Open access journal of the Ferrata-Storti Foundation, a non-profit organization
Opinion Article

The European Hematology Association Roadmap for European Hematology Research: a consensus document

Universität zu Köln, Cologne, Germany
IRCCS Policlinico San Matteo Foundation, Pavia, Italy
Leids Universitair Medisch Centrum, Leiden, the Netherlands
Université Claude Bernard, Lyon, France
Hôpitaux Universitaires Henri Mondor, Créteil, France
Universitätsklinikum Ulm, Germany
European Hematology Association, The Hague, the Netherlands
Medizinische Universität Wien, Vienna, Austria
Leids Universitair Medisch Centrum, Leiden, the Netherlands
Cambridge Institute for Medical Research, United Kingdom
European Hematology Association, The Hague, the Netherlands
Università Federico II di Napoli, Italy
Université Pierre et Marie Curie, Paris, France
Ospedale San Bortolo, Vicenza, Italy
Hospices Civils de Lyon/Université de Lyon, Pierre-Bénite, France
Universitair Medisch Centrum Groningen, the Netherlands
Vol. 101 No. 2 (2016): February, 2016 https://doi.org/10.3324/haematol.2015.136739

Abstract

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap.The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders.The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.

Introduction

Blood can be described as one of the human body’s largest organs. It is essentially a liquid tissue containing many different types of specialized cells needed for the normal functioning of the human body. When one or more of these cell types do not perform well, a wide variety of blood disorders can result, ranging from blood cancers and coagulation and platelet disorders to very common diseases such as anemia.

Hematology is the medical discipline concerned with diagnosing and treating all of these diseases.

In the European Union (EU) alone, an estimated 80 million people are currently affected with blood disorders.

Various types of anemia affect more than 50 million children and adults in the World Health Organization’s European region.1 Blood cancers, some of which mainly affect young people, contribute strongly to premature cancer-related mortality and lost productivity in Europe.2 Among cancers, blood cancers [leukemia, Hodgkin and non-Hodgkin lymphomas (HLs and NHLs), and multiple myeloma] together rank third after lung cancer and colorectal cancer in terms of age-adjusted mortality in the European Economic Area.3

Inherited blood diseases, such as thalassemia, sickle cell disease, and glucose-6-phosphate dehydrogenase deficiency, also affect millions of people and cause substantial morbidity and mortality. Rarer forms of congenital blood disorders represent an immense burden on those affected. Many infectious diseases affect various types of blood or blood-forming cells, causing widespread diseases such as malaria and HIV/AIDS.

In recent decades, enormous progress has been made in terms of diagnosis and treatment of these diseases. Unfortunately, many blood disorders remain incurable. Approximately 115,000 patients die each year.4

Blood disorders have immense economic consequences as well. The combined societal cost of hematologic diseases for the EU, Norway, Iceland, and Switzerland has been estimated at €23 billion per year.

At a European level, current public spending on hematology research does not match this vast medical need. Of the €6.1 billion that the European Union allocated to health research under its 7 Framework Programme (2007–2013), only 2.2% (€137 million) was granted to hematology research. That amounts to less than 0.1% of the societal cost of blood disorders in Europe over that same period.

Milestones in hematology and the contribution from Europe

Research in hematology has fundamentally improved our understanding of the biology of hematologic diseases and resulted in many innovative discoveries. Many of these discoveries are powerful examples of how carefully designed basic research can lead to new approaches that block or interact with key pathways in diseased cells, resulting in very impressive anti-tumor effects. European hematologists have pioneered important inventions and played leading roles in developing, for example, curative approaches for patients with malignant diseases, such as lymphomas and leukemias,65 which often affect young patients.

Key milestones included the characterization of hemoglobin (Hb),7 induced pluripotent stem cells (iPSCs),8 and somatic driver mutations.9 The discovery of the Philadelphia chromosome and the subsequent identification of the BCR-ABL1 tyrosine kinase and its role in chronic myeloid leukemia (CML)10 led to the successful development of potentially curative targeted treatment in this form of blood cancer.11 This was an unprecedented rate of success and it occurred in a malignancy that previously could only be treated by allogeneic transplant in a very select number of patients. Acute promyelocytic leukemia became one of the first malignancies that could be cured without conventional chemotherapy.12

Another key development in hematology was that of a wide range of monoclonal antibodies following the original invention by Köhler and Milstein in the UK.13 Humanized or fully human monoclonal antibodies are now used in hematology for both diagnostic and therapeutic purposes. The clinical breakthrough was a humanized monoclonal antibody targeting the CD20 antigen on B-cell lymphoma.14 Today, monoclonal antibodies or antibody-based conjugates are used successfully in most malignant lymphomas and leukemias. They can, however, also be effective in nonmalignant blood disorders such as paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired clonal stem cell defect leading to increased fragility of hematopoietic cells and hemolytic anemia (HA), thrombosis, and bone marrow failure (BMF). Prognosis of patients with severe PNH used to be less than five years, but changed radically with the advent of an anti-complement monoclonal antibody that counteracts membrane fragility.15 Today, PNH patients treated with this antibody have a normal life expectancy.

Severe hemophilia represents another story of unprecedented success. Patients used to be confined to wheelchairs or face the specter of death because of untreatable hemorrhage or blood-born infections such as HIV/AIDS. Today, new recombinant substitutive therapy is completely safe and effective in long-term prophylaxis. Hematology expects to further improve in this area, with innovative factor VIII or IX molecules that have increased activity and prolonged half-life.

Gene therapy is becoming a reality for more and more blood diseases, while treatment of malignant and nonmalignant hematologic diseases is impossible without blood transfusions and blood-derived medicinal products. “Haemovigilance”, a European initiative that provides a surveillance registry of serious unwanted transfusion effects, is now up and running in most EU member states.

European research policy

Governments, politicians and other policy makers carry the responsibility for making well informed decisions on regulation and funding priorities for health research and medicinal product development. The research community has a responsibility in providing policy makers with the kind of information and evidence that they need to make those informed decisions.

With respect to research funding, the authors feel that hematology was underfunded in the EU’s 7 Framework Programme. The current Framework Programme (Horizon 2020) was spared major budget cuts, but raising the relative level of funding for hematology research needs to be improved.

With respect to regulation, a key issue on the table is the EU’s new regulation on clinical trials on medicinal products for human use, which will come into effect in 2016. Over the past years, the number of clinical trials in Europe has decreased. These trials are key to medical research. European research groups have been instrumental in setting up multicenter clinical trials to test important new products. However, the new regulation has the potential of making future trials in Europe too expensive and too complex to carry out, especially in terms of academic research, and, therefore, may lead to a further decrease in clinical trials. A drop in the number of trials and the number of participants would harm the interests of European patients and damage Europe’s knowledge infrastructure and future economy.

The European Hematology Association Roadmap

In 2014, at its 19 Annual Congress in Milan, Italy, the European Hematology Association (EHA), Europe’s largest non-profit membership organization in the field of hematology, decided to launch a Roadmap project. One of its goals was to better inform European policy makers and other stakeholders about the urgent needs and priorities of patients with blood diseases and the field of hematology. Another goal was to help the European hematology research community in harnessing resources by bringing basic researchers, clinical trial networks and patient advocates together in comprehensive study groups. A European consensus on medical and research priorities will also promote excellence and collaboration between academics and the pharmaceutical industry.

The EHA Roadmap Task Force included EHA board members and other top experts from all fields of hematology. Hundreds of hematologists, clinical trial groups, drug makers, national hematology societies, patient representatives and others were invited to provide input and advice. Many contributed to the drafting of the document and the various stages of review.

This Roadmap is the outcome of this project. It identifies the greatest unmet needs in hematology research and clinical science, describing: 1) state-of-the-art hematologic research; 2) the most urgent research priorities; and 3) the anticipated impact this research could have.

The EHA Roadmap Task Force identified nine major ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation (HSCT). For each section, the Roadmap Task Force appointed one or two editors. Together, the Roadmap Task Force and section editors drafted and reviewed a more detailed framework of 60 ‘subsections’ of groups of diseases and conditions. Section editors selected experts from their various fields to contribute as subsection editors or authors. Each section and subsection adapted the same basic format.

Draft texts and figures were discussed by the Roadmap Task Force and section editors during three meetings between October 2014 and March 2015. Sections were then reviewed by the Roadmap Task Force, the EHA board, and a selection of experts. The final draft was sent for consultation to stakeholders such as national hematology societies, patients’ organizations, hematology trial groups, and other European organizations in, for example, overlapping disease areas. All comments were discussed and integrated before submission of the manuscript to Haematologica.

In all, around 300 European hematologists and top experts helped to create the Roadmap.

At the request of the EHA board, the University of Oxford simultaneously carried out a study into the societal burden and cost of blood disorders in Europe. Outcomes from their analysis also informed various parts of this Roadmap.

Some dominating topics and unmet needs can be recognized in nearly all of the nine EHA Roadmap sections. They include:

  • developing novel targeted therapies based on genomic profiling and chemical biology;
  • unleashing the power of cellular immunotherapy;
  • eradicating minimal residual disease (MRD) in hematologic malignancies;
  • creating smarter combination treatments;
  • developing better tolerated treatments for blood disorders with a special emphasis on elderly patients;
  • using gene therapy to tackle blood disorders;
  • maximizing the clinical application of hematopoietic stem cells (HSCs) for transfusion, immunomodulation, and repair.

Taken together, this EHA Roadmap highlights major past achievements in the diagnostics and treatment of blood disorders, identifies unmet clinical and scientific needs in those same areas, and will enable better funded and more focused European hematology research.

The EHA will pro-actively bring this Roadmap to the attention of all stakeholders involved in hematology, and calls upon those stakeholders to do the same.

  • Received December 15, 2015.
  • Accepted January 27, 2016.

