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.

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.

In the last decade, a deeper understanding of the pathogenesis of complement mediated hemolytic disorders, such as paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), warm type autoimmune hemolytic anemia (AIHA) with complement activation (wAIHA), and atypical hemolytic uremic syndrome (aHUS), paved the way to the therapeutic shift from purely supportive approaches to complement‐targeted therapies. This resulted in a significant improvement in disease management, survival, and quality of life. In this review, we will provide a snapshot of novel therapies for complement‐mediated hemolytic anemias with a focus on those ready to use in clinical practice. C5 inhibitors eculizumab and the long‐acting ravulizumab, are the established gold standard for untreated PNH patients, whilst the C3 inhibitor pegcetacoplan should be considered for suboptimal responders to anti‐C5 drugs. Several additional compounds targeting the complement cascade at different levels (other C5 inhibitors, factor B and D inhibitors) are under active investigation with promising results. In CAD, immunosuppression with rituximab remains the first‐line. However, recently FDA and EMA approved the anti‐C1s monoclonal antibody, sutimlimab, that showed dramatic responses and whose regulatory approval is soon awaited in many countries. Other drugs under investigation in AIHA include the C3 inhibitor pegcetacoplan, and the anti‐C1q ANX005 for warm AIHA with complement activation. Finally, aHUS is an indication for complement inhibitors. Eculizumab and ravulizumab have been approved, whilst other C5 inhibitors, and novel lectin pathway inhibitors are under active investigation in this disease.

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.

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.

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Hypogammaglobulinemia (HGG) is a frequent finding in patients with hematological malignancies, and is commonly described in chronic lymphocytic leukemia (CLL) before or after treatment. We reviewed published literature available online in the last thirty years through Medline search of indexed articles focusing on the main differences and advantages of the products now available on the market, namely intravenous Ig (IVIg) and subcutaneous Ig (SCIg) preparations. IgRT is effective and safe in the prophylaxis of infections in a selected group of patients with CLL and hypogammaglobulinemia and is therefore a valuable tool for clinicians in the everyday management of infectious risk. We encourage the use of SCIg formulations as they appear to have similar efficacy but better cost-effectiveness and tolerability.

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