Bruno Fattizzo

Clinical evolution of autoimmune cytopenias to idiopathic cytopenias/dysplasias of uncertain significance (ICUS/IDUS) and bone marrow failure syndromes

[1] Motta I, Boiocchi L, Delbini P, et al. A giant adrenal myelolipoma in a beta-thalassemia major patient: Does ineffective erythropoiesis play a role? Am J Hematol. 2016;91:1281–1282. [2] Oliveira CC, Felisberto G, Jr, Camolese VH, et al. Myelolipoma of the posterior mediastinum in a patient with chronic dyserythropoietic anemia. Autops Case Rep. 2016;6:35–39. [3] Nermoen I, Rørvik J, Holmedal SH, et al. High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency. Clin Endocrinol (Oxf). 2011;75: 753–759. [4] Scacchi M, Danesi L, Cattaneo A, et al. The pituitary-adrenal axis in adult thalassaemic patients. Eur J Endocrinol. 2010;162: 43–48. [5] Manz DH, Blanchette NL, Paul BT, Torti FM, Torti SV. Iron and cancer: recent insights. Ann N Y Acad Sci. 2016;1368: 149–161. [6] Ricchi P, Ammirabile M, Costantini S, et al. Nephrolithiasis in patients exposed to deferasirox and desferioxamine: probably an age-linked event with different effects on some renal parameters. Ann Hematol. 2014;93:525–527. Received: 29 November 2016 | Accepted: 1 December 2016 DOI 10.1002/ajh.24618

Mesenchymal Stem Cells in Myeloid Malignancies: A Focus on Immune Escaping and Therapeutic Implications

The importance of the bone marrow microenvironment forming the so-called niche in physiologic hemopoiesis is largely known, and recent evidences support the presence of stromal alterations from the molecular to the cytoarchitectural level in hematologic malignancies. Various alterations in cell adhesion, metabolism, cytokine signaling, autophagy, and methylation patterns of tumor-derived mesenchymal stem cells have been demonstrated, contributing to the genesis of a leukemic permissive niche. This niche allows both the ineffective haematopoiesis typical of myelodysplastic syndromes and the differentiation arrest, proliferation advantage, and clone selection which is the hallmark of acute myeloid leukemia. Furthermore, the immune system, both adaptive and innate, encompassing mesenchymal-derived cells, has been shown to take part to the leukemic niche. Here, we critically review the state of art about mesenchymal stem cell role in myelodysplastic syndromes and acute myeloid leukemia, focusing on immune escaping mechanisms as a target for available and future anticancer therapies.

Prognostic impact of bone marrow fibrosis and dyserythropoiesis in autoimmune hemolytic anemia

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Chronic lymphocytic leukemia (CLL) and prognostic models: A bridge between clinical and biological markers

Maria Joao Baptista, Isabel Granada, Mireia Morgades, María-Jos e Calasanz, Jordi Canals, Diego Robles De Castro, Elisa Lu~ no, Neus Ruiz-Xivill e, In es Rodríguez-Hern andez, Teresa Gonz alez, María-Jos e Terol, Alberto Valiente, Francisco Ortu~ no, María-Dolores Garcia-Malo, MaríaAngeles Pi~ nan, Ana Carla Oliveira, Maria Talavera, Ismael Bu~ no, Ana Batlle-L opez, Carol Moreno, Christelle Ferra, Francesc Sol e Hematology Department, ICO-Hospital Universitari Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Aut onoma de Barcelona, Badalona, Spain CIMA Lab Diagnostics, University of Navarra, Pamplona, Spain Hematology Department, Hospital Universitario de Alava, VitoriaGasteiz, Spain Hematology Department, Hospital Universitario Central de Asturias, Oviedo, Spain Fundaci on P ublica Galega de Medicina Xen omica, Santiago de Compostela, Spain Medical Oncology and Hematology Department, Hospital Clínic Universitari de València, Valencia, Spain Department of Genetics, Complejo Hospitalario de Navarra, Pamplona, Spain Medical Oncology and Hematology Department, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonaci on, IMIB-Arrixaca, Murcia, Spain Hematology Department, Hospital Universitario Cruces, Bilbao, Spain Clinical Hematology Department, ICO-Hospital Duran i Reynals, L’Hospitalet de Llobregat, Spain Department of Genetics, Hospital Universitario Ram on y Cajal, Madrid, Spain Laboratory of Hematological Genetics, Hematology Department, Hospital General Universitario Gregorio Mara~ n on, Instituto de Investigaci on Sanitaria Gregorio Mara~ n on (IiSGM), Madrid, Spain Haematology Integrated Diagnostic Unit, Haematology Department, Hospital Universitario Marqu es de Valdecilla, IBBTEC, IDIVAL, Santander, Spain Hematology Department, Hospital Santa Creu i Sant Pau, Josep Carreras Leukaemia Research Institute, Barcelona, Spain

Bone Marrow Fibrosis and Early Hematological Response as Predictors of Poor Outcome in Azacitidine Treated High Risk-Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