References

  1. WHO Global Database on Anemia. World Health Organization: Geneva; 2008. Google Scholar
  2. Hanly P, Soerjomataram I, Sharp L. Measuring the societal burden of cancer: the cost of lost productivity due to premature cancer-related mortality in Europe. Int J Cancer. 2015; 136(4):e136-145. PubMed|https://doi.org/10.1002/ijc.29105|Google Scholar
  3. Causes of death. 2015. Google Scholar
  4. Cancer Factsheets.Google Scholar
  5. Döhner H, Stilgenbauer S, Benner A. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000; 343(26):1910-1916. PubMed|https://doi.org/10.1056/NEJM200012283432602|Google Scholar
  6. Engert A, Plütschow A, Eich HT. Reduced treatment intensity in patients with early-stage Hodgkin’s Lymphoma. N Engl J Med. 2010; 363:640-652. PubMed|https://doi.org/10.1056/NEJMoa1000067|Google Scholar
  7. Perutz MF, Rossmann MG, Cullis AF. Structure of hemoglobin: a three-dimensional Fourier synthesis at 5.5-A. resolution, obtained by X-ray analysis. Nature. 1960; 185:416-422. PubMed|https://doi.org/10.1038/185416a0|Google Scholar
  8. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-676. PubMed|https://doi.org/10.1016/j.cell.2006.07.024|Google Scholar
  9. Malcovati L, Papaemmanuil E, Ambaglio I. Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia. Blood. 2014; 124(9):1513-1521. PubMed|https://doi.org/10.1182/blood-2014-03-560227|Google Scholar
  10. Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999; 341(3):164-172. PubMed|https://doi.org/10.1056/NEJM199907153410306|Google Scholar
  11. Druker BJ, Guilhot F, O’Brian SG. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006; 355(23):2408-2411. PubMed|https://doi.org/10.1056/NEJMoa062867|Google Scholar
  12. Lo-Coco F, Cicconi L. Outpatient oral treatment for acute promyelocytic leukemia. N Engl J Med. 2015; 372(9):884-885. https://doi.org/10.1056/NEJMc1500125|Google Scholar
  13. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975; 256:495-497. PubMed|https://doi.org/10.1038/256495a0|Google Scholar
  14. Coiffier B, Lepage E, Briere J. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002; 346(4):235-242. PubMed|https://doi.org/10.1056/NEJMoa011795|Google Scholar
  15. Hillmen P, Young NS, Schubert J. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006; 355(12):1233-1243. PubMed|https://doi.org/10.1056/NEJMoa061648|Google Scholar
  16. Dzierzak E, Philipsen S. Erythropoiesis: development and differentiation. Cold Spring Harb. Perspect. Med. 2013; 3(4):a011601. Google Scholar
  17. Weatherall DJ, Clegg JB. Thalassemia–a global public health problem. Nat Med. 1996; 2(8):847-849. PubMed|https://doi.org/10.1038/nm0896-847|Google Scholar
  18. Kountouris P, Lederer CW, Fanis P, Feleki X, Old J, Kleanthous M. IthaGenes: an interactive database for hemoglobin variations and epidemiology. PLoS One. 2014; 9(7):e103020. PubMed|https://doi.org/10.1371/journal.pone.0103020|Google Scholar
  19. Vainchenker W, Favale F. Myelofibrosis, JAK2 inhibitors and erythropoiesis. Leukemia. 2013; 27(6):1219-1223. PubMed|https://doi.org/10.1038/leu.2013.72|Google Scholar
  20. Nauseef WM, Borregaard N. Neutrophils at work. Nat Immunol. 2014; 15(7):602-611. PubMed|https://doi.org/10.1038/ni.2921|Google Scholar
  21. Dong F, Brynes RK, Tidow N, Welte K, Lowenberg B, Touw IP. Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. N Engl J Med. 1995; 333(8):487-493. PubMed|https://doi.org/10.1056/NEJM199508243330804|Google Scholar
  22. Theilgaard-Monch K, Jacobsen LC, Borup R. The transcriptional program of terminal granulocytic differentiation. Blood. 2005; 105(4):1785-1796. PubMed|https://doi.org/10.1182/blood-2004-08-3346|Google Scholar
  23. Reckzeh K, Bereshchenko O, Mead A. Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model. Leukemia. 2012; 26(7):1527-1536. PubMed|https://doi.org/10.1038/leu.2012.37|Google Scholar
  24. Kirstetter P, Schuster MB, Bereshchenko O. Modeling of C/EBPa mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia initiating cells. Cancer Cell. 2008; 13:299-310. PubMed|https://doi.org/10.1016/j.ccr.2008.02.008|Google Scholar
  25. Wendling F, Maraskovsky E, Debili N. cMpl ligand is a humoral regulator of megakaryocytopoiesis. Nature. 1994; 369(6481):571-574. PubMed|https://doi.org/10.1038/369571a0|Google Scholar
  26. Tijssen MR, Cvejic A, Joshi A. Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators. Dev Cell. 2011; 20(5):597-609. PubMed|https://doi.org/10.1016/j.devcel.2011.04.008|Google Scholar
  27. Sanjuan-Pla A, Macaulay IC, Jensen CT. Platelet-biased stem cells reside at the apex of the hematopoietic stem-cell hierarchy. Nature. 2013; 502(7470):232-236. PubMed|https://doi.org/10.1038/nature12495|Google Scholar
  28. Lordier L, Bluteau D, Jalil A. RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakary-ocyte polyploidization. Nat Commun. 2012; 3:717. PubMed|https://doi.org/10.1038/ncomms1704|Google Scholar
  29. Di Buduo CA, Wray LS, Tozzi L. Programmable 3D silk bone marrow niche for platelet generation ex vivo and modeling of megakaryopoiesis pathologies. Blood. 2015; 125(14):2254-2264. PubMed|https://doi.org/10.1182/blood-2014-08-595561|Google Scholar
  30. Cavazzana-Calvo M, Fischer A, Hacein-Bey-Abina S, Aiuti A. Gene therapy for primary immunodeficiencies: Part 1. Curr Opin Immunol. 2012; 24(5):580-584. PubMed|https://doi.org/10.1016/j.coi.2012.08.008|Google Scholar
  31. Plum J, De SM, Leclercq G, Taghon T, Kerre T, Vandekerckhove B. Human intrathymic development: a selective approach. Semin Immunopathol. 2008; 30(4):411-423. PubMed|https://doi.org/10.1007/s00281-008-0135-2|Google Scholar
  32. Taghon T, Waegemans E, Van de Walle I. Notch signaling during human T cell development. Curr Top Microbiol Immunol. 2012; 360:75-97. PubMed|https://doi.org/10.1007/82_2012_230|Google Scholar
  33. De Villartay JP, Fischer A, Durandy A. The mechanisms of immune diversification and their disorders. Nat Rev Immunol. 2003; 3(12):962-972. PubMed|https://doi.org/10.1038/nri1247|Google Scholar
  34. Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2011; 12(1):21-27. PubMed|https://doi.org/10.1038/ni.1962|Google Scholar
  35. Bystrykh LV, Verovskaya E, Zwart E, Broekhuis M, de Haan G. Counting stem cells: methodological constraints. Nat Methods. 2012; 9(6):567-574. PubMed|https://doi.org/10.1038/nmeth.2043|Google Scholar
  36. Geiger H, de Haan G, Florian MC. The ageing hematopoietic stem cell compartment. Nat Rev Immunol. 2013; 13(5):376-389. PubMed|https://doi.org/10.1038/nri3433|Google Scholar
  37. Pereira CF, Lemischka IR, Moore K. ‘From blood to blood’: de-differentiation of hematopoietic progenitors to stem cells. EMBO J. 2014; 33(14):1511-1513. PubMed|https://doi.org/10.15252/embj.201488980|Google Scholar
  38. Lassailly F, Foster K, Lopez-Onieva L, Currie E, Bonnet D. Multimodal imaging reveals structural and functional heterogeneity in different bone marrow compart ments: functional implications on hematopoietic stem cells. Blood. 2013; 122(10):1730-1740. PubMed|https://doi.org/10.1182/blood-2012-11-467498|Google Scholar
  39. Shlush LI, Zandi S, Mitchell A. Identification of pre-leukaemic hematopoietic stem cells in acute leukemia. Nature. 2014; 506(7488):328-333. PubMed|https://doi.org/10.1038/nature13038|Google Scholar
  40. Dzierzak E, Speck NA. Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol. 2008; 9(2):129-36. PubMed|https://doi.org/10.1038/ni1560|Google Scholar
  41. Medvinsky A, Rybtsov S, Taoudi S. Embryonic origin of the adult hematopoietic system: advances and questions. Development. 2011; 138(6):1017-1031. PubMed|https://doi.org/10.1242/dev.040998|Google Scholar
  42. Solaimani Kartalaei P, Yamada-Inagawa T, Vink CS. Whole-transcriptome analysis of endothelial to hematopoietic stem cell transition reveals a requirement for Gpr56 in HSC generation. J Exp Med. 2015; 212:93-106. PubMed|https://doi.org/10.1084/jem.20140767|Google Scholar
  43. Charbord P, Pouget C, Binder H. A systems biology approach for defining the molecular framework of the hematopoietic stem cell niche. Cell Stem Cell. 2014; 15(3):376-391. PubMed|https://doi.org/10.1016/j.stem.2014.06.005|Google Scholar
  44. Roberts I, O’Connor D, Roy A, Cowan G, Vyas P. The impact of trisomy 21 on foetal hematopoiesis. Blood Cells Mol Dis. 2013; 51(4):277-281. PubMed|https://doi.org/10.1016/j.bcmd.2013.07.008|Google Scholar
  45. Rashidi NM, Scott MK, Scherf N. In vivo time-lapse imaging shows diverse niche engagement by quiescent and naturally activated hematopoietic stem cells. Blood. 2014; 124(1):79-83. PubMed|https://doi.org/10.1182/blood-2013-10-534859|Google Scholar
  46. Krause DS, Fulzele K, Catic A. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat Med. 2013; 19(11):1513-1517. PubMed|https://doi.org/10.1038/nm.3364|Google Scholar
  47. Arranz L, Sanchez-Aguilera A, Martin-Perez D. Neuropathy of hematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature. 2014; 512(7512):78-81. PubMed|https://doi.org/10.1038/nature13383|Google Scholar
  48. Raaijmakers MH, Mukherjee S, Guo S. Bone progenitor dysfunction induces myelodysplasia and secondary leukemia. Nature. 2010; 464(7290):852-857. PubMed|https://doi.org/10.1038/nature08851|Google Scholar
  49. Chen L, Kostadima M, Martens JH. Transcriptional diversity during lineage commitment of human blood progenitors. Science. 2014; 345(6204):1251033. PubMed|https://doi.org/10.1126/science.1251033|Google Scholar
  50. Martens JH, Brinkman AB, Simmer F. PML-RARalpha/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia. Cancer Cell. 2010; 17(2):173-185. PubMed|https://doi.org/10.1016/j.ccr.2009.12.042|Google Scholar
