Autoimmune hemolytic anemia during pregnancy and puerperium: an international multicenter experience.

Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here, we report 45 pregnancies in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women diagnosed with AIHA before pregnancy, 10 had a relapse. An additional 13 patients developed de novo AIHA during gestation/puerperium (2 patients had AIHA relapse during a second pregnancy). Among 24 hemolytic events, anemia was uniformly severe (median Hb, 6.4 g/dL; range, 3.1-8.7) and required treatment in all cases (96% steroids ± intravenous immunoglobulin, IVIG, 58% transfusions). Response was achieved in all patients and was complete in 65% of the cases. Antithrombotic prophylaxis was administered to 8 patients (33%). After delivery, rituximab was administered to 4 patients, and cyclosporine was added to 1 patient. The rate of maternal complications, including premature rupture of membranes, placental detachment, and preeclampsia, was 15%. Early miscarriages occurred in 13% of the pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and 2 perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry out a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications.

Transfusions in autoimmune hemolytic anemias: Frequency and clinical significance of alloimmunization.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) may be associated with transfusion reactions and risk of alloimmunization. OBJECTIVES: To evaluate the transfusion policy and rate of alloimmunization and its clinical significance in AIHA. METHODS: Data from 305 AIHA patients followed at a reference hematologic Center in Milan, Italy from 1997 to 2022 were retrospectively/prospectively collected (NCT05931718). RESULTS: Overall, 33% patients required transfusions with a response rate of 83% and eight transfusion reactions (7%), none hemolytic. Alloantibodies were detected in 19% of patients, being associated with higher transfusion burden (p = 0.01), lower Hb increase post-transfusion (p = 0.05), and transfusion reactions (p = 0.04). Along decades, the rate of RBC transfusions decreased from 53% to 20% and that of alloimmunization dropped from 30% to 6% likely due to the adoption of prestorage leukoreduction, the use of more restrictive Hb thresholds, and the implementation of molecular typing. CONCLUSIONS: Severe symptomatic AIHA may be safely transfused provided appropriate matching of patients and donors.

Current use of androgens in bone marrow failure disorders: a report from the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation.

Androgens represent the historical therapeutic backbone of bone marrow failure (BMF) syndromes. However, their role has rarely been analyzed in a prospective setting, and systematic and long-term data regarding their usage, effectiveness and toxicity in both acquired and inherited BMF are currently unavailable. Here, taking advantage of a unique disease-specific international dataset, we retrospectively analyzed the largest cohort so far of BMF patients who received androgens before or in the absence of an allogeneic hematopoietic cell transplantation (HCT), re-evaluating their current use in these disorders. We identified 274 patients across 82 European Society for Blood and Marrow Transplantation (EBMT) affiliated centers: 193 with acquired (median age 32 years) and 81 with inherited (median age 8 years) BMF. With a median duration of androgen treatment of 5.6 and 20 months, respectively, complete and partial remission rates at 3 months were 6% and 29% in acquired and 8% and 29% in inherited disorders. Five-year overall survival and failure-free survival (FFS) were respectively 63% and 23% in acquired and 78% and 14% in inherited BMF. Androgen initiation after second-line treatments for acquired BMF, and after >12 months post diagnosis for inherited BMF were identified as factors associated with improved FFS in multivariable analysis. Androgen use was associated with a manageable incidence of organ-specific toxicity, and low rates of solid and hematologic malignancies. Sub-analysis of transplant-related outcomes after exposure to these compounds showed probabilities of survival and complications similar to other transplanted BMF cohorts. This study delivers a unique opportunity to track androgen use in BMF syndromes and represents the basis for general recommendations on this category of therapeutics on behalf of the Severe Aplastic Anemia Working Party of the EBMT.

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.

COVID-19 vaccine safety and immunogenicity in patients with cold agglutinin disease receiving concomitant sutimlimab.

Patients with cold agglutinin disease (CAD) are more vulnerable to infectious agents, thus the COVID-19 pandemic has posed a particular risk to this population. Sutimlimab Phase 3 studies CARDINAL and CADENZA spanned the period before and during the pandemic; investigators were advised to vaccinate enrolled patients without stopping treatment. Of 61 completers from both studies, 47 received ≥1 dose of a COVID-19 vaccine. In the immunogenicity analysis (n = 27) all patients developed an immune response post-COVID-19 vaccination, with detectable immunoglobulin G anti-spike antibodies. Analysis of six patients with booster vaccinations demonstrated increased immune responses pre- to post-booster. COVID-19 vaccines were well tolerated in patients with CAD receiving sutimlimab treatment, and no signs of hemolytic exacerbations were observed post-vaccination.

