Publications by authors named "Wilma Barcellini"

125 Publications

Targeted Next Generation Sequencing and Diagnosis of Congenital Hemolytic Anemias: A Three Years Experience Monocentric Study.

Front Physiol 2021 21;12:684569. Epub 2021 May 21.

UOS Fisiopatologia delle Anemie, UOC Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Congenital hemolytic anemias (CHAs) are heterogeneous and rare disorders caused by alterations in structure, membrane transport, metabolism, or red blood cell production. The pathophysiology of these diseases, in particular the rarest, is often poorly understood, and easy-to-apply tools for diagnosis, clinical management, and patient stratification are still lacking. We report the 3-years monocentric experience with a 43 genes targeted Next Generation Sequencing (t-NGS) panel in diagnosis of CHAs; 122 patients from 105 unrelated families were investigated and the results compared with conventional laboratory pathway. Patients were divided in two groups: 1) cases diagnosed with hematologic investigations to be confirmed at molecular level, and 2) patients with unexplained anemia after extensive hematologic investigation. The overall sensitivity of t-NGS was 74 and 35% for families of groups 1 and 2, respectively. Inside this cohort of patients we identified 26 new pathogenic variants confirmed by functional evidence. The implementation of laboratory work-up with t-NGS increased the number of diagnoses in cases with unexplained anemia; cytoskeleton defects are well detected by conventional tools, deserving t-NGS to atypical cases; the diagnosis of Gardos channelopathy, some enzyme deficiencies, familial siterosterolemia, X-linked defects in females and other rare and ultra-rare diseases definitely benefits of t-NGS approaches.
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http://dx.doi.org/10.3389/fphys.2021.684569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176228PMC
May 2021

SARS-CoV-2 vaccination induces breakthrough hemolysis in paroxysmal nocturnal hemoglobinuria on complement inhibitor.

Am J Hematol 2021 May 31. Epub 2021 May 31.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1002/ajh.26262DOI Listing
May 2021

The impact of Parvovirus B19 on hereditary haemolytic anaemias.

Br J Haematol 2021 May 30;193(4):703-704. Epub 2021 Apr 30.

Department of Woman's and Child's Health, University of Padua, Padua, Italy.

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http://dx.doi.org/10.1111/bjh.17485DOI Listing
May 2021

Real-world use of thrombopoietin receptor agonists in elderly patients with primary immune thrombocytopenia.

Blood 2021 Apr 22. Epub 2021 Apr 22.

(Institute of Hematology, Bologna, Italy.

The efficacy and safety of thrombopoietin-receptor agonists (TRAs) in elderly patients with primary immune thrombocytopenia (ITP) is uncertain. In 384 ITP patients treated with TRAs when aged ≥60 years, we investigated TRAs response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROT). After 3 months, 82.5% and 74.3% of eltrombopag and romiplostim-treated patients achieved a response, respectively (p=0.09); 66.7% maintained the response (median follow-up: 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; while no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. During TRA, 34 major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, and were associated with thrombosis history (SHR: 2.04, p=0.05) and platelet count <20x109/L at TRA start (SHR: 1.69, p=0.04), respectively. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but one during persisting TRA treatment (incidence rate: 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRA; 53 (13.8%) patients maintained SROT, which was associated with TRA discontinuation in complete response (p<0.001). Very old age (≥75, 41.1%) was associated with more frequent TRAs start in persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in elderly ITP patients, with no fatal haemorrhages and with SROT in a significant portion of patients; in patients with thrombosis history caution is warranted and a careful risk/benefit balance should be carried out.
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http://dx.doi.org/10.1182/blood.2021010735DOI Listing
April 2021

Seasonal variation in the incidence of cold agglutinin disease in Norway, Denmark, and Italy.

Am J Hematol 2021 07 3;96(7):E262-E265. Epub 2021 May 3.

Department of Haematology, Odense University Hospital, Odense, Denmark.

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http://dx.doi.org/10.1002/ajh.26196DOI Listing
July 2021

Sutimlimab in Cold Agglutinin Disease.