  51. Moignard V, Macaulay IC, Swiers G. Characterization of transcriptional networks in blood stem and progenitor cells using high-throughput single-cell gene expression analysis. Nat Cell Biol. 2013; 15(4):363-372. PubMed|https://doi.org/10.1038/ncb2709|Google Scholar
  52. Saeed S, Quintin J, Kerstens HH. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014; 345(6204):1251086. PubMed|https://doi.org/10.1126/science.1251086|Google Scholar
  53. Wilson NK, Foster SD, Wang X. Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell. 2010; 7(4):532-544. PubMed|https://doi.org/10.1016/j.stem.2010.07.016|Google Scholar
  54. Eilken HM, Nishikawa S, Schroeder T. Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature. 2009; 457(7231):896-900. PubMed|https://doi.org/10.1038/nature07760|Google Scholar
  55. Lancrin C, Sroczynska P, Stephenson C, Allen T, Kouskoff V, Lacaud G. The haemangioblast generates hematopoietic cells through a haemogenic endothelium stage. Nature. 2009; 457(7231):892-895. PubMed|https://doi.org/10.1038/nature07679|Google Scholar
  56. Ledran MH, Krassowska A, Armstrong L. Efficient hematopoietic differentiation of human embryonic stem cells on stromal cells derived from hematopoietic niches. Cell Stem Cell. 2008; 3(1):85-98. PubMed|https://doi.org/10.1016/j.stem.2008.06.001|Google Scholar
  57. Mittra J, Tait J, Mastroeni M, Turner ML, Mountford JC, Bruce K. Identifying viable regulatory and innovation pathways for regenerative medicine: a case study of cultured red blood cells. Nat Biotechnol. 2015; 32(1):180-190. Google Scholar
  58. Bussmann LH, Schubert A, Vu Manh TP. A robust and highly efficient immune cell reprogramming system. Cell Stem Cell. 2009; 5(5):554-566. PubMed|https://doi.org/10.1016/j.stem.2009.10.004|Google Scholar
  59. Sant M, Allemani C, Tereanu C. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010; 116(19):3724-3734. PubMed|https://doi.org/10.1182/blood-2010-05-282632|Google Scholar
  60. Marcos-Gragera R, Allemani C, Tereanu C. Survival of European patients diagnosed with lymphoid neoplasms in 2000–2002: results of the HAEMACARE project. Haematologica. 2011; 96(5):720-728. PubMed|https://doi.org/10.3324/haematol.2010.034264|Google Scholar
  61. Testoni M, Zucca E, Young KH, Bertoni F. Genetic lesions in diffuse large B-cell lymphomas. Ann Onc. 2015; 26(6):1069-1080. PubMed|https://doi.org/10.1093/annonc/mdv019|Google Scholar
  62. Pileri SA, Piccaluga PP. New molecular insights into peripheral T cell lymphomas. J Clin Invest. 2012; 122(10):3448-3455. PubMed|https://doi.org/10.1172/JCI61205|Google Scholar
  63. Puente XS, Pinyol M, Quesada V. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011; 475(7354):101-105. PubMed|https://doi.org/10.1038/nature10113|Google Scholar
  64. Google Scholar
  65. Beà S, Valdés-Mas R, Navarro A. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci USA. 2013; 110(45):18250-18255. PubMed|https://doi.org/10.1073/pnas.1314608110|Google Scholar
  66. Lemonnier F, Couronne L, Parrens M. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012; 120(7):1466-1469. PubMed|https://doi.org/10.1182/blood-2012-02-408542|Google Scholar
  67. Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014; 14:517-534. PubMed|https://doi.org/10.1038/nrc3774|Google Scholar
  68. Chubb D, Weinhold N, Broderick P. Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat Genet. 2013; 45(10):1221-1225. PubMed|https://doi.org/10.1038/ng.2733|Google Scholar
  69. Cerhan JR, Berndt SI, Vijai J. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat Genet. 2014; 46(11):1233-1238. PubMed|https://doi.org/10.1038/ng.3105|Google Scholar
  70. Cruz RD, Tricot G, Zangari M, Zhan F. Progress in myeloma stem cells. Am J Blood Res. 2011; 1(3):135-145. PubMed|Google Scholar
  71. Martinez-Climent JA, Fontan L, Gascoyne RD, Siebert R, Prosper F. Lymphoma stem cells: enough evidence to support their existence¿. Haematologica. 2010; 95(2):293-302. PubMed|https://doi.org/10.3324/haematol.2009.013318|Google Scholar
  72. Roulland S, Kelly RS, Morgado E. t(14;18) Translocation: A predictive blood biomarker for follicular lymphoma. J Clin Oncology. 2014; 32(13):1347-1355. PubMed|https://doi.org/10.1200/JCO.2013.52.8190|Google Scholar
  73. Sant M, Minicozzi P, Mounier M. Survival for haematological malignancies in Europe between 1997 and 2008 by region and age: Results of EUROCARE-5, a population-based study. Lancet Oncol. 2014; 15(9):931-942. PubMed|https://doi.org/10.1016/S1470-2045(14)70282-7|Google Scholar
  74. Oerlemans S, Mols F, Nijziel MR, Lybeert M, van de Poll-Franse LV. The impact of treatment, socio-demographic and clinical characteristics on health-related quality of life among Hodgkin’s and non-Hodgkin’s lymphoma survivors: a systematic review. Ann Hematol. 2011; 90(9):993-1004. PubMed|https://doi.org/10.1007/s00277-011-1274-4|Google Scholar
  75. Behringer K, Goergen H, Hitz F. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin’s lymphoma (GHSG HD13): an open-label, randomized, non-inferiority trial. Lancet. 2014; 14:6736-6769. Google Scholar
  76. Diehl V, Franklin J, Pfreundschuh M. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003; 348:2386-2395. PubMed|https://doi.org/10.1056/NEJMoa022473|Google Scholar
  77. Raemaekers JM, André MP, Federico M. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014; 32:1188-1194. PubMed|https://doi.org/10.1200/JCO.2013.51.9298|Google Scholar
  78. Barrington SF, Mikhaeel NG, Kostakoglu L. Role of imaging in the staging and response assessment of lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014; 32:3048-3058. PubMed|https://doi.org/10.1200/JCO.2013.53.5229|Google Scholar
  79. Younes A, Gopal AK, Smith SE. Results of a pivotal phase II study of bren-tuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012; 30:2183-2189. PubMed|https://doi.org/10.1200/JCO.2011.38.0410|Google Scholar
  80. Coiffier B, Thieblemont C, Van Den Neste E. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010; 116:2040-2045. PubMed|https://doi.org/10.1182/blood-2010-03-276246|Google Scholar
  81. Ziepert M, Hasenclever D, Kuhnt E. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol. 2010; 28:2373-2380. PubMed|https://doi.org/10.1200/JCO.2009.26.2493|Google Scholar
  82. Hummel M, Bentink S, Berger H. A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006; 354:2419-2430. PubMed|https://doi.org/10.1056/NEJMoa055351|Google Scholar
  83. Pott C, Hoster E, Delfau-Larue M-H. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study. Blood. 2010; 115:3215-3223. PubMed|https://doi.org/10.1182/blood-2009-06-230250|Google Scholar
  84. Hoster E, Dreyling M, Klapper W. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008; 111:558-565. PubMed|https://doi.org/10.1182/blood-2007-06-095331|Google Scholar
  85. Geisler CH, Kolstad A, Laurell A. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008; 112:2687-2693. PubMed|https://doi.org/10.1182/blood-2008-03-147025|Google Scholar
  86. Kluin-Nelemans HC, Hoster E, Hermine O. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012; 367:520-531. PubMed|https://doi.org/10.1056/NEJMoa1200920|Google Scholar
  87. Wang ML, Rule S, Martin P. Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2013; 369:507-516. PubMed|https://doi.org/10.1056/NEJMoa1306220|Google Scholar
  88. Okosun J, Bodor C, Wang J. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet. 2014; 46(2):176-181. PubMed|https://doi.org/10.1038/ng.2856|Google Scholar
  89. Salles G, Seymour JF, Offner F. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011; 377(9759):42-51. PubMed|https://doi.org/10.1016/S0140-6736(10)62175-7|Google Scholar
  90. Tellier J, Menard C, Roulland S. Human t(14;18)positive germinal center B cells: a new step in follicular lymphoma pathogenesis¿. Blood. 2014; 123(22):3462-3465. PubMed|https://doi.org/10.1182/blood-2013-12-545954|Google Scholar
  91. Bodor C, Grossmann V, Popov N. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. 2013; 122(18):3165-3168. PubMed|https://doi.org/10.1182/blood-2013-04-496893|Google Scholar
  92. Sander B, de Jong D, Rosenwald A. The reliability of immunohistochemical analysis of the tumor microenvironment in follicular lymphoma: a validation study from the Lunenburg Lymphoma Biomarker Consortium. Haematologica. 2014; 99(4):715-725. PubMed|https://doi.org/10.3324/haematol.2013.095257|Google Scholar
  93. Ferreri AJ, Govi S, Ponzoni M. Marginal zone lymphomas and infectious agents. Semin Cancer Biol. 2013; 23:431-440. PubMed|https://doi.org/10.1016/j.semcancer.2013.09.004|Google Scholar
  94. Montalban C, Abraira V, Arcaini L. Simplification of risk stratification for splenic marginal zone lymphoma: a point-based score for practical use. Leuk Lymphoma. 2014; 55:929-931. PubMed|https://doi.org/10.3109/10428194.2013.818143|Google Scholar
  95. Salar A, Domingo-Domenech E, Panizo C. First-line response-adapted treatment with the combination of bendamustine and rituximab for patients with mucosa-associated lymphoid tissue lymphoma (MALT2008-01): a multicenter, single arm, phase II trial. Lancet Haematol. 2014; 1:e104-111. https://doi.org/10.1016/S2352-3026(14)00021-0|Google Scholar
  96. Zucca E, Conconi A, Laszlo D. Addition of rituximab to chlorambucil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 Randomized Study. J Clin Oncol. 2013; 31:565-572. PubMed|https://doi.org/10.1200/JCO.2011.40.6272|Google Scholar
  97. Arcaini L, Vallisa D, Rattotti S. Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi. Ann Oncol. 2014; 25:1404-1410. PubMed|https://doi.org/10.1093/annonc/mdu166|Google Scholar
  98. Gaulard P, de Leval L. Pathology of Peripheral T-Cell Lymphomas: Where Do We Stand. Sem Hematol. 2014; 51(1):5-16. PubMed|https://doi.org/10.1053/j.seminhematol.2013.11.003|Google Scholar
