Federica Pilo

Hemopoietic stem cell transplantation in thalassemia: a report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry, 2000–2010

Allogeneic hemopoietic stem cell transplantation (HSCT) is the only method currently available to cure transfusion-dependent thalassemia major that has been widely used worldwide. To verify transplantation distribution, demography, activity, policies and outcomes inside the European Group for Blood and Marrow Transplantation (EBMT), we performed a retrospective non-interventional study, extracting data from the EBMT hemoglobinopathy prospective registry database. We included 1493 consecutive patients with thalassemia major transplanted between 1 January 2000 and 31 December 2010. In total, 1359 (91%) transplants were performed on patients <18 years old, 1061 were from a human leukocyte Ag-identical sibling donor. After a median observation time of 2 years, the 2-year overall survival (OS) and event-free survival (EFS; that is, thalassemia-free survival) were 88±1% and 81±1%, respectively. Transplantation from a human leukocyte Ag-identical sibling offered the best results, with OS and EFS of 91±1% and 83±1%, respectively. No significant differences in survival were reported between countries. The threshold age for optimal transplant outcomes was around 14 years, with an OS of 90–96% and an EFS of 83–93% when transplants were performed before this age. Allogeneic HSCT for thalassemia is a curative approach that is employed internationally and produces excellent results.

Treosulfan/fludarabine as an allogeneic hematopoietic stem cell transplant conditioning regimen for high-risk patients†

In recent years, new conditioning regimens have been explored in patients not eligible for conventional transplant with the aim to reduce transplant‐related mortality. In a phase II multicentric prospective trial, we investigated the safety and feasibility of the treosulfan–fludarabine combination prior to allogeneic hematopoietic stem cell transplant in patients with various hematological malignancies not eligible for conventional regimens because of previous intensive treatment, older age, and comorbidities. Forty‐six consecutive patients, median age 48 years (range 17–69), were enrolled. Sixteen of them were in complete remission, and 20 had a HSCT comorbidity index ≥ 1. Forty‐four patients had regular and sustained engraftment, and 39 out of 40 evaluable patients developed complete chimerism. Nonhematological toxicity was limited. Risk of transplant‐related mortality was 9% (95% CI, 2–17%) at day +100 and plotted at 15% (95% CI, 7–22%) after 7 months. The estimated overall survival and progression‐free survival with a median follow‐up of 20 months were 51% and 38%, respectively. The estimated 30 months progression‐free survival for patients transplanted in remission was 56%. The treosulfan–fludarabine combination is a reduced‐toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional transplant regimens. Longer follow‐up and further prospective studies are necessary to evaluate this regimen.

Management of iron overload before, during, and after hematopoietic stem cell transplantation for thalassemia major

Solid evidence has established the negative impact of high iron burden and related tissue damage on the outcome of hemopoietic stem cell transplantation for thalassemia major. Recent improvements in our knowledge of iron metabolism have been focused on elevated non‐transferrin‐bound iron and labile plasma iron levels in the peritransplantation period as potential contributors to tissue toxicity and subsequent adverse transplant outcome. As mouse models have shown, iron overload can injure bone marrow hematopoiesis by increasing reactive oxygen species. The Pesaro experience, conducted in the deferoxamine‐only era, clearly defined three iron‐related factors (liver fibrosis, hepatomegaly, and quality of lifelong chelation) as significantly affecting transplant outcome. The detrimental effect of iron has only been clarified in recent years. Active interventional strategies are ongoing. Although successful hematopoietic stem cell transplantation clinically resolves the thalassemia marrow defect, patients still remain carriers of iron overload and of all the clinical complications acquired during prior years of transfusion therapy. Therefore, adequate “iron diagnosis” and management is mandatory after hemopoietic stem cell transplantation. In transplanted thalassemia patients, body iron should be returned to within the normal range. Phlebotomy is the gold standard to reduce iron burden; though deferoxamine is a proven, acceptable alternative, clinical investigations on deferasirox are ongoing.

Treatment of hepatitis C in patients with thalassemia

Liver disease has long been recognized as an important cause of morbidity and mortality in thalassemia. In this perspective article, Drs. Angelucci and Pilo examine the epidemiology of hepatitis C virus infection in subjects with thalassemia and discuss the current treatment of this condition. See related articles on pages 1243 and 1247.

The evolving clinical scenario of myelodysplastic syndrome: The need for a complete and up to date upfront diagnostic assessment

Until the beginning of the current millennium, few concrete therapeutic possibilities were available for myelodysplastic syndrome (MDS) patients. This situation has dramatically changed in the last decade when new knowledge, new drugs and new opportunities have become available for physicians and their MDS patients. A correct diagnostic and prognostic assessment of all MDS patients wherever they are first seen in a hematology or internal medicine department is mandatory to identify the best therapeutic option and the most appropriate resources allocation. This article will review modern diagnostic criteria and classification together with correlated new therapeutic opportunities.