N Engl J Med 2021 04;384(14):1323-1334

From the Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany (A.R.); Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Ospedale Maggiore Policlinico, Milan, Italy (W.B.); the Centre for Waldenström's Macroglobulinaemia and Related Conditions, University College London Hospitals National Health Service Foundation Trust, London (S.D.); the Thrombosis and Hemostasis Center, Saitama Medical University Hospital, Saitama, Japan (Y.M.); the Division of Hematology, MedStar Georgetown University Hospital, Washington, DC (C.M.B.); the Department of Internal Medicine, Henri-Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France (M.M.); the Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston (D.J.K.), Bioverativ, Cambridge (J.F.), and Sanofi, Waltham (X.J., S.L., C.R., J.M.-A., W.H.) - all in Massachusetts; the Department of Clinical Pharmacology, Medical University of Vienna, Vienna (B.J.); and the Section for Hematology, Department of Medicine, Haukeland University Hospital, Bergen (T.H.A.T.), and the Department of Research and Innovation, Haugesund Hospital, Haugesund (S.B.) - both in Norway.

Background: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway.

Methods: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol.

Results: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred.

Conclusions: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.).
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http://dx.doi.org/10.1056/NEJMoa2027760DOI Listing
April 2021

Autoimmune Complications in Hematologic Neoplasms.

Cancers (Basel) 2021 Mar 26;13(7). Epub 2021 Mar 26.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Autoimmune cytopenias (AICy) and autoimmune diseases (AID) can complicate both lymphoid and myeloid neoplasms, and often represent a diagnostic and therapeutic challenge. While autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are well known, other rarer AICy (autoimmune neutropenia, aplastic anemia, and pure red cell aplasia) and AID (systemic lupus erythematosus, rheumatoid arthritis, vasculitis, thyroiditis, and others) are poorly recognized. This review analyses the available literature of the last 30 years regarding the occurrence of AICy/AID in different onco-hematologic conditions. The latter include chronic lymphocytic leukemia (CLL), lymphomas, multiple myeloma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, and acute leukemias. On the whole, AICy are observed in up to 10% of CLL and with higher frequencies in certain subtypes of non-Hodgkin lymphoma, whilst they occur in less than 1% of low-risk MDS and CMML. AID are described in up to 30% of myeloid and lymphoid patients, including immune-mediated hemostatic disorders (acquired hemophilia, thrombotic thrombocytopenic purpura, and anti-phospholipid syndrome) that may be severe and fatal. Additionally, AICy/AID are found in about 10% of patients receiving hematopoietic stem cell transplant or treatment with new checkpoint inhibitors. Besides the diagnostic difficulties, these AICy/AID may complicate the clinical management of already immunocompromised patients.
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http://dx.doi.org/10.3390/cancers13071532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037071PMC
March 2021

Difficult Cases of Paroxysmal Nocturnal Hemoglobinuria: Diagnosis and Therapeutic Novelties.

J Clin Med 2021 Mar 1;10(5). Epub 2021 Mar 1.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.

Paroxysmal nocturnal hemoglobinuria (PNH) is an intriguing disease that can pose many difficulties to physicians, as well as to hematologists, who are unfamiliar with it. Research regarding its pathophysiologic, diagnostic, and therapeutic aspects is still ongoing. In the last ten years, new flow cytometry techniques with high sensitivity enabled us to detect PNH clones as small as <1% of a patient's hematopoiesis, resulting in increasing incidence but more difficult data interpretation. Particularly, the clinical significance of small PNH clones in patients with bone marrow failures, including aplastic anemia and myelodysplastic syndromes, as well as in uncommon associations, such as myeloproliferative disorders, is still largely unknown. Besides current treatment with the anti-C5 eculizumab, which reduced PNH-related morbidity and mortality, new complement inhibitors will likely fulfill unmet clinical needs in terms of patients' quality of life and better response rates (i.e., responses in subjects with C5 polymorphisms; reduction of extravascular hemolysis and breakthrough hemolysis episodes). Still, unanswered questions remain for these agents regarding their use in mono- or combination therapy, when to treat, and which drug is the best for which patient. Lastly, long-term safety needs to be assessed in real-life studies. In this review, we describe some clinical vignettes illustrating practical aspects of PNH diagnosis and management; moreover, we discuss recent advances in PNH diagnostic and therapeutic approaches.
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http://dx.doi.org/10.3390/jcm10050948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957780PMC
March 2021

The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease.

Front Immunol 2021 1;12:649441. Epub 2021 Mar 1.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.

Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.
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http://dx.doi.org/10.3389/fimmu.2021.649441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956980PMC
March 2021

Secondary Hemophagocytic Lymphohistiocytosis and Autoimmune Cytopenias: Case Description and Review of the Literature.