  99. Chaudhary RK, Bhatt VR, Vose JM. Management of extranodal natural killer/T-cell lymphoma, nasal type. Clin Lymphoma Myeloma Leuk. 2015; 15(5):245-252. PubMed|https://doi.org/10.1016/j.clml.2014.12.014|Google Scholar
  100. Inghirami G, Chan WC, Pileri S. Peripheral T-cell and NK cell lymphoproliferative disorders: Cell of origin, clinical and pathological implications. Immunol Rev. 2015; 263(1):124-159. PubMed|https://doi.org/10.1111/imr.12248|Google Scholar
  101. DeSimone JA, Sodha P, Ignatova D, Dummer R, Cozzio A, Guenova E. Recent advances in primary cutaneous T-cell lymphoma. Curr Opin Oncol. 2015; 27(2):128-133. PubMed|https://doi.org/10.1097/CCO.0000000000000161|Google Scholar
  102. San-Juan R, Manuel O, Hirsch HH. Current preventive strategies and management of Epstein Barr virus-related post-transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH questionnaire-based Cross-sectional Survey. Clin Microbiol Infect. 2015; 21(6):604.e1-9. https://doi.org/10.1016/j.cmi.2015.02.002|Google Scholar
  103. Vickers MA, Wilkie GM, Robinson N. Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease. Br J Haematol. 2014; 167:402-410. PubMed|https://doi.org/10.1111/bjh.13051|Google Scholar
  104. Barta SK, Samuel MS, Xue X. Changes in the influence of lymphoma- and HIV-specific factors on outcomes in AIDS-related non-Hodgkin lymphoma. Ann Oncol. 2015;mdv036. Google Scholar
  105. Barta SK, Xue X, Wang D. A new prognostic score for AIDS-related lymphoma in the rituximabera. Haematologica. 2014; 99:1731-1737. PubMed|https://doi.org/10.3324/haematol.2014.111112|Google Scholar
  106. Castillo JJ, Bower M, Brühlmann J. HIV-Associated Hodgkin Lymphoma in the cART Era Study Group. Prognostic factors for advanced-stage human immunodeficiency virus-associated classical Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine, and dacarbazine plus combined antiretroviral therapy: A multi-institutional retrospective study. Cancer. 2015; 121:423-431. PubMed|https://doi.org/10.1002/cncr.29066|Google Scholar
  107. Dühren-von Minden M, Übelhart R, Schneider D. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature. 2012; 489(7415):309-312. PubMed|https://doi.org/10.1038/nature11309|Google Scholar
  108. Woyach JA, Furman RR, Liu TM. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014; 370(24):2286-2294. PubMed|https://doi.org/10.1056/NEJMoa1400029|Google Scholar
  109. Hallek M, Fischer K, Fingerle-Rowson G. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010; 376:1164-1174. PubMed|https://doi.org/10.1016/S0140-6736(10)61381-5|Google Scholar
  110. Goede V, Fischer K, Busch R. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014; 370(12):1101-1110. PubMed|https://doi.org/10.1056/NEJMoa1313984|Google Scholar
  111. Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood. 2013; 122:3723-3734. PubMed|https://doi.org/10.1182/blood-2013-05-498287|Google Scholar
  112. Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011; 29(5):532-543. PubMed|https://doi.org/10.1200/JCO.2010.30.1382|Google Scholar
  113. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia. 2007; 21:604-611. PubMed|Google Scholar
  114. Holleman A, Cheok MH, den Boer ML. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med. 2004; 351(6):533-542. PubMed|https://doi.org/10.1056/NEJMoa033513|Google Scholar
  115. Ma X, Edmonson M, Yergeau D. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia. Nat Commun. 2015; 6:6604. PubMed|https://doi.org/10.1038/ncomms7604|Google Scholar
  116. Vassal G, Rousseau R, Blanc P. Creating a unique, multi-stakeholder Paediatric Oncology Platform to improve drug development for children and adolescents with cancer. Eur J Cancer. 2015; 51(2):218-224. PubMed|https://doi.org/10.1016/j.ejca.2014.10.029|Google Scholar
  117. Rawstron AC, Orfao A, Beksac M. Report of the European Myeloma Network on multiparametric flow cytometry in mul tiple myeloma and related disorders. Haematologica. 2008; 93(3):431-438. PubMed|https://doi.org/10.3324/haematol.11080|Google Scholar
  118. Palumbo A, Bringhen S, Ludwig H. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011; 118(17):4519-4529. PubMed|https://doi.org/10.1182/blood-2011-06-358812|Google Scholar
  119. Ross FM, Avet-Loiseau H, Ameye G. Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica. 2012; 97(8):1272-1277. PubMed|https://doi.org/10.3324/haematol.2011.056176|Google Scholar
  120. Dimopoulos MA, García-Sanz R, Gavriatopoulou M. Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood. 2013; 122(19):3276-3282. PubMed|https://doi.org/10.1182/blood-2013-05-503862|Google Scholar
  121. Engelhardt M, Terpos E, Kleber M. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma. Haematologica. 2014; 99(2):232-242. PubMed|https://doi.org/10.3324/haematol.2013.099358|Google Scholar
  122. Sanders MA, Valk PJ. The evolving molecular genetic landscape in acute myeloid leukemia. Curr Opin Hematol. 2013; 20(2):79-85. PubMed|https://doi.org/10.1097/MOH.0b013e32835d821c|Google Scholar
  123. Cazzola M, Kralovics R. From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood. 2014; 123(24):3714-3719. PubMed|https://doi.org/10.1182/blood-2014-03-530865|Google Scholar
  124. Harrison C, Kiladjian JJ, Al-Ali HK. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012; 366(9):787-798. PubMed|https://doi.org/10.1056/NEJMoa1110556|Google Scholar
  125. Vannucchi AM, Kiladjian JJ, Griesshammer M. Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera. N Engl J Med. 2015; 372(5):426-435. PubMed|https://doi.org/10.1056/NEJMoa1409002|Google Scholar
  126. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol. 2009; 10(3):223-232. PubMed|https://doi.org/10.1016/S1470-2045(09)70003-8|Google Scholar
  127. Dombret H, Seymour JF, Butrym A. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015; 126(3):291-299. PubMed|https://doi.org/10.1182/blood-2015-01-621664|Google Scholar
  128. Lo-Coco F, Avvisati G, Vignetti M, Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013; 369(2):111-121. PubMed|https://doi.org/10.1056/NEJMoa1300874|Google Scholar
  129. Hehlmann R, Grimwade D, Simonsson B. The European LeukemiaNet - Achievements and perspectives. Haematologica. 2011; 96(1):156-162. PubMed|https://doi.org/10.3324/haematol.2010.032979|Google Scholar
  130. Malcovati L, Hellstrom-Lindberg E, Bowen D. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013; 122:2943-2964. PubMed|https://doi.org/10.1182/blood-2013-03-492884|Google Scholar
  131. Döhner H, Estey EH, Amadori S. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010; 115(3):453-474. PubMed|https://doi.org/10.1182/blood-2009-07-235358|Google Scholar
  132. Baccarani M, Deininger MW, Rosti G. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013; 122:872-884. PubMed|https://doi.org/10.1182/blood-2013-05-501569|Google Scholar
  133. Barosi G, Tefferi A, Besses C. Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT). Leukemia. 2015; 29(1):20-26. PubMed|https://doi.org/10.1038/leu.2014.250|Google Scholar
  134. Papaemmanuil E, Cazzola M, Boultwood J. Somatic SF3B1 mutation in myelodys-plasia with ring sideroblasts. N Engl J Med. 2011; 365:1384-1395. PubMed|https://doi.org/10.1056/NEJMoa1103283|Google Scholar
  135. Papaemmanuil E, Gerstung M, Malcovati L. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013; 122:3616-3627. PubMed|https://doi.org/10.1182/blood-2013-08-518886|Google Scholar
  136. Niemeyer CM, Kang MW, Shin DH. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010; 42:794-800. PubMed|https://doi.org/10.1038/ng.641|Google Scholar
  137. Jadersten M, Malcovati L, Dybedal I. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol. 2008; 26:3607-3613. PubMed|https://doi.org/10.1200/JCO.2007.15.4906|Google Scholar
  138. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015; 373(12):1136-1152. PubMed|https://doi.org/10.1056/NEJMra1406184|Google Scholar
  139. Cornelissen JJ, Gratwohl A, Schlenk RF. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012; 9(10):579-590. PubMed|https://doi.org/10.1038/nrclinonc.2012.150|Google Scholar
  140. Falini B, Mecucci C, Tiacci E, Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005; 352:254-266. PubMed|https://doi.org/10.1056/NEJMoa041974|Google Scholar
  141. Genovese G, Kähler AK, Handsaker RE. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014; 371(26):2477-2487. PubMed|https://doi.org/10.1056/NEJMoa1409405|Google Scholar
  142. Hoffmann VS, Baccarani M, Hasford J. The EUTOS population-based registry: Incidence and clinical characteristics of 2904 CML patients in twenty European Countries. Leukemia. 2015; 29(6):1336-1343. PubMed|https://doi.org/10.1038/leu.2015.73|Google Scholar
  143. Hanfstein B, Shlyakhto V, Lauseker M. Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia. 2014; 28:1988-1992. PubMed|https://doi.org/10.1038/leu.2014.153|Google Scholar
  144. Cross NC, White HE, Colomer D. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015; 29(5):999-1003. PubMed|https://doi.org/10.1038/leu.2015.29|Google Scholar
  145. Mahon FX, Réa D, Guilhot J. Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010; 11:1029-1035. PubMed|https://doi.org/10.1016/S1470-2045(10)70233-3|Google Scholar
  146. James C, Ugo V, Le Couedic JP. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature. 2005; 434(7037):1144-1148. PubMed|https://doi.org/10.1038/nature03546|Google Scholar
  147. Nangalia J, Massie CE, Baxter EJ. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. N Engl J Med. 2013; 369(25):2391-2405. PubMed|https://doi.org/10.1056/NEJMoa1312542|Google Scholar
  148. Klampfl T, Gisslinger H, Harutyunyan AS. Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. N Engl J Med. 2013; 369(25):2379-2390. PubMed|https://doi.org/10.1056/NEJMoa1311347|Google Scholar