Transplantation in thalassemia: Revisiting the Pesaro risk factors 25 years later

Hematology, IRCCS Azienda Ospedaliera Universitaria, San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; Hematology and Transplant Center, Ospedale Oncologico di Riferimento Regionale “Armando Businco”, Azienda Ospedaliera Brotzu, Cagliari, Italy; Hematology, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California Correspondence Emanuele Angelucci, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 Genova, Italy. Email: emnang@tin.it

A storm in the niche: Iron, oxidative stress and haemopoiesis

Iron, although essential, is harmful in high amounts. Oxidative stress as a result of excess reactive oxygen species (ROS) and a prooxidative/antioxidative imbalance between ROS production and elimination, play a key role in cellular damage. There is evidence to support the role of ROS in the pathogenesis of a range of diseases including the myelodysplastic syndromes (MDS) and leukaemia. Oxidative stress seems to affect the self-renewal, proliferation and differentiation of haematopoietic stem cells and impair cell growth. Three aspects of these defective haemopoietic mechanisms may be associated with the activities of ROS: clonal evolution, haematological improvement and recovery of haemopoiesis after haematopoietic stem cell transplantation (HSCT). This review aims to provide haematologists with an overview of results from in vitro and murine models and preliminary clinical evidence on the diagnostic, prognostic and therapeutic implications of the complex interactions between the haemopoietic niche, iron, oxidative stress and inadequate haemopoiesis.

Management of Transfusional Chronic Iron Overload: Focus on Deferasirox

Most patients with hereditary or chronic acquired anemias are dependent on regular red cell transfusions. Untreated iron overload from transfusions is responsible for morbidity and mortality in patients with thalassemia major. However, clinical consequences of parenchymal iron overload have been reported not only in thalassemia major but also in patients with myelodysplastic syndrome. The current standard in iron chelation therapy is deferoxamine mesylate (Desferal®). Deferasirox is the first oral iron chelator approved in the Europe Union for use in patients with transfusional iron overload with different diseases. The aim of this review is to examine the properties and management of Deferasirox.

Hematopietic stem cell transplantation in thalassemia and related disorders.

The basis of allogeneic hemopoietic stem cell (HSC) transplantation in thalassemia consists in substituting the ineffective thalassemic erythropoiesis with and allogeneic effective one. This cellular replacement therapy is an efficient way to obtain a long lasting, probably permanent, clinical effective correction of the anaemia avoiding transfusion requirement and subsequent complications like iron overload. The first HSC transplant for thalassemia was performed in Seattle on Dec 2, 1981. In the early eighties transplantation procedure was limited to very few centres worldwide. Between 17 December 1981 and 31 January 2003, over 1000 consecutive patients, aged from 1 to 35 years, underwent transplantation in Pesaro. After the pioneering work by the Seattle and Pesaro groups, this therapeutic approach is now widely applied worldwide. Medical therapy of thalassemia is one of the most spectacular successes of the medical practice in the last decades. In recent years advances in knowledge of iron overload patho-physiopathology, improvement and diffusion of diagnostic capability together with the development of new effective and safe oral chelators promise to further increase success of medical therapy. Nevertheless situation is dramatically different in non-industrialized countries were the very large majority of patients live today. Transplantation technologies have improved substantially during the last years and transplantation outcome is likely to be much better today than in the ‘80s. Recent data indicated a probability of overall survival and thalassemia free survival of 97% and 89% for patients with no advanced disease and of 87% and 80% for patients with advanced disease. Thus the central role of HSC in thalassemia has now been fully established. HSC remains the only definitive curative therapy for thalassemia and other hemoblobinopathies. The development of oral chelators has not changed this position. However this has not settled the controversy on how this curative but potentially lethal treatment stands in front of medical therapy for adults and advanced disease patients. In sickle cell disease HSC transplantation currently is reserved almost exclusively for patients with clinical features that indicate a poor outcome or significant sickle-related morbidity.

Cardiogenic Shock during First Infusion of Anthracycline Chemotherapy in a Patient with Hodgkin Lymphoma: An Unusual Event

Introduction: Hodgkin lymphoma (HL) is one of the most common types of cancers of the lymphatic system. The currently available therapies enable a cure in approximately 80-85% of treated patients. However, the cardiotoxicity of HL treatment has become a major cause of morbidity and mortality in survivors mainly related to the use of anthracycline. Case Report: An HL, staged IIIB, was diagnosed in a 60-year-old man with no cardiovascular disease. During the first cycle of ABVD chemotherapy (Adriamycin; bleomycin; vinblastine; dacarbazine), near the end of the dacarbazine infusion, the patient presented a sudden cardiogenic shock characterized by a severe left ventricular systolic dysfunction. Laboratory and instrumental examinations performed did not suggest any specific etiology. After 15 days of medical support, the patient presented a complete cardiac function and clinical recovery. Subsequently bendamustine chemotherapy was started because of its limited extrahematological toxicity, but after 4 cycles the patient had progressive disease and died of septic shock. We concluded that a very rare hyperacute anthracycline cardiotoxicity was the most likely reason for this critical scenario. Conclusions: This rare event stresses our inability to correctly predict the risk of a patient developing cardiotoxicity and also highlights the need to improve the knowledge of underlying pathophysiological mechanisms; in fact, it suggests a possible genetic predisposition to develop cardiotoxicity due to a relatively limited dosage.