J Clin Med 2021 Feb 20;10(4). Epub 2021 Feb 20.

Oncohematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Hemophagocytic lymphohistocytosis (HLH) is a rare hyperinflammatory condition which may be primary or secondary to many diseases, including hematologic malignancies. Due to its life-threatening evolution, a timely diagnosis is paramount but challenging, since it relies on non-specific clinical and laboratory criteria. The latter are often altered in other diseases, including autoimmune cytopenias (AIC), which in turn can be secondary to infections, systemic autoimmune or lymphoproliferative disorders. In the present article, we describe two patients presenting at the emergency department with acute AICs subsequently diagnosed as HLH with underlying diffuse large B cell lymphoma. We discuss the diagnostic challenges in the differential diagnosis of acute cytopenias in the internal medicine setting, providing a literature review of secondary HLH and AIC.
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http://dx.doi.org/10.3390/jcm10040870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923749PMC
February 2021

Recent insights into the role of the microbiome in malignant and benign hematologic diseases.

Crit Rev Oncol Hematol 2021 Apr 2;160:103289. Epub 2021 Mar 2.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Growing evidence suggests the impact of microbiome alteration, named dysbiosis, on the development of neoplasms, infections, inflammatory diseases, and immuno-mediated disorders. Regarding hematologic diseases, most data regard hematopoietic stem cell transplant (HSCT). In this review, we systematically evaluate the studies concerning microbiome in malignant and benign hematologic disorders beyond HSCT. A permissive microbiota is associated to the development of hematologic malignancies (including acute leukemia, lymphoma, and multiple myeloma), as well as of iron deficiency anemia, autoimmune cytopenias, and aplastic anemia. This happens through various mechanisms; chronic inflammatory triggering, epithelial barrier alteration, antigen dissequestration, and molecular mimicry. Hematologic therapies (chemo and immunosuppression) may induce/worsen dysbiosis and favour disease progression and infectious complications. Antibiotics may also induce dysbiosis with possible long-term consequences. Finally, novel target therapies are likely to alter microbiome, inducing gut inflammation (i.e. small molecules such as tyrosine-kinase-inhibitors) or enhancing host's immune system (as observed with CAR-T cells and checkpoint inhibitors).
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http://dx.doi.org/10.1016/j.critrevonc.2021.103289DOI Listing
April 2021

Clinical and prognostic significance of small paroxysmal nocturnal hemoglobinuria clones in myelodysplastic syndrome and aplastic anemia.

Leukemia 2021 Mar 4. Epub 2021 Mar 4.

Department of Hematological medicine, King's College Hospital, London, UK.

In this large single-centre study, we report high prevalence (25%) of, small (<10%) and very small (<1%), paroxysmal nocturnal hemoglobinuria (PNH) clones by high-sensitive cytometry among 3085 patients tested. Given PNH association with bone marrow failures, we analyzed 869 myelodysplastic syndromes (MDS) and 531 aplastic anemia (AA) within the cohort. PNH clones were more frequent and larger in AA vs. MDS (p = 0.04). PNH clone, irrespective of size, was a good predictor of response to immunosuppressive therapy (IST) and to stem cell transplant (HSCT) (in MDS: 84% if PNH+ vs. 44.7% if PNH-, p = 0.01 for IST, and 71% if PNH+ vs. 56.6% if PNH- for HSCT; in AA: 78 vs. 50% for IST, p < 0.0001, and 97 vs. 77%, p = 0.01 for HSCT). PNH positivity had a favorable impact on disease progression (0.6% vs. 4.9% IPSS-progression in MDS, p < 0.005; and 2.1 vs. 6.9% progression to MDS in AA, p = 0.01), leukemic evolution (6.8 vs. 12.7%, p = 0.01 in MDS), and overall survival [73% (95% CI 68-77) vs. 51% (48-54), p < 0.0001], with a relative HR for mortality of 2.37 (95% CI 1.8-3.1; p < 0.0001) in PNH negative cases, both in univariate and multivariable analysis. Our data suggest systematic PNH testing in AA/MDS, as it might allow better prediction/prognostication and consequent clinical/laboratory follow-up timing.
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http://dx.doi.org/10.1038/s41375-021-01190-9DOI Listing
March 2021

Eltrombopag second-line therapy in adult patients with primary immune thrombocytopenia in an attempt to achieve sustained remission off-treatment: results of a phase II, multicentre, prospective study.

Br J Haematol 2021 Apr 22;193(2):386-396. Epub 2021 Feb 22.

Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

Up to 30% immune thrombocytopenia (ITP) patients achieve a sustained remission off-treatment (SROT) after discontinuation of thrombopoietin receptor agonists (TPO-RAs). Factors predictive of response are lacking. Patients aged ≥18 years with newly diagnosed or persistent ITP were treated with eltrombopag for 24 weeks. Primary end-point was SROT: the proportion of responders that were able to taper and discontinue eltrombopag maintaining the response during a period of observation (PO) of six months. Secondary end-points included the association between some immunological parameters (TPO serum levels, cytokines and lymphocyte subsets) and response. Fifty-one patients were evaluable. Primary end-point was achieved in 13/51 (25%) treated patients and 13/34 (38%) patients who started the tapering. Baseline TPO levels were not associated with response at week 24 nor with SROT. Higher baseline levels of IL-10, IL-4, TNF-α and osteopontin were negative factors predictive of response (P = 0·001, 0·008, 0·02 and 0·03 respectively). This study confirms that SROT is feasible for a proportion of ITP patients treated with eltrombopag. Some biological parameters were predictive of response.
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http://dx.doi.org/10.1111/bjh.17334DOI Listing
April 2021

Are Patients With Autoimmune Cytopenias at Higher Risk of COVID-19 Pneumonia? The Experience of a Reference Center in Northern Italy and Review of the Literature.

Front Immunol 2020;11:609198. Epub 2021 Jan 26.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

During COVID-19 pandemic the care of onco-hematologic and autoimmune patients has raised the question whether they are at higher risk of infection and/or worse outcome. Here, we describe the clinical course of COVID-19 pneumonia in patients with autoimmune cytopenias (AIC) regularly followed at a reference center in Northern Italy. The study period started from COVID-19 outbreak (February 22, 2020) until the time of writing. Moreover, we provide a review of the literature, showing that most cases reported so far are AIC developed during or secondary to COVID-19 infection. At variance, data about AIC pre-existing to COVID infection are scanty. The 4 patients here described (2 autoimmune hemolytic anemias, AIHA, 1 Evans syndrome, and 1 immune thrombocytopenia) with COVID-19 pneumonia belong to a large cohort of 500 AIC patients, making this study nearly population-based. The observed frequency (4/501; 0.7%) is only slightly superior to that of the general population admitted to hospital/intensive care unit (0.28/0.03%, respectively) in Lombardy in the same period of observation. All cases occurred between March 21 and 25, whilst no more AIC were recorded later on. Although different in intensity of care needed, all patients recovered from COVID-19 pneumonia, with apparently no detrimental effect of previous/current immunomodulatory treatments. AIHA relapse occurred in two patients, but promptly responded to therapy. With limitations due to sample size, these results suggest a favorable outcome and a lower-than-expected incidence of COVID-19 pneumonia in patients with previously diagnosed AIC, and allow speculating that immunomodulatory drugs used for AIC may play a beneficial rather than a harmful effect on COVID-19 infection.
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http://dx.doi.org/10.3389/fimmu.2020.609198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870679PMC
February 2021

How I treat warm autoimmune hemolytic anemia.

Blood 2021 Mar;137(10):1283-1294

Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; and.

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.
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http://dx.doi.org/10.1182/blood.2019003808DOI Listing
March 2021

Predicting the probability of Gaucher disease in subjects with splenomegaly and thrombocytopenia.

Sci Rep 2021 Jan 28;11(1):2594. Epub 2021 Jan 28.

General Medicine Unit, Rare Diseases Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via F. Sforza, 35, 20122, Milan, Italy.

Hematologists are frequently involved in the diagnostic pathway of Gaucher disease type 1 (GD1) patients since they present several hematological signs. However, GD1 is mainly underdiagnosed because of a lack of awareness. In this multicenter study, we combine the use of a diagnostic algorithm with a simple test (β-glucosidase activity on Dried Blood Spot) in order to facilitate the diagnosis in a population presenting to the hematologist with splenomegaly and/or thrombocytopenia associated with other hematological signs. In this high-risk population, the prevalence of GD1 is 3.3%. We propose an equation that predicts the probability of having GD1 according to three parameters that are routinely evaluated: platelet count, ferritin, and transferrin saturation.
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http://dx.doi.org/10.1038/s41598-021-82296-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843616PMC
January 2021

Circulating extracellular vesicles and cytokines in congenital and acquired hemolytic anemias.

Am J Hematol 2021 04 9;96(4):E129-E132. Epub 2021 Feb 9.

UOC Ematologia non tumorale e Coagulopatie, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.

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http://dx.doi.org/10.1002/ajh.26108DOI Listing
April 2021

Infectious Complications in Autoimmune Hemolytic Anemia.

J Clin Med 2021 Jan 5;10(1). Epub 2021 Jan 5.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100 Milan, Italy.

Autoimmune hemolytic anemia (AIHA) may be frequently challenged by infectious complications, mainly as a result of immunosuppressive treatments administered. Furthermore, infectious agents are known triggers of AIHA onset and relapse. Although being risk factors for mortality, infections are an underestimated issue in AIHA. This review will collect the available evidence on the frequency and type of infectious complications in AIHA, detailing the risk related to each treatment (i.e., steroids, rituximab, splenectomy, classic immunosuppressive agents, and new target drugs). Moreover, we will briefly discuss the infectious complications in AIHA secondary to other diseases that harbor an intrinsic infectious risk (e.g., primary immunodeficiencies, systemic autoimmune diseases, lymphoproliferative disorders, solid organ and hematopoietic stem cell transplants). Finally, viral and bacterial reactivations during immune suppressive therapies will be discussed, along with suggested screening and prophylactic strategies.
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http://dx.doi.org/10.3390/jcm10010164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796467PMC
January 2021

Hypoplastic Myelodysplastic Syndromes: Just an Overlap Syndrome?

Cancers (Basel) 2021 Jan 3;13(1). Epub 2021 Jan 3.

Department of Oncology and Onco-Hematology, University of Milan, 20122 Milan, Italy.

Myelodysplasias with hypocellular bone marrow (hMDS) represent about 10-15% of MDS and are defined by reduced bone marrow cellularity (i.e., <25% or an inappropriately reduced cellularity for their age in young patients). Their diagnosis is still an object of debate and has not been clearly established in the recent WHO classification. Clinical and morphological overlaps with both normo/hypercellular MDS and aplastic anemia include cytopenias, the presence of marrow hypocellularity and dysplasia, and cytogenetic and molecular alterations. Activation of the immune system against the hematopoietic precursors, typical of aplastic anemia, is reckoned even in hMDS and may account for the response to immunosuppressive treatment. Finally, the hMDS outcome seems more favorable than that of normo/hypercellular MDS patients. In this review, we analyze the available literature on hMDS, focusing on clinical, immunological, and molecular features. We show that hMDS pathogenesis and clinical presentation are peculiar, albeit in-between aplastic anemia (AA) and normo/hypercellular MDS. Two different hMDS phenotypes may be encountered: one featured by inflammation and immune activation, with increased cytotoxic T cells, increased T and B regulatory cells, and better response to immunosuppression; and the other, resembling MDS, where T and B regulatory/suppressor cells prevail, leading to genetic clonal selection and an increased risk of leukemic evolution. The identification of the prevailing hMDS phenotype might assist treatment choice, inform prognosis, and suggest personalized monitoring.
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http://dx.doi.org/10.3390/cancers13010132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795441PMC
January 2021

Comorbidities and complications in adults with pyruvate kinase deficiency.

Eur J Haematol 2021 Apr 24;106(4):484-492. Epub 2021 Jan 24.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

Objectives: Pyruvate kinase (PK) deficiency is caused by PKLR gene mutations, leading to defective red blood cell glycolysis and hemolytic anemia. Rates of comorbidities and complications by transfusion history and relative to the general population remain poorly quantified.

Methods: Data for patients aged ≥ 18 years with two confirmed PKLR mutations were obtained from the PK deficiency Natural History Study (NCT02053480). Frequencies of select conditions were compared with an age- and sex-matched cohort from a general insured US population without PK deficiency.

Results: Compared with the matched population (n = 1220), patients with PK deficiency (n = 122) had significantly higher lifetime rates of osteoporosis, liver cirrhosis, and pulmonary hypertension; splenectomy and cholecystectomy rates were also significantly higher in the 8 years before the index date. Sixty-five (53.3%) patients with PK deficiency were classified as regularly transfused, 30 (24.6%) as occasionally transfused, and 27 (22.1%) as never transfused. Regularly transfused patients were significantly more likely than never transfused patients to have had splenectomy, cholecystectomy, and/or thrombosis. Liver iron overload was reported in 62% of patients and occurred regardless of transfusion cohort.

Conclusions: Even never transfused patients with PK deficiency had higher rates of select comorbidities and complications than individuals without PK deficiency.
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http://dx.doi.org/10.1111/ejh.13572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985869PMC
April 2021

Gardos channelopathy: functional analysis of a novel KCNN4 variant.

Blood Adv 2020 12;4(24):6336-6341

Unità Operativa Semplice (UOS) Fisiopatologia delle Anemie, Unità Operativa Complessa (UOC) Ematologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1182/bloodadvances.2020003285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756992PMC
December 2020

New Insights in Autoimmune Hemolytic Anemia: From Pathogenesis to Therapy Stage 1.

J Clin Med 2020 Nov 27;9(12). Epub 2020 Nov 27.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, 20100 Milan, Italy.

Autoimmune hemolytic anemia (AIHA) is a highly heterogeneous disease due to increased destruction of autologous erythrocytes by autoantibodies with or without complement involvement. Other pathogenic mechanisms include hyper-activation of cellular immune effectors, cytokine dysregulation, and ineffective marrow compensation. AIHAs may be primary or associated with lymphoproliferative and autoimmune diseases, infections, immunodeficiencies, solid tumors, transplants, and drugs. The direct antiglobulin test is the cornerstone of diagnosis, allowing the distinction into warm forms (wAIHA), cold agglutinin disease (CAD), and other more rare forms. The immunologic mechanisms responsible for erythrocyte destruction in the various AIHAs are different and therefore therapy is quite dissimilar. In wAIHA, steroids represent first line therapy, followed by rituximab and splenectomy. Conventional immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine) are now considered the third line. In CAD, steroids are useful only at high/unacceptable doses and splenectomy is uneffective. Rituximab is advised in first line therapy, followed by rituximab plus bendamustine and bortezomib. Several new drugs are under development including B-cell directed therapies (ibrutinib, venetoclax, parsaclisib) and inhibitors of complement (sutimlimab, pegcetacoplan), spleen tyrosine kinases (fostamatinib), or neonatal Fc receptor. Here, a comprehensive review of the main clinical characteristics, diagnosis, and pathogenic mechanisms of AIHA are provided, along with classic and new therapeutic approaches.
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http://dx.doi.org/10.3390/jcm9123859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759854PMC
November 2020

Difficult Cases of Autoimmune Hemolytic Anemia: A Challenge for the Internal Medicine Specialist.

J Clin Med 2020 Nov 27;9(12). Epub 2020 Nov 27.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20100 Milan, Italy.

Autoimmune hemolytic anemia (AIHA) is diagnosed in the presence of anemia, hemolysis, and direct antiglobulin test (DAT) positivity with monospecific antisera. Many confounders of anemia and hemolytic markers should be included in the initial workup (i.e., nutrients deficiencies, chronic liver or kidney diseases, infections, and cancers). Besides classical presentation, there are difficult cases that may challenge the treating physician. These include DAT negative AIHA, diagnosed after the exclusion of other causes of hemolysis, and supported by the response to steroids, and secondary cases (infections, drugs, lymphoproliferative disorders, immunodeficiencies, etc.) that should be suspected and investigated through careful anamnesis physical examination, and specific tests in selected cases. The latter include autoantibody screening in patients with signs/symptoms of systemic autoimmune diseases, immunoglobulins (Ig) levels in case of frequent infections or suspected immunodeficiency, and ultrasound/ computed tomography (CT) studies and bone marrow evaluation to exclude hematologic diseases. AIHA occurring in pregnancy is a specific situation, usually manageable with steroids and intravenous (iv) Ig, although refractory cases have been described. Finally, AIHA may complicate specific clinical settings, including intensive care unit (ICU) admission, reticulocytopenia, treatment with novel anti-cancer drugs, and transplant. These cases are often severe, more frequently DAT negative, and require multiple treatments in a short time.
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http://dx.doi.org/10.3390/jcm9123858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760866PMC
November 2020

The variable manifestations of disease in pyruvate kinase deficiency and their management.

Haematologica 2020 09 1;105(9):2229-2239. Epub 2020 Sep 1.

Dana/Farber Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia and results in a broad spectrum of disease. The diagnosis of PKD requires a high index of suspicion and judicious use of laboratory tests that may not always be informative, including pyruvate kinase enzyme assay and genetic analysis of the PKLR gene. A significant minority of patients with PKD have occult mutations in non-coding regions of PKLR which are missed on standard genetic tests. The biochemical consequences of PKD result in hemolytic anemia due to red cell pyruvate and ATP deficiency while simultaneously causing increased red cell 2,3-diphosphoglycerate, which facilitates oxygen unloading. This phenomenon, in addition to numerous other factors such as genetic background and differences in splenic function result in a poor correlation between symptoms and degree of anemia from patient to patient. Red cell transfusions should, therefore, be symptom-directed and not based on a hemoglobin threshold. Patients may experience specific complications, such as paravertebral extramedullary hematopoiesis and chronic debilitating icterus, which require personalized treatment. The decision to perform splenectomy or hematopoietic stem cell transplantation is nuanced and depends on disease burden and long-term outlook given that targeted therapeutics are in development. In recognition of the complicated nature of the disease and its management and the limitations of the PKD literature, an international working group of ten PKD experts convened to better define the disease burden and manifestations. This article summarizes the conclusions of this working group and is a guide for clinicians and investigators caring for patients with PKD.
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http://dx.doi.org/10.3324/haematol.2019.240846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556504PMC
September 2020

Recommendations for Pregnancy in Rare Inherited Anemias.

Hemasphere 2020 Aug 12;4(4):e446. Epub 2020 Aug 12.

United Onlus - Federazione Italiana delle Thalassemie, Emoglobinopatie Rare e Drepanocitosi, Ferrara, Italy.

Rare inherited anemias are a subset of anemias caused by a genetic defect along one of the several stages of erythropoiesis or in different cellular components that affect red blood cell integrity, and thus its lifespan. Due to their low prevalence, several complications on growth and development, and multi-organ system damage are not yet well defined. Moreover, during the last decade there has been a lack of proper understanding of the impact of rare anemias on maternal and fetal outcomes. In addition, there are no clear-cut guidelines outlining the pathophysiological trends and management options unique to this special population. Here, we present on behalf of the European Hematology Association, evidence- and consensus-based guidelines, established by an international group of experts in different fields, including hematologists, gynecologists, general practitioners, medical geneticists, and experts in rare inherited anemias from various European countries for standardized and appropriate choice of therapeutic interventions for the management of pregnancy in rare inherited anemias, including Diamond-Blackfan Anemia, Congenital Dyserythropoietic Anemias, Thalassemia, Sickle Cell Disease, Enzyme deficiency and Red cell membrane disorders.
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http://dx.doi.org/10.1097/HS9.0000000000000446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437563PMC
August 2020

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

Int J Mol Sci 2020 Jul 30;21(15). Epub 2020 Jul 30.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy.

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.
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http://dx.doi.org/10.3390/ijms21155438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432231PMC
July 2020

Management of pyruvate kinase deficiency in children and adults.

Blood 2020 09;136(11):1241-1249

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis and management of patients with PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis. Current treatment approaches are supportive and include transfusions, splenectomy, and chelation. Complications, including iron overload, bilirubin gallstones, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis, are related to the chronic hemolytic anemia and its current management and can occur at any age. Disease-modifying therapies in clinical development may decrease symptoms and findings associated with chronic hemolysis and avoid the complications associated with current treatment approaches. As these disease-directed therapies are approved for clinical use, clinicians will need to define the types of symptoms and findings that determine the optimal patients and timing for initiating these therapies. In this article, we highlight disease manifestations, monitoring approaches, strategies for managing complications, and novel therapies in development.
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http://dx.doi.org/10.1182/blood.2019000945DOI Listing
September 2020

Congenital Hemolytic Anemias: Is There a Role for the Immune System?

Front Immunol 2020 23;11:1309. Epub 2020 Jun 23.

UOS Fisiopatologia delle Anemie, UOC Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Congenital hemolytic anemias (CHAs) are a heterogeneous group of rare hereditary conditions including defects of erythrocyte membrane proteins, red cell enzymes, and disorders due to defective erythropoiesis. They are characterized by variable degree of anemia, chronic extravascular hemolysis, reduced erythrocyte life span, splenomegaly, jaundice, biliary lithiasis, and iron overload. Although few data are reported on the role of the immune system in CHAs, several immune-mediated mechanisms may be involved in the pathogenesis of these rare diseases. We reported in ~60% of patients with hereditary spherocytosis (HS), the presence of naturally-occurring autoantibodies (NAbs) directed against different membrane proteins (α- and β-spectrin, band 3, and dematin). Positive HS subjects showed a more hemolytic pattern and NAbs were more evident in aged erythrocytes. The latter is in line with the function of NAbs in the opsonization of damaged/senescent erythrocytes and their consequent removal in the spleen. Splenectomy, usually performed to reduce erythrocyte catheresis and improve Hb levels, has different efficacy in various CHAs. Median Hb increase is 3 g/dL in HS, 1.6-1.8 g/dL in pyruvate kinase deficiency (PKD), and 1 g/dL in congenital dyserythropoietic anemias (CDA) type II. Consistently with clinical severity, splenectomy is performed in 20% of HS, 45% of CDAII, and in 60% of PKD patients. Importantly, sepsis and thrombotic events have been registered, particularly in PKD with a frequency of ~7% for both. Furthermore, we analyzed the role of pro-inflammatory cytokines and found that interleukin 10 and interferon γ, and to a lesser extent interleukin 6, were increased in all CHAs compared with controls. Moreover, CDAII and enzymatic defects showed increased tumor necrosis factor-α and reduced interleukin 17. Finally, we reported that iron overload occurred in 31% of patients with membrane defects, in ~60% of CDAII cases, and in up to 82% of PKD patients (defined by MRI liver iron concentration >4 mg Fe/gdw). Hepcidin was slightly increased in CHAs compared with controls and positively correlated with ferritin and with the inflammatory cytokines interleukin 6 and interferon γ. Overall the results suggest the existence of a vicious circle between chronic hemolysis, inflammatory response, bone marrow dyserythropoiesis, and iron overload.
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http://dx.doi.org/10.3389/fimmu.2020.01309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324678PMC
April 2021

The Changing Landscape of Autoimmune Hemolytic Anemia.

Front Immunol 2020 3;11:946. Epub 2020 Jun 3.

UO Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Autoimmune hemolytic anemia (AIHA) is a greatly heterogeneous disease due to autoantibodies directed against erythrocytes, with or without complement activation. The clinical picture ranges from mild/compensated to life-threatening anemia, depending on the antibody's thermal amplitude, isotype and ability to fix complement, as well as on bone marrow compensation. Since few years ago, steroids, immunesuppressants and splenectomy have been the mainstay of treatment. More recently, several target therapies are increasingly used in the clinical practice or are under development in clinical trials. This has led to the accumulation of refractory/relapsed cases that often represent a clinical challenge. Moreover, the availability of several drugs acting on the different pathophysiologic mechanisms of the disease pinpoints the need to harness therapy. In particular, it is advisable to define the best choice, sequence and/or combination of drugs during the different phases of the disease. In particular relapsed/refractory cases may resemble pre-myelodysplastic or bone marrow failure syndromes, suggesting a careful use of immunosuppressants, and vice versa advising bone marrow immunomodulating/stimulating agents. A peculiar setting is AIHA after autologous and allogeneic hematopoietic stem cell transplantation, which is increasingly reported. These cases are generally severe and refractory to standard therapy, and have high mortality. AIHAs may be primary/idiopathic or secondary to infections, autoimmune diseases, malignancies, particularly lymphoproliferative disorders, and drugs, further complicating their clinical picture and management. Regarding new drugs, the false positivity of the Coombs test (direct antiglobulin test, DAT) following daratumumab adds to the list of difficult diagnosis, together with the passenger lymphocyte syndrome after solid organ transplants. Diagnosis of DAT-negative AIHAs and evaluation of disease-related risk factors for relapse and mortality, notwithstanding improvement in diagnostic approach, are still an unmet need. Finally, AIHA is increasingly described following therapy of solid cancers with inhibitors of immune checkpoint molecules. On the whole, the double-edged sword of new pathogenetic insights and therapies has changed the landscape of AIHA, both providing enthusiastic knowledge and complicating the clinical management of this disease.
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http://dx.doi.org/10.3389/fimmu.2020.00946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325906PMC
March 2021