Glycolytic activity and in vitro effect of the pyruvate kinase activator AG-946 in red blood cells from low-risk myelodysplastic syndromes patients: A proof-of-concept study.

Glycolytic activity and in vitro effect of the pyruvate kinase activator AG-946 in red blood cells from low-risk myelodysplastic syndromes patients. Data showed decreased glycolytic activity in red blood cells of 2/3 of patients with lower-risk MDS. These results highlight a potential effect of the PK activator in this setting.

Moving toward Individual Treatment Goals with Pegcetacoplan in Patients with PNH and Impaired Bone Marrow Function.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, potentially life-threatening haematological disease characterised by chronic complement-mediated haemolysis with multiple clinical consequences that impair quality of life. This post hoc analysis assessed haematological and clinical responses to the first targeted complement C3 inhibitor pegcetacoplan in patients with PNH and impaired bone marrow function in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. For patients with impaired bone marrow function, defined herein as haemoglobin <10 g/dL and absolute neutrophil count <1.5 × 109 cells/L, normalisation of the parameters may be difficult. Indeed, 20% and 43% had normalised haemoglobin in PEGASUS and PRINCE, respectively; 60% and 57% had normalised LDH, and 40% and 29% had normalised fatigue scores. A new set of parameters was applied using changes associated with clinically meaningful improvements, namely an increase in haemoglobin to ≥2 g/dL above baseline, decrease in LDH to ≤1.5× the upper limit of normal, and an increase in fatigue scores to ≥5 points above baseline. With these new parameters, 40% and 71% of PEGASUS and PRINCE patients had improved haemoglobin; 60% and 71% had an improvement in LDH, and 60% and 43% had an improvement in fatigue scores. Thus, even patients with impaired bone marrow function may achieve clinically meaningful improvements with pegcetacoplan.

How I treat warm autoimmune hemolytic anemia.

Warm autoimmune hemolytic anemia (wAIHA) is caused by increased erythrocyte destruction by immunoglobulin G (IgG) autoantibodies, with or without complement activation. Antibody-dependent cell-mediated cytotoxicity by macrophages/activated lymphocytes occurs in the lymphoid organs and spleen (extravascular hemolysis). The ability of the bone marrow (BM) to compensate determines clinical severity. The different pathogenic mechanisms, their complex interplay, and changes over time may explain wAIHA's great clinical heterogeneity and unpredictable course. The disease may be primary, drug induced, or associated with lymphoproliferative neoplasms, autoimmune and infectious diseases, immunodeficiencies, solid tumors, or transplants. Therapeutic interventions include steroids, splenectomy, immunosuppressants, and rituximab; the latter is increasingly used in steroid-refractory cases based on evidence from the literature and a few prospective trials. We present 5 patient case studies highlighting important issues: (1) the diagnosis and proper use of steroid therapy, (2) the concerns about the choice between rituximab and splenectomy in second-line treatment, (3) the need of periodical re-evaluation of the disease to assess the possible evolution of relapsed/refractory cases in myelodysplastic and BM failure syndromes, and (4) the difficulties in managing cases of severe/acute disease that are at high risk of relapse. Incorporating novel targeted therapies into clinical practice will be an exciting challenge in the future.

Molecular pharmacology in complement-mediated hemolytic disorders.

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.

Luspatercept in combination with recombinant erythropoietin in patients with myelodysplastic syndrome with ring sideroblasts: Stimulating early and late-stage erythropoiesis.

Patients with myelodysplastic syndromes and ring sideroblasts (MDS RS) are clinically characterized by severe anemia and transfusion need. Erythropoiesis-stimulating agents (ESAs), which stimulate hemoglobin production and early maturation of erythroid precursors, are effective only in a portion of patients and for limited time. Luspatercept, an inhibitor of the TGF-beta pathway, is beneficial in unblocking late-stage erythropoiesis and has been approved for MDS RS patients failing or not-candidate to ESAs. ESAs and/or luspatercept failure represents an unmet clinical need and most patients become life-long transfusion dependent. Here, we describe the clinical combination of luspatercept with ESAs (subcutaneous epoetin alpha 40-80 000 IU/week) in seven MDS RS patients. Two patients had ESAs as pre-existing therapy, while five were re-challenged with ESAs as add-on treatment due to luspatercept failure. Three patients achieved hematologic improvement, and one became transfusion independent. No adverse events were noted. This is the first clinical evidence that stimulating both early and late-stage erythropoiesis may offer a further option for this challenging patient population.

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.

Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients.