  149. Andro M, Le Squere P, Estivin S, Gentric A. Anemia and cognitive performances in the elderly: a systematic review. Eur J Neurol. 2013; 20(9):1234-1240. PubMed|https://doi.org/10.1111/ene.12175|Google Scholar
  150. Abel GJ, Sander N. Quantifying Global International Migration Flows. Science. 2014; 343(6178):1520-1522. PubMed|https://doi.org/10.1126/science.1248676|Google Scholar
  151. Buermans HP, den Dunnen JT. Next generation sequencing technology: Advances and applications. Biochim Biophys Acta. 2014; 1842(10):1932-1941. Google Scholar
  152. Iolascon A, Andolfo I, Russo R. Red cells in post-genomic era: impact of personalized medicine in the treatment of anemias. Haematologica. 2015; 100(1):3-6. PubMed|https://doi.org/10.3324/haematol.2014.120733|Google Scholar
  153. Thein SL. Genetic association studies in β-hemoglobinopathies. Hematology Am Soc Hematol Educ Program. 2013; 2013:354-361. PubMed|https://doi.org/10.1182/asheducation-2013.1.354|Google Scholar
  154. Rivella S. β-Thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies. Haematologica. 2015; 100:418-430. PubMed|https://doi.org/10.3324/haematol.2014.114827|Google Scholar
  155. Telen MJ. Cellular adhesion and the endothelium: E-selectin, L-selectin, and pan-selectin inhibitors. Hematol Oncol Clin North Am. 2014; 28(2):341-354. PubMed|https://doi.org/10.1016/j.hoc.2013.11.010|Google Scholar
  156. Bauer DE, Kamran SC. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science. 2013; 342(6155):253-257. PubMed|https://doi.org/10.1126/science.1242088|Google Scholar
  157. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015; 372:793-795. PubMed|https://doi.org/10.1056/NEJMp1500523|Google Scholar
  158. Kassebaum NJ, Jasrasaria R, Naghavi M. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014; 123:615-624. PubMed|https://doi.org/10.1182/blood-2013-06-508325|Google Scholar
  159. Sazawal S, Black RE, Ramsan M. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet. 2006; 367:133-143. PubMed|https://doi.org/10.1016/S0140-6736(06)67962-2|Google Scholar
  160. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010; 142:24-38. PubMed|https://doi.org/10.1016/j.cell.2010.06.028|Google Scholar
  161. Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood. 2010; 116:4754-4761. PubMed|https://doi.org/10.1182/blood-2010-05-286260|Google Scholar
  162. Camaschella C. Treating iron overload. N Engl J Med. 2013; 368:2325-2327. PubMed|https://doi.org/10.1056/NEJMcibr1304338|Google Scholar
  163. Gulbis B, Eleftheriou A, Angastiniotis M. Epidemiology of rare anemias in Europe. Adv Exp Med Biol. 2010; 686:375-396. PubMed|https://doi.org/10.1007/978-90-481-9485-8_22|Google Scholar
  164. Iolascon A, Heimpel H, Wahlin A, Tamary H. Congenital dyserythropoietic anemias: molecular insights and diagnostic approach. Blood. 2013; 122:2162-2166. PubMed|https://doi.org/10.1182/blood-2013-05-468223|Google Scholar
  165. Vlachos A, Rosenberg PS, Atsidaftos E, Alter BP, Lipton JM. Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood. 2012; 119:3815-3819. PubMed|https://doi.org/10.1182/blood-2011-08-375972|Google Scholar
  166. Vlachos A, Blanc L, Lipton JM. Diamond Blackfan anemia: a model for the translational approach to understanding human disease. Expert Rev Hematol. 2014; 7:359-372. PubMed|https://doi.org/10.1586/17474086.2014.897923|Google Scholar
  167. Breda L, Rivella S. Modulators of erythropoiesis: emerging therapies for hemoglobinopathies and disorders of red cell production. Hematol Oncol Clin North Am. 2014; 28:375-386. PubMed|https://doi.org/10.1016/j.hoc.2013.12.001|Google Scholar
  168. Flatt JF, Guizouarn H, Burton NM. Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome. Blood. 2011; 118(19):5267-5277. PubMed|https://doi.org/10.1182/blood-2010-12-326645|Google Scholar
  169. Andolfo I, Alper SL, De Franceschi L. Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1. Blood. 2013; 121(19):3925-3935. PubMed|https://doi.org/10.1182/blood-2013-02-482489|Google Scholar
  170. A White Book. Prodrug Multimedia, SL: Madrid, Spain; 2014. Google Scholar
  171. King M-J, Garçon L, Hoyer JD. ICSH Guidelines for the laboratory diagnosis of non-immune hereditary red cell membrane disorders. Int J Lab Hematol. 2015. Google Scholar
  172. Nathan and Oski’s Hematology of Infancy and Childhood. 6. PA Saunders: Philadelphia; 2003. Google Scholar
  173. Dufour C, Corcione A, Svahn J. TNF-alpha and IFN-gamma are overexpressed in the bone marrow of Fanconi anemia patients and TNF-alpha suppresses erythropoiesis in vitro. Blood. 2003; 102:2053-2059. PubMed|https://doi.org/10.1182/blood-2003-01-0114|Google Scholar
  174. Scheinberg P, Nunez O, Weinstein B. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011; 365:430-438. PubMed|https://doi.org/10.1056/NEJMoa1103975|Google Scholar
  175. Marsh JC, Bacigalupo A, Schrezenmeier H. Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anemia Working Party. Blood. 2012; 119:5391-5396. PubMed|https://doi.org/10.1182/blood-2012-02-407684|Google Scholar
  176. Rabbit ATG for aplastic anemia treatment: a backward step¿. Lancet. 2011; 378:1831-1833. PubMed|https://doi.org/10.1016/S0140-6736(11)60817-9|Google Scholar
  177. Weatherall DJ, Williams TN, Allen SJ, O’Donnell A. The population genetics and dynamics of the thalassemias. Hematol Oncol Clin North Am. 2010; 24(6):1021-1031. PubMed|https://doi.org/10.1016/j.hoc.2010.08.010|Google Scholar
  178. Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010; 115(22):4331-4336. PubMed|https://doi.org/10.1182/blood-2010-01-251348|Google Scholar
  179. Cappellini MD, Cohen A, Porter J, Taher A, Viprasik V. Guidelines for the management of Transfusion Dependent Thalassaemia (TDT). 2014. Google Scholar
  180. Angelucci E, Matthes-Martin S, Baronciani D. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014; 99(5):811-820. PubMed|https://doi.org/10.3324/haematol.2013.099747|Google Scholar
  181. Rivella S, Rachmilewitz E. Future alternative therapies for β-thalassemia. Expert Rev Hematol. 2009; 2(6):685. PubMed|https://doi.org/10.1586/ehm.09.56|Google Scholar
  182. Roetto A, Papanikolaou G, Politou M. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 200. 33(1):21-22. Google Scholar
  183. Montosi G, Donovan A, Totaro A. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001; 108(4):619-623. PubMed|https://doi.org/10.1172/JCI200113468|Google Scholar
  184. Nicolas G, Viatte L, Lou DQ. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet. 2003; 34(1):97-101. PubMed|https://doi.org/10.1038/ng1150|Google Scholar
  185. Van Eijk LT, John AS, Schwoebel F. Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans. Blood. 2014; 124:2643-2646. PubMed|https://doi.org/10.1182/blood-2014-03-559484|Google Scholar
  186. Gaskell H, Derry S, Andrew Moore R, McQuay HJ. Prevalence of anemia in older persons: systematic review. BMC Geriatrics. 2008; 8:1. PubMed|https://doi.org/10.1186/1471-2318-8-1|Google Scholar
  187. Bach V, Schruckmayer G, Sam I, Kemmler G, Stauder R. Prevalence and possible causes of anemia in the elderly: a cross-sectional analysis of a large European university hospital cohort. Clinical Interventions in Aging. 2014; 9:1187-1196. PubMed|Google Scholar
  188. Busti F, Campostrini N, Martinelli N, Girelli D. Iron deficiency in the elderly population, revisited in the hepcidin era. Front Pharmacol. 2014; 5:83. PubMed|Google Scholar
  189. Stauder R, Thein SL. Anemia in the elderly – clinical implications and new therapeutic concepts. Haematologica. 2014; 99(7):1127-1130. PubMed|https://doi.org/10.3324/haematol.2014.109967|Google Scholar
  190. Fung E, Nemeth E. Manipulation of the hepcidin pathway for therapeutic purposes. Haematologica. 2013; 98(11):1667-1676. PubMed|https://doi.org/10.3324/haematol.2013.084624|Google Scholar
  191. Murray CJ, Vos T, Lozano R. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380(9859):2197-2223. PubMed|https://doi.org/10.1016/S0140-6736(12)61689-4|Google Scholar
  192. Hassel KL. Population estimates of sickle cell disease in the US. Am J Prev Med. 2010; 38(4 Suppl):s512-521. PubMed|https://doi.org/10.1016/j.amepre.2009.12.022|Google Scholar
  193. De Franceschi L, Cappellini MD, Olivieri O. Thrombosis and sickle cell disease. Semin Thromb Hemost. 2011; 37(3):226-236. PubMed|https://doi.org/10.1055/s-0031-1273087|Google Scholar
  194. Hebbel RP. The systems biology-based argument for taking a bold step in chemo-prophylaxis of sickle vasculopathy. Am J Hematol. 2009; 84(9):543-545. PubMed|https://doi.org/10.1002/ajh.21474|Google Scholar
  195. Yawn BP, Buchanan GR, Afenyi-Annan AN. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAIMA. 2014; 312(10):1033-1048. PubMed|https://doi.org/10.1001/jama.2014.10517|Google Scholar
  196. Balduini CL, Pecci A, Noris P. Diagnosis and management of inherited thrombocytopenias. Semin Thromb Hemost. 2013; 39(2):161-171. PubMed|https://doi.org/10.1055/s-0032-1333540|Google Scholar
  197. Greinacher A, Fürll B, Selleng S. Heparin-induced thrombocytopenia. Methods Mol Biol. 2013; 992:301-318. PubMed|https://doi.org/10.1007/978-1-62703-339-8_23|Google Scholar
  198. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014; 371(7):654-666. PubMed|https://doi.org/10.1056/NEJMra1312353|Google Scholar
  199. Scully M. Trends in the diagnosis and management of TTP: European perspective. Transfus Apher Sci. 2014; 51(1):11-14. PubMed|https://doi.org/10.1016/j.transci.2014.08.001|Google Scholar
  200. Furlan M, Robles R, Galbusera M. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998; 339(22):1578-1584. PubMed|https://doi.org/10.1056/NEJM199811263392202|Google Scholar
