-class, potent, selective and reversible proteasome inhibitor approved for the treatment of multiple myeloma (MM) and relapsed/refractory mantle cell lymphoma. In these diseases, bortezomib targets plasma cells and lymphocytes reducing tumor burden. Recently, preclinical evidence highlighted its efficacy in reducing long-lived plasma cells responsible of autoantibodies production in several models of autoimmune conditions. These findings paved the way to a number of experiences of bortezomib use in patients with various autoimmune conditions, including autoimmune hemolytic anemia (AIHA). The latter is a nice model of autoimmunity in hematology and is caused by the production of autoantibodies against erythrocytes resulting in various degrees of hemolytic anemia. AIHA is classified in warm and cold forms according to the thermal characteristics of the autoantibody, and first-line treatment mainly relies on steroids for warm cases and the anti-CD20 rituximab for cold ones. Relapsed/refractory cases are still an unmet need, and bortezomib has been proposed in this setting with intriguing efficacy. In this review, we collected available literature on bortezomib use in AIHA and in other immune-mediated hematologic and non-hematologic diseases. Overall, most experiences highlight bortezomib efficacy even in multi-relapsed/refractory patients and suggest to consider its use in AIHA after rituximab failure.

Off-Label Use of Thrombopoietin Receptor Agonists: Case Series and Review of the Literature.

Since their license in 2008, studies on thrombopoietin receptor agonists (TPO-RAs) are proceeding at a fast pace. Their favorable efficacy and safety profile makes them good candidates for the management of thrombocytopenia in different settings, even beyond their current indications. In the last 10 years, we faced patients with refractory thrombocytopenia that required treatment with off-label TPO-RA, despite the paucity of data in the literature and the possible risks, particularly that of thrombosis. We hereby report our 10-year real-life single-center experience of TPO-RA used off-label. Fourteen patients were divided into three groups according to the etiology of thrombocytopenia: myelodysplastic syndromes, post-transplantation, and lymphoproliferative diseases. Clinical features and results are reported within each group. Overall, TPO-RA proved effective in all these conditions achieving responses also in heavily pretreated patients. The overall response rate (ORR) was 100% in patients with thrombocytopenia after transplantation and in those with lymphoproliferative diseases and 75% in patients with myelodysplastic syndromes. The median duration of therapy was 285 days (range 93-1,513 days). Four patients (29%) discontinued treatment because of lack of response (n=2) or a sustained response (n=2). No grade 3-4 adverse events occurred, particularly no thrombosis. In our real-life experience, TPO-RAs were effective and safe and proved of value in the challenging management of patients with refractory thrombocytopenia associated with different conditions.

Large Granular Lymphocyte Expansion in Myeloid Diseases and Bone Marrow Failure Syndromes: Whoever Seeks Finds.

Large granular lymphocytes (LGL) are lymphoid cells characterized by either a T-cell or a natural killer phenotype whose expansion may be reactive to toxic, infectious, and neoplastic conditions, or result from clonal selection. Recently, the higher attention to LGL clones led to their detection in many clinical conditions including myeloid neoplasms and bone marrow failures. In these contexts, it is still unclear whether LGL cells actively contribute to anti-stem cell autoimmunity or are only a reaction to dysplastic/leukemic myelopoiesis. Moreover, some evidence exists about a common clonal origin of LGL and myeloid clones, including the detection of STAT3 mutations, typical of LGL, in myeloid precursors from myelodysplastic patients. In this article we reviewed available literature regarding the association of LGL clones with myeloid neoplasms (myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukemias) and bone marrow failures (aplastic anemia and pure red cell aplasia, PRCA) focusing on evidence of pathogenic, clinical, and prognostic relevance. It emerged that LGL clones may be found in up to one third of patients, particularly those with PRCA, and are associated with a more cytopenic phenotype and good response to immunosuppression. Pathogenically, LGL clones seem to expand after myeloid therapies, whilst immunosuppression leading to LGL depletion may favor leukemic escape and thus requires caution.