Outcomes for patients with hematologic malignancy infected with COVID-19 have not been aggregated. The objective of this study was to perform a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. We searched PubMed and EMBASE up to 20 August 2020 to identify reports of patients with hematologic malignancy and COVID-19. The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included risk of intensive care unit admission and ventilation in hospitalized patients. Subgroup analyses included mortality stratified by age, treatment status, and malignancy subtype. Pooled prevalence, risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-four adult and 5 pediatric studies (3377 patients) from Asia, Europe, and North America were included (14 of 34 adult studies included only hospitalized patients). Risk of death among adult patients was 34% (95% CI, 28-39; N = 3240) in this sample of predominantly hospitalized patients. Patients aged ≥60 years had a significantly higher risk of death than patients <60 years (RR, 1.82; 95% CI, 1.45-2.27; N = 1169). The risk of death in pediatric patients was 4% (95% CI, 1-9; N = 102). RR of death comparing patients with recent systemic anticancer therapy to no treatment was 1.17 (95% CI, 0.83-1.64; N = 736). Adult patients with hematologic malignancy and COVID-19, especially hospitalized patients, have a high risk of dying. Patients ≥60 years have significantly higher mortality; pediatric patients appear to be relatively spared. Recent cancer treatment does not appear to significantly increase the risk of death.

Cold agglutinin disease revisited: a multinational, observational study of 232 patients.

We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.

Pulmonary embolism in a patient with eltrombopag-treated aplastic anaemia and paroxysmal nocturnal haemoglobinuria clone during COVID-19 pneumonia.

Thrombosis in patients with thrombocytopenia has several risk factors, both disease-related and treatment-associated. Recently, COVID-19 infection was recognized as an additional risk factor, further complicating the delicate balance between thrombosis and bleeding in these patients. Here we describe the case of a patient with aplastic anaemia on eltrombopag who developed pulmonary embolism during COVID-19 pneumonia, despite receiving oral anticoagulation with edoxaban. Notably, he was also carrying a large paroxysmal nocturnal haemoglobinuria clone, although without evidence of haemolysis. The presented case recapitulates some of the open questions in thrombotic risk management of cytopenic patients, such as the management of thrombopoietin receptor agonists and the choice of anticoagulation in PNH, while also accounting for the additional thrombotic risk linked to COVID-19.

Mesenchymal Stem Cells in Aplastic Anemia and Myelodysplastic Syndromes: The "Seed and Soil" Crosstalk.

There is growing interest in the contribution of the marrow niche to the pathogenesis of bone marrow failure syndromes, i.e., aplastic anemia (AA) and myelodysplastic syndromes (MDSs). In particular, mesenchymal stem cells (MSCs) are multipotent cells that contribute to the organization and function of the hematopoietic niche through their repopulating and supporting abilities, as well as immunomodulatory properties. The latter are of great interest in MDSs and, particularly, AA, where an immune attack against hematopoietic stem cells is the key pathogenic player. We, therefore, conducted Medline research, including all available evidence from the last 10 years concerning the role of MSCs in these two diseases. The data presented show that MSCs display morphologic, functional, and genetic alterations in AA and MDSs and contribute to immune imbalance, ineffective hematopoiesis, and leukemic evolution. Importantly, adoptive MSC infusion from healthy donors can be exploited to heal the "sick" niche, with even better outcomes if cotransplanted with allogeneic hematopoietic stem cells. Finally, future studies on MSCs and the whole microenvironment will further elucidate AA and MDS pathogenesis and possibly improve treatment.

Iron overload in congenital haemolytic anaemias: role of hepcidin and cytokines and predictive value of ferritin and transferrin saturation.

Iron overload (IO) is poorly investigated in the congenital haemolytic anaemias (CHAs), a heterogeneous group of rare inherited diseases encompassing abnormalities of the erythrocyte membrane and metabolism, and defects of the erythropoiesis. In this study we systematically evaluated routine iron parameters and cardiac and hepatic magnetic resonance imaging, together with erythropoietin, hepcidin, non-transferrin bound iron (NTBI), and cytokine serum levels in patients with different CHAs. We found that 40% of patients had a liver iron concentration (LIC) >4 mg Fe/g dry weight. Hepatic IO was associated with ferritin levels (P = 0·0025), transferrin saturation (TfSat, P = 0·002) and NTBI (P = 0·003). Moreover, ferritin >500 µg/l plus TfSat >60% was demonstrated as the best combination able to identify increased LIC, and TfSat alteration as more important in cases with discordant values. Possible confounding factors, such as transfusions, hepatic disease, metabolic syndrome and hereditary haemochromatosis-associated mutations, had negligible effects on IO. Erythropoietin and hepcidin levels were increased in CHAs compared with controls, correlating with LIC and ferritin, respectively. Regarding cytokines, γ-interferon (IFN-γ) was increased, and both interleukin 6 and IFN-γ levels positively correlated with ferritin and hepcidin levels. Overall, these findings suggest the existence of a vicious cycle between chronic haemolysis, inflammatory response and IO in CHAs.