  201. Basciano PA, Bussel J, Hafeez Z, Christos PJ, Giannakakou P. The beta 1 tubulin R307H single nucleotide polymorphism is associated with treatment failures in immune thrombocytopenia (ITP). Br J Hematol. 2013; 160(2):237-243. PubMed|https://doi.org/10.1111/bjh.12124|Google Scholar
  202. Pecci A, Klersy C, Gresele P. MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. Hum Mutat. 2014; 35(2):236-247. PubMed|https://doi.org/10.1002/humu.22476|Google Scholar
  203. Iraqi M, Perdomo J, Yan F, Choi PY, Chong BH. Immune thrombocytopenia: antiplatelet autoantibodies inhibit pro-platelet formation by megakaryocytes and impair platelet production in vitro. Haematologica. 2015; 100(5):623-632. PubMed|https://doi.org/10.3324/haematol.2014.115634|Google Scholar
  204. Kühne T. Treatment of pediatric primary immune thrombocytopenia with thrombopoietin receptor agonists. Semin Hematol. 2015; 52(1):25-30. PubMed|https://doi.org/10.1053/j.seminhematol.2014.10.004|Google Scholar
  205. Rodeghiero F, Ruggeri M. Treatment of immune thrombocytopenia in adults: the role of thrombopoietin-receptor agonists. Semin Hematol. 2015; 52(1):16-24. PubMed|https://doi.org/10.1053/j.seminhematol.2014.10.006|Google Scholar
  206. Gresele P, Harrison P, Bury L. Diagnosis of suspected inherited platelet function disorders: results of a worldwide survey. J Thromb Haemost. 2014; 12(9):1562-1569. PubMed|https://doi.org/10.1111/jth.12650|Google Scholar
  207. Rodeghiero F, Michel M, Gernsheimer T. Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group. Blood. 2013; 121(14):2596-2606. PubMed|https://doi.org/10.1182/blood-2012-07-442392|Google Scholar
  208. Noris P, Schlegel N, Klersy C. Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Haematologica. 2014; 99(8):1387-1394. PubMed|https://doi.org/10.3324/haematol.2014.105924|Google Scholar
  209. Gresele P, Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost. 2015; 13(2):314-322. PubMed|https://doi.org/10.1111/jth.12792|Google Scholar
  210. Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med. 2014; 5:15-23. PubMed|Google Scholar
  211. Mele C, Remuzzi G, Noris M. Hemolytic uremic syndrome. Semin Immunopathol. 2014; 36(4):399-420. PubMed|https://doi.org/10.1007/s00281-014-0416-x|Google Scholar
  212. Dawood BB, Lowe GC, Lordkipanidzé M. Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel. Blood. 2012; 120(25):5041-5049. PubMed|https://doi.org/10.1182/blood-2012-07-444281|Google Scholar
  213. Westbury SK, Turro E, Lentaigne C. Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders. Genome Med. 2015; 7(1):36. PubMed|https://doi.org/10.1186/s13073-015-0151-5|Google Scholar
  214. Bluteau D, Balduini A, Balayn N. Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. J Clin Invest. 2014; 124(2):580-591. PubMed|https://doi.org/10.1172/JCI71861|Google Scholar
  215. Bender M, Stritt S, Nurden P. Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott-Aldrich syndrome-like platelet defect. Nat Commun. 2014; 5:4746. PubMed|https://doi.org/10.1038/ncomms5746|Google Scholar
  216. Scharf RE. Drugs that affect platelet function. Semin Thromb Hemost. 2012; 38(8):865-883. PubMed|https://doi.org/10.1055/s-0032-1328881|Google Scholar
  217. Witters P, Freson K, Verslype C. Review article: blood platelet number and function in chronic liver disease and cirrhosis. Aliment Pharmacol Ther. 2008; 27(11):1017-1029. PubMed|https://doi.org/10.1111/j.1365-2036.2008.03674.x|Google Scholar
  218. Boccardo P, Remuzzi G, Galbusera M. Platelet dysfunction in renal failure. Semin Thromb Hemost. 2004; 30(5):579-589. PubMed|https://doi.org/10.1055/s-2004-835678|Google Scholar
  219. Sousa-Uva M, Storey R, Huber K, Eur Heart J. 2014; 35(23):1510-1514. PubMed|https://doi.org/10.1093/eurheartj/ehu158|Google Scholar
  220. Hamzeh-Cognasse H, Damien P, Chabert A, Pozzetto B, Cognasse F, Garraud O. Platelets and infections - complex interac tions with bacteria. Front Immunol. 2015; 6:82. PubMed|Google Scholar
  221. Rodeghiero F, Stasi R, Gernsheimer T. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009; 113(11):2386-2393. PubMed|https://doi.org/10.1182/blood-2008-07-162503|Google Scholar
  222. Newland A. Thrombopoietin receptor agonists in the treatment of thrombocytopenia. Curr Opin Hematol. 2009; 16(5):357-364. PubMed|https://doi.org/10.1097/MOH.0b013e32832e06e4|Google Scholar
  223. Khellaf M, Charles-Nelson A, Fain O. Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. Blood. 2014; 124(22):3228-3236. PubMed|https://doi.org/10.1182/blood-2014-06-582346|Google Scholar
  224. Kamphuis MM, Paridaans NP, Porcelijn L, Lopriore E, Oepkes D. Incidence and consequences of neonatal alloimmune thrombocytopenia: a systematic review. Pediatrics. 2014; 133(4):715-721. PubMed|https://doi.org/10.1542/peds.2013-3320|Google Scholar
  225. Bakchoul T, Bassler D, Heckmann M. Management of infants born with severe neonatal alloimmune thrombocytopenia: the role of platelet transfusions and intravenous immunoglobulin. Transfusion. 2014; 54(3):640-645. Google Scholar
  226. Warkentin TE, Greinacher A. CRC Press: Boca Raton, USA; 2013. Google Scholar
  227. Arnold DM, Curtis BR, Bakchoul T, Recommendations for standardization of laboratory testing for drug-induced immune thrombocytopenia: communication from the SSC of the ISTH. J Thromb Haemost. 2015; 13(4):676-678. PubMed|https://doi.org/10.1111/jth.12852|Google Scholar
  228. Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH, Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost. 2011; 9(12):2498-2500. PubMed|https://doi.org/10.1111/j.1538-7836.2011.04536.x|Google Scholar
  229. Rollin J, Pouplard C, Cheng Sung H. Increased risk of thrombosis in FcγRIIA 131RR patients with HIT due to defective control of platelet activation by plasma IgG2. Blood. 2015; 125(15):2397-2404. PubMed|https://doi.org/10.1182/blood-2014-09-594515|Google Scholar
  230. Jaax ME, Krauel K, Marschall T. Complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor 4. Blood. 2013; 122(2):272-281. PubMed|https://doi.org/10.1182/blood-2013-01-478966|Google Scholar
  231. Coppo P, Veyradier A. Thrombotic microangiopathies: towards a pathophysiology-based classification. Cardiovasc Hematol Disord Drug Targets. 2009; 9(1):36-50. PubMed|https://doi.org/10.2174/187152909787581318|Google Scholar
  232. Froissart A, Buffet M, Veyradier A, Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med. 2012; 40(1):104-111. PubMed|https://doi.org/10.1097/CCM.0b013e31822e9d66|Google Scholar
  233. Legendre CM, Licht C, Muus P. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013; 368(23):2169-2181. PubMed|https://doi.org/10.1056/NEJMoa1208981|Google Scholar
  234. Scully M, Brown J, Patel R, McDonald V, Brown CJ, Machin S. Human leukocyte antigen association in idiopathic thrombotic thrombocytopenic purpura: evidence for an immunogenetic link. J Thromb Haemost. 2010; 8(2):257-262. PubMed|https://doi.org/10.1111/j.1538-7836.2009.03692.x|Google Scholar
  235. Kremer Hovinga JA, Vesely SK, Terrell DR, Lämmle B, George JN. Survival and relapse in patients with thrombotic thrombocy-topenic purpura. Blood. 2010; 115(8):1500-1511. PubMed|https://doi.org/10.1182/blood-2009-09-243790|Google Scholar
  236. Cohen AT, Agnelli G, Anderson FA, Venous thromboembolism (VTE) in Europe—the number of VTE events and associated morbidity and mortality. J Thromb Haemost. 2007; 98:756-764. Google Scholar
  237. Owen CA. Recent advances in blood coagulation. Historical remarks. Semin Thromb Hemost. 1985; 11:335-336. PubMed|https://doi.org/10.1055/s-2007-1004389|Google Scholar
  238. Stormorken H, Paul A. Owren and the Golden Era of Haemostasis. Gazettebok: Oslo; 2005. Google Scholar
  239. Franchini M, Mannucci PM. The history of hemophilia. Semin Thromb Hemost. 2014; 40:571-576. PubMed|https://doi.org/10.1055/s-0034-1381232|Google Scholar
  240. Brewer DB. Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br J Hematol. 2006; 133:251-258. PubMed|https://doi.org/10.1111/j.1365-2141.2006.06036.x|Google Scholar
  241. Bagot CN, Arya R. Virchow and his triad: a question of attribution. Br J Hematol. 2008; 143:180-190. PubMed|https://doi.org/10.1111/j.1365-2141.2008.07323.x|Google Scholar
  242. Galanaud JP, Laroche JP, Righini M. The history and historical treatments of deep vein thrombosis. J Thromb Haemost. 2013; 11:402-411. PubMed|https://doi.org/10.1111/jth.12127|Google Scholar
  243. Google Scholar
  244. Harper K, Winter RM, Pembrey ME, Hartley D, Davies KE, Tuddenham EG. A clinically useful DNA probe closely linked to haemophilia A. Lancet. 1984; 2(8393):6-8. PubMed|Google Scholar
  245. Bertina RM, Koeleman BP, Koster T. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994; 369(6475):64-67. PubMed|https://doi.org/10.1038/369064a0|Google Scholar
  246. Albers CA, Cvejic A, Favier R. Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nat Genet. 2011; 43(8):735-737. PubMed|https://doi.org/10.1038/ng.885|Google Scholar
  247. Germain M, Chasman DI, de Haan H. Meta-analysis of 65,734 Individuals Identifies TSPAN15 and SLC44A2 as Two Susceptibility Loci for Venous Thromboembolism. Am J Hum Genet. 2015; 96:532-542. PubMed|https://doi.org/10.1016/j.ajhg.2015.01.019|Google Scholar
  248. Zöller B, Li X, Sundquist J, Sundquist K. Age- and gender-specific familial risks for venous thromboembolism: a nationwide epidemiological study based on hospitalizations in Sweden. Circulation. 2011; 124(9):1012-1020. PubMed|https://doi.org/10.1161/CIRCULATIONAHA.110.965020|Google Scholar
  249. Renne T, Schmaier AH, Nickel KF, Blomback M, Maas C. In vivo roles of factor XII. Blood. 2012; 120:4296-4303. PubMed|https://doi.org/10.1182/blood-2012-07-292094|Google Scholar
  250. Kannemeier C, Shibamiya A, Nakazawa F. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA. 2007; 104:6388-6393. PubMed|https://doi.org/10.1073/pnas.0608647104|Google Scholar
  251. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Lippincott Williams & Wilkins; 2012. Google Scholar
  252. Langer F, Ruf W. Synergies of phosphatidylserine and protein disulfide isomerase in tissue factor activation. J Thromb Haemost. 2014; 111:590-597. https://doi.org/10.1160/TH13-09-0802|Google Scholar
  253. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013; 13:34-45. PubMed|https://doi.org/10.1038/nri3345|Google Scholar
  254. Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA. 1993; 90:1004-1008. PubMed|https://doi.org/10.1073/pnas.90.3.1004|Google Scholar
  255. Bertina RM1, Koeleman BP, Koster T. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994; 369:64-67. PubMed|https://doi.org/10.1038/369064a0|Google Scholar
  256. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3-untranslated region of the prothrom-bin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996; 88:3698-3703. PubMed|Google Scholar
  257. Reitsma PH. Genetics in thrombophilia. Hämostaseolgie. 2015; 35:47-51. Google Scholar
  258. Braekkan SK, Mathiesen EB, Njolstad I, Wilsgaard T, Stormer J, Hansen JB. Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromso study. J Thromb Haemost. 2008; 6:1851-1857. PubMed|https://doi.org/10.1111/j.1538-7836.2008.03102.x|Google Scholar
  259. Engbers MJ, van Hylckama Vlieg A, Rosendaal FR. Venous thrombosis in the elderly: incidence, risk factors and risk groups. J Thromb Haemost. 2010; 8:2105-2112. PubMed|https://doi.org/10.1111/j.1538-7836.2010.03986.x|Google Scholar
  260. Franchini M. Hemostasis and aging. Critical reviews in oncology/hematology. 2006; 60:144-151. PubMed|https://doi.org/10.1016/j.critrevonc.2006.06.004|Google Scholar
  261. Weill-Engerer S, Meaume S, Lahlou A. Risk factors for deep vein thrombosis in inpatients aged 65 and older: a case-control multicenter study. J Am Geriatr Soc. 2004; 52:1299-1304. PubMed|https://doi.org/10.1111/j.1532-5415.2004.52359.x|Google Scholar
  262. Blix K, Braekkan SK, le Cessie S, Skjeldestad FE, Cannegieter SC, Hansen JB. The increased risk of venous thromboembolism by advancing age cannot be attributed to the higher incidence of cancer in the elderly: the Tromso study. European journal of epidemiology. 2014; 29:277-284. PubMed|https://doi.org/10.1007/s10654-014-9902-7|Google Scholar
  263. Mannucci PM, Shi Q, Bonanad S, Klamroth R. Novel investigations on the protective role of the FVIII/VWF complex in inhibitor development. Haemophilia. 2014; 20(Suppl 6):2-16. Google Scholar
  264. Lillicrap D, Fijnvandraat K, Santagostino E. Inhibitors - genetic and environmental factors. Haemophilia. 2014; 20(Suppl 4):87-93. PubMed|https://doi.org/10.1111/hae.12412|Google Scholar
  265. Van den Berg HM. Epidemiological aspects of inhibitor development redefine the clinical importance of inhibitors. Haemophilia. 2014; 20(Suppl 4):76-79. PubMed|https://doi.org/10.1111/hae.12404|Google Scholar
  266. Peyvandi F, Palla R, Menegatti M. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012; 10(4):615-621. PubMed|https://doi.org/10.1111/j.1538-7836.2012.04653.x|Google Scholar
  267. Goodeve A, Eikenboom J, Castaman G. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood. 2007; 109(1):112-121. PubMed|https://doi.org/10.1182/blood-2006-05-020784|Google Scholar
  268. World Federation of Hemophilia. 2014. Google Scholar
  269. Shankar M, Lee CA, Sabin CA, Economides DL, Kadir RA. Von Willebrand disease in women with menorrhagia: a systematic review. BJOG. 2004; 111:734-740. PubMed|https://doi.org/10.1111/j.1471-0528.2004.00176.x|Google Scholar
  270. Tsui NB, Kadir RA, Chan KC. Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA. Blood. 2011; 117:3684-3691. PubMed|https://doi.org/10.1182/blood-2010-10-310789|Google Scholar
  271. Collins PW, Lilley G, Bruynseels D. Fibrin-based clot formation an early and rapidly biomarker for progression of postpartum hemorrhage: a prospective study. Blood. 2014; 124:1727-1736. PubMed|https://doi.org/10.1182/blood-2014-04-567891|Google Scholar
  272. Rodger MA, Hague WM, Kingdom J. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet. 2014; 8:1673-1683. Google Scholar
  273. Rohde JM, Dimcheff DE, Blumberg N. Health Care–Associated Infection After Red Blood Cell Transfusion. A Systematic Review and Meta-analysis. JAMA. 2014; 311:1317-1326. PubMed|https://doi.org/10.1001/jama.2014.2726|Google Scholar
  274. Almeida de JP, Vincent JL, Gomes Galas FRB. Transfusion Requirements in Surgical Oncology Patients, A Prospective, Randomized Controlled Trial. Anesthesiology. 2015; 122:29-38. PubMed|https://doi.org/10.1097/ALN.0000000000000511|Google Scholar
  275. Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med. 2014; 370:847-859. PubMed|https://doi.org/10.1056/NEJMra1208626|Google Scholar
  276. Fragkou PC, Torrance HD, Pearse RM. Perioperative transfusion is associated with a gene transcription profile characteristic of immunosuppression: a prospective cohort study. Critical Care. 2014; 18:541. PubMed|https://doi.org/10.1186/s13054-014-0541-x|Google Scholar
  277. Van Hoeven LR, Janssen MP, Rautmann G. The Collection, testing and use of blood and blood components in Europe, 2011 report. Council of Europe, European Directorate for the Quality of Medicines & HealthCare: Strasbourg, France; 2011. Google Scholar
  278. Shander A, van Aken H, Colomina MJ. Patient Blood management in Europe. Br J Anaesth. 2012; 109(1):55-68. PubMed|https://doi.org/10.1093/bja/aes139|Google Scholar
  279. Sewell WA, Kerr J, Behr-Gross ME, Peter HH, European consensus proposal for immunoglobulin therapy. Eur J Immunol. 2014; 44(8):2207-2214. PubMed|https://doi.org/10.1002/eji.201444700|Google Scholar
  280. Storry JR, Castilho L, Daniels G. International Society of Blood Transfusion working party on red cell immunogenetics and blood group terminology. Vox Sang. 2014; 107:90-96. PubMed|https://doi.org/10.1111/vox.12127|Google Scholar
  281. Silvy M, Bres JC, Grimaldi A. A simple genotyping procedure without DNA extraction to identify rare blood donors. Vox Sang. 2015; 109(2):173-180. PubMed|https://doi.org/10.1111/vox.12261|Google Scholar
  282. Kormoczi GF, Mayr WR. Responder individuality in red blood cell alloimmunization. Transfus Med Hemather. 2014; 41:446-451. Google Scholar
  283. Karahan GE, de Vaal YJH, Roelen DL. Quantification of HLA class II specific memory B cells in HLA-sensitized individuals. Human Immunology. 2015; 76:129-136. PubMed|Google Scholar
  284. Noizat-Pirenne F, Bachir D, Chadebech P. Rituximab for prevention of delayed hemolytic transfusion reaction in sickle cell disease. Haematologica. 2007; 92:e132-135. PubMed|https://doi.org/10.3324/haematol.12074|Google Scholar
  285. Figueiredo C, Wedekind D, Müller T. MHC Universal Cells Survive in an Allogeneic Environment after Incompatible Transplantation. Biomed Res Int. 2013; 2013:796046. PubMed|Google Scholar
  286. Moore C, Sambrook J, Walker M. The INTERVAL trial to determine whether intervals between blood donations can be safely and acceptably decreased to optimise blood supply: study protocol for a randomised controlled trial. Trials. 2014; 15:363. PubMed|https://doi.org/10.1186/1745-6215-15-363|Google Scholar
  287. Narhi M, Natri O, Desbois I. Collection, processing and testing of bone, corneas, umbilical cord blood and hematopoietic stem cells by European Blood Alliance members. Vox Sang. 2013; 105:346-354. PubMed|https://doi.org/10.1111/vox.12053|Google Scholar
  288. Goodnough LT, Murphy MF. Do liberal transfusions cause more harm than goodû. BMJ. 2014; 5:g6897. PubMed|https://doi.org/10.1136/bmj.g6897|Google Scholar
  289. Rebulla P, Finazzi G, Marangoni F. The threshold for platelet transfusions for adults with acute myeloid leukemia. N Engl J Med. 1997; 337:1870-1875. PubMed|https://doi.org/10.1056/NEJM199712253372602|Google Scholar
  290. Stanworth SJ, Estcourt LJ, Powter G. No-Prophylaxis Platelet transfusion strategy for hematologic cancers. N Engl J Med. 2013; 368:1771-1780. PubMed|https://doi.org/10.1056/NEJMoa1212772|Google Scholar
  291. Seidel MG, Peters C, Wacker A. Randomized phase III study of granulocyte transfusions in neutropenic patients. Bone Marrow Transplant. 2008; 42:679-684. PubMed|https://doi.org/10.1038/bmt.2008.237|Google Scholar
  292. Holst LB, Haase N, Wetterslev J. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014; 371:1381-1391. PubMed|https://doi.org/10.1056/NEJMoa1406617|Google Scholar
  293. Gupta N, Culina S, Meslier Y. Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance. Sci Transl Med. 2015; 7(275):275ra21. PubMed|https://doi.org/10.1126/scitranslmed.aaa1957|Google Scholar
  294. McIntosh J, Lenting PJ, Rosales C. Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood. 2013; 121(17):3335-3344. PubMed|https://doi.org/10.1182/blood-2012-10-462200|Google Scholar
  295. von Gunten S, Shoenfeld Y, Blank M. IVIG pluripotency and the concept of Fcsialylation: challenges to the scientist. Nat Rev Immunol. 2014; 14(5):349. PubMed|https://doi.org/10.1038/nri3401-c1|Google Scholar
  296. Trinath J, Hegde P, Sharma M. Intravenous immunoglobulin expands regulatory T cells via induction of cyclooxyge-nase-2-dependent prostaglandin E2 in human dendritic cells. Blood. 2013; 122(8):1419-1427. PubMed|https://doi.org/10.1182/blood-2012-11-468264|Google Scholar
  297. Fiebiger BM, Maamary J, Pincetic A, Ravetch JV. Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs. Proc Natl Acad Sci USA. 2015; 112(18):e2385-2394. PubMed|https://doi.org/10.1073/pnas.1505292112|Google Scholar
  298. Schwartz J, Winters JL, Padmanabhan A. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher. 2013; 28:154-284. Google Scholar
  299. Pierelli L, Perseghin P, Marchetti M. Best practice for peripheral blood progenitor cell mobilization and collection in adults and children: results of a Società Italiana Di Emaferesi e Manipolazione Cellulare (SIDEM) and Gruppo Italiano Trapianto Midollo Osseo (GITMO) consensus process. Transfusion. 2012; 52:893-905. Google Scholar
  300. Das-Gupta E, Dignan F, Shaw B. Extracorporeal photopheresis for treatment of adults and children with acute GVHD: UK consensus statement and review of published literature. Bone Marrow Transplant. 2014; 49:1251-1258. PubMed|https://doi.org/10.1038/bmt.2014.106|Google Scholar
  301. International standards for cellular therapy product collection, processing, and administration. 2012. Google Scholar
  302. Amrein K, Katschnig C, Sipurzynski S. Apheresis affects bone and mineral metabolism. Bone. 2010; 46:789-795. PubMed|https://doi.org/10.1016/j.bone.2009.11.008|Google Scholar
  303. Chitty LS, Finning K, Wade A. Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: population based cohort study. BMJ. 2014; 349:g5243. PubMed|https://doi.org/10.1136/bmj.g5243|Google Scholar
  304. Avent ND, Martinez A, Flegel WA. The Bloodgen Project of the European Union, 2003–2009. Transfus Med Hemother. 2009; 36:162-167. PubMed|https://doi.org/10.1159/000218192|Google Scholar
  305. Sanchez-Mazas A, Vidan-Jeras B, Nunes JM. Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations. Int J Immunogenetics. 2012; 39:459-476. https://doi.org/10.1111/j.1744-313X.2012.01113.x|Google Scholar
  306. Allen DL, Metcalfe P, Kaplan C. Sensitivity of assays for the detection of HPA-1a antibodies: results of an international workshop demonstrating the impact of cation chelation from integrin aIIbb3 on three widely used assays. Vox Sang. 2013; 105:167-173. PubMed|https://doi.org/10.1111/vox.12043|Google Scholar
  307. Tambur AR, Claas FHJ. HLA epitopes as viewed by antibodies: What is it all aboutû. Am J Transplant. 2015; 15(5):1148-1154. PubMed|https://doi.org/10.1111/ajt.13192|Google Scholar
  308. Bochennek K, Allwinn R, Langer R. Differential loss of immunity against measles, mumps, rubella and varicella zoster in children treated for cancer. Vaccine. 2014; 32:3357-3361. PubMed|https://doi.org/10.1016/j.vaccine.2014.04.042|Google Scholar
  309. Abravanel F, Lhommes S, Dubois M. Hepatitis E virus. Med Mal Infect. 2013; 43:263-270. PubMed|https://doi.org/10.1016/j.medmal.2013.03.005|Google Scholar
  310. Schmidt M, Geilenkeuser WJ, Sireis W, Seifried E, Hourfar K. Emerging Pathogens - How Safe is Blood¿. Transfus Med Hemother. 2014; 41(1):10-17. PubMed|https://doi.org/10.1159/000368056|Google Scholar
  311. Schlenke P. Pathogen inactivation technologies for cellular blood components: an update. Transfus Med Hemother. 2014; 41(4):309-325. PubMed|https://doi.org/10.1159/000365646|Google Scholar
  312. Kaiser-Guignard J, Canellini G, Lion N, Abonnenc M, Osselaer JC, Tissot JD. The clinical and biological impact of new pathogen inactivation technologies on platelet concentrates. Blood Rev. 2014; 28(6):235-241. PubMed|https://doi.org/10.1016/j.blre.2014.07.005|Google Scholar
  313. Prudent M, D’Alessandro A, Cazenave JP. Proteome changes in platelets after pathogen inactivation–an interlaboratory consensus. Transfus Med Rev. 2014; 28(2):72-83. PubMed|https://doi.org/10.1016/j.tmrv.2014.02.002|Google Scholar
  314. Seghatchian J, Putter JS. Pathogen inactivation of whole blood and red cell components: an overview of concept, design, developments, criteria of acceptability and storage lesion. Transfus Apher Sci. 2014; 49(2):357-363. Google Scholar
  315. Anstee DJ, Gampel A, Toye AM. Ex-vivo generation of human red cells for transfusion. Curr Opin Hematol. 2012; 19:163-169. PubMed|https://doi.org/10.1097/MOH.0b013e328352240a|Google Scholar
  316. Dunois-Larde C, Capron C, Fichelson S, Bauer T, Cramer-Borde E, Baruch D. Exposure of human megakaryocytes to high shear rates accelerates platelet production. Blood. 2009; 114:1875-1883. PubMed|https://doi.org/10.1182/blood-2009-03-209205|Google Scholar
  317. Giarratana MC, Rouard H, Dumont A, Kiger L, Safeukui I. Proof of principle for transfusion of in vitro-generated red blood cells. Blood. 2011; 118:5071-5079. PubMed|https://doi.org/10.1182/blood-2011-06-362038|Google Scholar
  318. Migliaccio G, Sanchez M, Masiello F. Humanized culture medium for clinical expansion of human erythroblasts. Cell Transplant. 2010; 19:453-469. PubMed|https://doi.org/10.3727/096368909X485049|Google Scholar
  319. Van den Akker E, Satchwell TJ, Pellegrin S, Daniels G, Toye AM. The majority of the in vitro erythroid expansion potential resides in CD34(−) cells, outweighing the contribution of CD34(+) cells and significantly increasing the erythroblast yield from peripheral blood samples. Haematologica. 2010; 95:1594-1598. PubMed|https://doi.org/10.3324/haematol.2009.019828|Google Scholar
  320. Klastersky J, Zinner SH, Calandra T. Empiric antimicrobial therapy for febrile granulocytopenic cancer patients: lessons from four EORTC trials. Eur J Cancer Clin Oncol. 1988; 24(Suppl 1):S35-45. PubMed|Google Scholar
  321. Gratwohl A, Brand R, Frassoni F. Cause of death after allogeneic hematopoietic stem cell transplantation in early leukemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant. 2005; 36(9):757-769. PubMed|https://doi.org/10.1038/sj.bmt.1705140|Google Scholar
  322. Caira M, Candoni A, Verga L. Pre-chemotherapy risk factors for invasive fungal diseases: prospective analysis of 1,192 patients with newly diagnosed acute myeloid leukemia (SEIFEM 2010-a multicenter study). Haematologica. 2015; 100(2):284-292. PubMed|https://doi.org/10.3324/haematol.2014.113399|Google Scholar
  323. Gyssens IC, Kern WV, Livermore DM, The role of antibiotic stewardship in limiting antibacterial resistance among hematology patients. Haematologica. 2013; 98(12):1821-1825. PubMed|https://doi.org/10.3324/haematol.2013.091769|Google Scholar
  324. Robin C, Beckerich F, Cordonnier C. Immunization in cancer patients: Where we stand. Pharmacol Res. 2015; 92C:23-30. PubMed|https://doi.org/10.1016/j.phrs.2014.10.002|Google Scholar
  325. Leen AM, Bollard CM, Mendizabal AM. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood. 2013; 121(26):5113-5123. PubMed|https://doi.org/10.1182/blood-2013-02-486324|Google Scholar
  326. Zerr DM, Boeckh M, Delaney C. HHV-6 Reactivation and Associated Sequelae after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2012; 18(11):1700-1708. PubMed|https://doi.org/10.1016/j.bbmt.2012.05.012|Google Scholar
  327. Waghmare A, Pergam SA, Jerome KR, Englund JA, Boeckh M, Kuypers J. Clinical disease due to lenterovirus D68 in adult hematologic malignancy patients and hematopoietic cell transplant recipients. Blood. 2015; 125(11):1724-1729. PubMed|https://doi.org/10.1182/blood-2014-12-616516|Google Scholar
  328. Versluis J, Pas SD, Agteresch HJ. Hepatitis E virus: an underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation. Blood. 2013; 122(6):1079-1086. PubMed|https://doi.org/10.1182/blood-2013-03-492363|Google Scholar
  329. Rubin LG, Levin MJ, Ljungman P. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014; 58(3):309-318. PubMed|https://doi.org/10.1093/cid/cit816|Google Scholar
  330. Satlin MJ, Jenkins SG, Walsh TJ. The global challenge of carbapenem-resistant Enterobacteriaceae in transplant recipients and patients with hematologic malignancies. Clin Infect Dis. 2014; 58:1274-1283. PubMed|https://doi.org/10.1093/cid/ciu052|Google Scholar
  331. Lehners N, Schnitzler P, Geis S. Risk factors and containment of respiratory syncytial virus outbreak in a hematology and transplant unit. Bone Marrow Transplant. 2013; 48:1548-1553. PubMed|https://doi.org/10.1038/bmt.2013.94|Google Scholar
  332. Eckmanns T, Rüden H, Gastmeier P. The influence of high-efficiency particulate air filtration on mortality and fungal infection among highly immunosuppressed patients: a systematic review. J Infect Dis. 2006; 193:1408-1418. PubMed|https://doi.org/10.1086/503435|Google Scholar
  333. Iida N, Dzutsev A, Stewart CA. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013; 342:967-970. PubMed|https://doi.org/10.1126/science.1240527|Google Scholar
  334. Taur Y, Jenq RR, Perales MA. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014; 124:1174-1182. PubMed|https://doi.org/10.1182/blood-2014-02-554725|Google Scholar
  335. Blimark C, Holmberg E, Mellqvist UH. Multiple myeloma and infections: a pop ulation-based study on 9253 multiple myeloma patients. Haematologica. 2015; 100:107-113. PubMed|https://doi.org/10.3324/haematol.2014.107714|Google Scholar
  336. Boucher HW, Talbot GH, Bradley JS. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009; 48:1-12. PubMed|https://doi.org/10.1086/595011|Google Scholar
  337. Bow EJ. Fluoroquinolones, antimicrobial resistance and neutropenic cancer patients. Curr Opin Infect Dis. 2011; 24:545-553. PubMed|https://doi.org/10.1097/QCO.0b013e32834cf054|Google Scholar
  338. Gilchrist M, Seaton RA. Outpatient parenteral antimicrobial therapy and antimicrobial stewardship: challenges and checklists. J Antimicrob Chemother. 2015; 70(4):965-970. PubMed|https://doi.org/10.1093/jac/dku517|Google Scholar
  339. Viscoli C, Management of infection in cancer patients. studies of the EORTC International Antimicrobial Therapy Group (IATG). Eur J Cancer. 2002; 38(Suppl 4):s82-87. PubMed|Google Scholar
  340. Lanari M, Vandini S, Capretti MG, Lazzarotto T, Faldella G. Respiratory syncytial virus infections in infants affected by primary immunodeficiency. J Immunol Res. 2014; 2014:850831. PubMed|Google Scholar
  341. Li S, Bizzarro MJ. