Publications by authors named "Bruno Fattizzo"

86 Publications

Evans syndrome in the SARS-CoV-2 era: "springing up like mushrooms".

Authors:
Bruno Fattizzo

Blood Transfus 2021 Dec 1. Epub 2021 Dec 1.

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

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http://dx.doi.org/10.2450/2021.0224-21DOI Listing
December 2021

Complement Mediated Hemolytic Anemias in the COVID-19 Era: Case Series and Review of the Literature.

Front Immunol 2021 25;12:791429. Epub 2021 Nov 25.

Hematology Unit, King's College Hospital, London, United Kingdom.

The complex pathophysiologic interplay between SARS-CoV-2 infection and complement activation is the subject of active investigation. It is clinically mirrored by the occurrence of exacerbations of complement mediated diseases during COVID-19 infection. These include complement-mediated hemolytic anemias such as paroxysmal nocturnal hemoglobinuria (PNH), autoimmune hemolytic anemia (AIHA), particularly cold agglutinin disease (CAD), and hemolytic uremic syndrome (HUS). All these conditions may benefit from complement inhibitors that are also under study for COVID-19 disease. Hemolytic exacerbations in these conditions may occur upon several triggers including infections and vaccines and may require transfusions, treatment with complement inhibitors and/or immunosuppressors (i.e., steroids and rituximab for AIHA), and result in thrombotic complications. In this manuscript we describe four patients (2 with PNH and 2 with CAD) who experienced hemolytic flares after either COVID-19 infection or SARS-Cov2 vaccine and provide a review of the most recent literature. We report that most episodes occurred within the first 10 days after COVID-19 infection/vaccination and suggest laboratory monitoring (Hb and LDH levels) in that period. Moreover, in our experience and in the literature, hemolytic exacerbations occurring during COVID-19 infection were more severe, required greater therapeutic intervention, and carried more complications including fatalities, as compared to those developing after SARS-CoV-2 vaccine, suggesting the importance of vaccinating this patient population. Patient education remains pivotal to promptly recognize signs/symptoms of hemolytic flares and to refer to medical attention. Treatment choice should be based on the severity of the hemolytic exacerbation as well as of that of COVID-19 infection. Therapies include transfusions, complement inhibitor initiation/additional dose in the case of PNH, steroids/rituximab in patients with CAD and warm type AIHA, plasma exchange, hemodialysis and complement inhibitor in the case of atypical HUS. Finally, anti-thrombotic prophylaxis should be always considered in these settings, provided safe platelet counts.
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http://dx.doi.org/10.3389/fimmu.2021.791429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655106PMC
December 2021

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

Front Oncol 2021 11;11:756589. Epub 2021 Nov 11.

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

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 -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.
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http://dx.doi.org/10.3389/fonc.2021.756589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632248PMC
November 2021

Bortezomib in autoimmune hemolytic anemia and beyond.

Ther Adv Hematol 2021 12;12:20406207211046428. Epub 2021 Nov 12.

Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.

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.
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http://dx.doi.org/10.1177/20406207211046428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593301PMC
November 2021

A case of severe aplastic anaemia after SARS-CoV-2 vaccination.

Br J Haematol 2021 Nov 16. Epub 2021 Nov 16.

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

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http://dx.doi.org/10.1111/bjh.17947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8652946PMC
November 2021

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

Front Oncol 2021 18;11:701604. Epub 2021 Oct 18.

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

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 -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 ( = 0.001), with better performance status ( = 0.02) and in the presence of driver mutations ( = 0.003). Contrarily, a worse survival was significantly associated with the occurrence of infections ( < 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.
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http://dx.doi.org/10.3389/fonc.2021.701604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558405PMC
October 2021

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

Front Oncol 2021 1;11:748610. Epub 2021 Oct 1.

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

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.
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http://dx.doi.org/10.3389/fonc.2021.748610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517436PMC
October 2021

Immune Phenomena in Myeloid Neoplasms: An " Question.

Front Immunol 2021 29;12:751630. Epub 2021 Sep 29.

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

Immune phenomena are increasingly reported in myeloid neoplasms, and include autoimmune cytopenias/diseases and immunodeficiency, either preceding or complicating acute myeloid leukemia, myelodysplastic syndromes (MDS), chronic myeloproliferative neoplasms, and bone marrow failure (BMF) syndromes. Autoimmunity and immunodeficiency are the two faces of a dysregulated immune tolerance and surveillance and may result, along with contributing environmental and genetic factors, in an increased incidence of both tumors and infections. The latter may fuel both autoimmunity and immune activation, triggering a vicious circle among infections, tumors and autoimmune phenomena. Additionally, alterations of the microbiota and of mesenchymal stem cells (MSCs) pinpoint to the importance of a permissive or hostile microenvironment for tumor growth. Finally, several therapies of myeloid neoplasms are aimed at increasing host immunity against the tumor, but at the price of increased autoimmune phenomena. In this review we will examine the epidemiological association of myeloid neoplasms with autoimmune diseases and immunodeficiencies, and the pivotal role of autoimmunity in the pathogenesis of MDS and BMF syndromes, including the paroxysmal nocturnal hemoglobinuria conundrum. Furthermore, we will briefly examine autoimmune complications following therapy of myeloid neoplasms, as well as the role of MSCs and microbiota in these settings.
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http://dx.doi.org/10.3389/fimmu.2021.751630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511478PMC
January 2022

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

Front Oncol 2021 28;11:680411. Epub 2021 Sep 28.

Department of Oncology and Onco-hematology, Università degli Studi di Milano, Milan, Italy.

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.
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http://dx.doi.org/10.3389/fonc.2021.680411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505995PMC
September 2021

Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia: Italian Delphi-based consensus recommendations.

Ther Adv Hematol 2021 9;12:20406207211048361. Epub 2021 Oct 9.

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

Introduction: In patients with primary immune thrombocytopenia (ITP), a short course of steroids is routinely given as first-line therapy. However, the response is often transient and additional therapy is usually needed. Thrombopoietin receptor agonists (TPO-RAs) are frequently used as second-line therapy, although there is little clinical guidance on the timing of their administration and on tapering/discontinuation of the drug. To provide clinical recommendations, we used the Delphi technique to obtain consensus for statements regarding administration and on tapering/discontinuation of second-line TPO-RAs among a group of Italian clinicians with expertise in management of ITP.

Methods: The Delphi process was used to obtain agreement on five statements regarding initiation and on tapering/discontinuation of second-line TPO-RAs. Agreement was considered when 75% of participants approved the statement. Eleven experts participated in the voting.

Results: Full consensus was reached for three of the five statements. The experts held that an early switch from corticosteroids to a TPO-RA has the dual advantage of sparing patients from corticosteroid abuse and improve long-term clinical outcomes. All felt that dose reduction of TPO-RAs can be considered in patients with a stable response and platelet count >100 × 10/L that is maintained for at least 6 months in the absence of concomitant treatments, although there was less agreement in patients with a platelet count >50 × 10/L. Near consensus was reached regarding the statement that early treatment with a TPO-RA is associated with an increase in clinically significant partial or complete response. The experts also agreed that optimization of tapering and discontinuation of TPO-RA therapy in selected patients can improve the quality of life.

Conclusion: The present consensus can help to provide guidance on use of TPO-RAs in daily practice in patients with ITP.

Plain Language Summary: There is little guidance on the timing of administration and tapering/discontinuation of thrombopoietin receptor agonists (TPO-RAs) in patients with primary immune thrombocytopenia (ITP).The Delphi technique was used to obtain consensus for five statements.The present consensus among Italian clinicians aims to provide guidance on second-line use of TPO-RAs for patients with ITP in daily practice.
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http://dx.doi.org/10.1177/20406207211048361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504223PMC
October 2021

Confounding factors in the diagnosis and clinical course of rare congenital hemolytic anemias.

Orphanet J Rare Dis 2021 10 9;16(1):415. Epub 2021 Oct 9.

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

Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5'-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs.
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http://dx.doi.org/10.1186/s13023-021-02036-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501562PMC
October 2021

Evans syndrome in adults: an observational multicenter study.

Blood Adv 2021 12;5(24):5468-5478

Hematology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Evans syndrome (ES) is a rare condition, defined as the presence of 2 autoimmune cytopenias, most frequently autoimmune hemolytic anemia and immune thrombocytopenia (ITP) and rarely autoimmune neutropenia. ES can be classified as primary or secondary to various conditions, including lymphoproliferative disorders, other systemic autoimmune diseases, and primary immunodeficiencies, particularly in children. In adult ES, little is known about clinical features, disease associations, and outcomes. In this retrospective international study, we analyzed 116 adult patients followed at 13 European tertiary centers, focusing on treatment requirements, occurrence of complications, and death. ES was secondary to or associated with underlying conditions in 24 cases (21%), mainly other autoimmune diseases and hematologic neoplasms. Bleeding occurred in 42% of patients, mainly low grade and at ITP onset. Almost all patients received first-line treatment (steroids with or without intravenous immunoglobulin), and 23% needed early additional therapy for primary refractoriness. Additional therapy lines included rituximab, splenectomy, immunosuppressants, thrombopoietin receptor agonists, and others, with response rates >80%. However, a remarkable number of relapses occurred, requiring ≥3 therapy lines in 54% of cases. Infections and thrombotic complications occurred in 33% and 21% of patients, respectively, mainly grade ≥3, and correlated with the number of therapy lines. In addition to age, other factors negatively affecting survival were severe anemia at onset and occurrence of relapse, infection, and thrombosis. These data show that adult ES is often severe and marked by a relapsing clinical course and potentially fatal complications, pinpointing the need for high clinical awareness, prompt therapy, and anti-infectious/anti-thrombotic prophylaxis.
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http://dx.doi.org/10.1182/bloodadvances.2021005610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714709PMC
December 2021

Severe Presentation of Congenital Hemolytic Anemias in the Neonatal Age: Diagnostic and Therapeutic Issues.

Diagnostics (Basel) 2021 Aug 26;11(9). Epub 2021 Aug 26.

Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.

Congenital hemolytic anemias (CHAs) are a group of diseases characterized by premature destruction of erythrocytes as a consequence of intrinsic red blood cells abnormalities. Suggestive features of CHAs are anemia and hemolysis, with high reticulocyte count, unconjugated hyperbilirubinemia, increased lactate dehydrogenase (LDH), and reduced haptoglobin. The peripheral blood smear can help the differential diagnosis. In this review, we discuss the clinical management of severe CHAs presenting early on in the neonatal period. Appropriate knowledge and a high index of suspicion are crucial for a timely differential diagnosis and management. Here, we provide an overview of the most common conditions, such as glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and hereditary spherocytosis. Although rare, congenital dyserythropoietic anemias are included as they may be suspected in early life, while hemoglobinopathies will not be discussed, as they usually manifest at a later age, when fetal hemoglobin (HbF) is replaced by the adult form (HbA).
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http://dx.doi.org/10.3390/diagnostics11091549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467765PMC
August 2021

SARS-CoV-2 vaccination in patients with autoimmune cytopenias: The experience of a reference center.

Am J Hematol 2021 11 16;96(11):E413-E416. Epub 2021 Sep 16.

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

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http://dx.doi.org/10.1002/ajh.26345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646755PMC
November 2021

Autoimmune Hemolytic Anemia as a Complication of Congenital Anemias. A Case Series and Review of the Literature.

J Clin Med 2021 Aug 2;10(15). Epub 2021 Aug 2.

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

Congenital anemias may be complicated by immune-mediated hemolytic crisis. Alloantibodies are usually seen in chronically transfused patients, and autoantibodies have also been described, although they are rarely associated with overt autoimmune hemolytic anemia (AIHA), a serious and potentially life-threatening complication. Given the lack of data on the AIHA diagnosis and management in congenital anemias, we retrospectively evaluated all clinically relevant AIHA cases occurring at a referral center for AIHA, hemoglobinopathies, and chronic hemolytic anemias, focusing on clinical management and outcome. In our cohort, AIHA had a prevalence of 1% (14/1410 patients). The majority were warm AIHA. Possible triggers were recent transfusion, infection, pregnancy, and surgery. All the patients received steroid therapy as the first line, and about 25% required further treatment, including rituximab, azathioprine, intravenous immunoglobulins, and cyclophosphamide. Transfusion support was required in 57% of the patients with non-transfusion-dependent anemia, and recombinant human erythropoietin was safely administered in one third of the patients. AIHA in congenital anemias may be challenging both from a diagnostic and a therapeutic point of view. A proper evaluation of hemolytic markers, bone marrow compensation, and assessment of the direct antiglobulin test is mandatory.
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http://dx.doi.org/10.3390/jcm10153439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347040PMC
August 2021

Switching to an alternative recombinant erythropoietin agent in patients with myelodysplastic syndromes: a second honeymoon?

Br J Haematol 2021 11 26;195(4):e147-e150. Epub 2021 Jul 26.

Department of Hematology and Oncology, Niguarda Cancer Center, ASST Ospedale Niguarda, Milan, Italy.

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http://dx.doi.org/10.1111/bjh.17722DOI Listing
November 2021

Innovative Treatments for Rare Anemias.

Hemasphere 2021 Jun 1;5(6):e576. Epub 2021 Jun 1.

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

Rare anemias (RA) are mostly hereditary disorders with low prevalence and a broad spectrum of clinical severity, affecting different stages of erythropoiesis or red blood cell components. RA often remains underdiagnosed or misdiagnosed, and treatment options have been limited to supportive care for many years. During the last decades, the elucidation of the molecular mechanisms underlying several RA paved the way for developing new treatments. Innovative treatments other than supportive care and allogeneic bone marrow transplantation are currently in clinical trials for β-thalassemias, sickle cell disease (SCD), and congenital hemolytic anemias. Recently, luspatercept, an activin receptor ligand trap targeting ineffective erythropoiesis, has been approved as the first pharmacological treatment for transfusion-dependent β-thalassemia. L-glutamine, voxelotor, and crizanlizumab are new drugs approved SCD, targeting different steps of the complex pathophysiological mechanism. Gene therapy represents an innovative and encouraging strategy currently under evaluation in several RA and recently approved for β-thalassemia. Moreover, the advent of gene-editing technologies represents an additional option, mainly focused on correcting the defective gene or editing the expression of genes that regulate fetal hemoglobin synthesis. In this review, we aim to update the status of innovative treatments and the ongoing trials and discuss RA treatments' future directions. Interestingly, several molecules that showed promising results for treating one of these disorders are now under evaluation in the others. In the near future, the management of RA will probably consist of polypharmacotherapy tailored to patients' characteristics.
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http://dx.doi.org/10.1097/HS9.0000000000000576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171369PMC
June 2021

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

Am J Hematol 2021 09 18;96(9):E344-E346. Epub 2021 Jun 18.

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

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http://dx.doi.org/10.1002/ajh.26262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212106PMC
September 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

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
September 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 11 4;35(11):3223-3231. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550969PMC
November 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

Evans syndrome and infections: a dangerous cocktail to manage with caution.

Authors:
Bruno Fattizzo

Blood Transfus 2021 01;19(1):5-8

Department of Oncology and Oncohematology, University of Milan, Milan, Italy.

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http://dx.doi.org/10.2450/2021.0351-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850928PMC
January 2021
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