Azacitidine (AZA) treatment is effective treatment for patients with myeloid disorders, and factors predictive of treatment outcome are under investigation. Little is known about the effect of bone marrow fibrosis on response to AZA therapy. We, retrospectively, evaluated clinical predictors of overall survival (OS) and overall response rate (ORR) for patients treated with AZA in a real-life cohort. We evaluated 94 consecutive patients treated with AZA outside of clinical trials (75mg/m2/day for 7 days every 28 days; 5 + 2 + 2 schedule), from June 2009 to February 2016. Ninety-three patients were evaluated for response. After a median of 6 cycles, ORR-complete response (CR; including marrow CR) + partial response (PR) + hematological improvement (HI)-was 41.9% (CR = 18.3%; PR = 11.8%; HI = 11.8%). Stable disease was observed in 21.5%, and failure in 36.5%. Pre-AZA bone marrow blast percentage, International Prognostic Scoring System (IPSS) or IPSS-R category, and time from diagnosis to AZA had no effect on response. Median OS from start of therapy was 18.5 months, and was significantly related to higher IPSS category (P = .01), poor cytogenetics according to the IPSS (P = .01), poor and very poor cytogenetics according to the IPSS-R (P = .02), and lower ORR (P = .006). Patients with MF-0 pre-AZA demonstrated significantly higher ORR, (CR + PR + HI) and stable disease, and lower failure rates than those with any grade of fibrosis. Indeed, cases with pre-AZA fibrosis > MF-1 had shorter OS (P = .005). Achievement of HI before 4 cycles of treatment negatively impacted OS (P = .009).

Autoimmune hemolytic anemia - progress in emerging treatment options

ABSTRACT Introduction: AIHA is a complex and heterogeneous disease involving antigen-autoantibody reaction, T-cell co-stimulation, complement activation, phagocytosis and bone marrow compensatory response. Several drugs targeting these mechanisms are under development in addition to standard therapies: steroids, immunesuppressors and splenectomy. Areas covered: Rituximab is the first biologic therapy used in AIHA, and its association with bendamustine and fludarabine has been shown more effective in relapse/refractory cold agglutinin disease. In these cases bortezomib was also beneficial with an overall response in about 30% of cases, and several complement inhibitors (eculizumab, BIVV009, and APL-2) are currently under investigation. B-cell receptor inhibitors (ibrutinib, acalabrutinib, and idelalisib) are promising therapeutic options for lymphoproliferative associated secondary forms. Finally, targeting IgG driven extravascular hemolysis (SYNT001 and fostamatinib) is an exciting new treatment approach. Expert opinion: AIHAs have been historically considered benign and easy to treat, however relapsing/refractory cases represent a clinical challenge. In these cases a target therapy would be ideal as traditional treatments are often ineffective/unfeasible. Moreover, the several mechanisms involved may be variably acting in the single patient and unpredictably changing overtime. Since several exciting target-therapies are emerging, only prospective studies would clarify the best choice, association, and sequence of these new drugs.

Idelalisib rapidly improves platelet function tests in patients with chronic lymphocytic leukaemia

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Biological and molecular characterization of a rare case of cutaneous Richter syndrome.

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia in a high‐grade lymphoma usually presenting nodal and bone marrow involvement. Richter syndrome can be localized at extranodal sites including the gastrointestinal tract, lungs, and skin. Cutaneous RS is an extremely rare disease apparently showing a less aggressive course than common presentations. While nodal RS has been extensively investigated in literature, pathogenesis and prognosis of cutaneous RS are still partially unknown, even if a role of Epstein‐Barr virus infection and p53 disruption has been suggested. Herein, we characterized the histopathological, immunohistochemical features and cytogenetics and molecular alterations of a case of cutaneous RS developed after 8 years chronic lymphocytic leukemia history. Moreover, we reviewed the literature reports concerning cutaneous RS and made a focus on biological patterns and prognostic implications.

Concomitant occurrence of blastic plasmacytoid dendritic cell neoplasm and acute myeloid leukaemia after lenalidomide treatment for del(5q) myelodysplastic syndrome

BACKGROUND Myelodysplastic syndromes with chromosome 5 long arm deletion (5q-mds) may benefit from lenalidomide treatment. However, unresponsive patients have a high risk for clonal evolution and progression to acute myeloid leukemia. Case: We describe a 5q-patient treated with lenalidomide, who concomitantly developed acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm, a rare and highly aggressive lymphoma. CONCLUSIONS Evolution of 5q- syndrome to acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm may have occurred through various mechanisms, including persistence of neoplastic lenalidomide-resistant stem cells and selection of a more aggressive clone via lenalidomide augmentation of the ARPC1B gene, or because of lenalidomide stimulation on dendritic cells. Further studies are needed to clarify lenalidomide oncogenic potential.

Treating chronic lymphocytic leukemia with obinutuzumab: safety and efficacy considerations

ABSTRACT Introduction: Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody (MoAb) with a higher affinity for CD20 epitope. It was approved by the United States Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL). Areas covered: This article evaluates the safety of obinutuzumab in CLL patients, also addressing pharmacokinetics/pharmacodynamics (PK/PD), clinical use and efficacy. Moreover, a comparison with other anti-CD20 MoAb is performed. The principal available studies on obinutuzumab are reviewed, focusing on CLL. A PubMed literature search (August 2002 to September 2015) was conducted using the terms obinutuzumab, GA101, anti-CD20 antibody, and CLL. Expert opinion: Obinutuzumab, a third-generation anti-CD20 MoAb, is a safe and effective treatment for elderly patients who are un-fit for fludarabine-based regimen. Its use, proven in the CLL11 study and the results of many ongoing trials evaluating other obinutuzumab-based regimen can lead obinutuzumab to be a candidate to replace rituximab as the first-line treatment option.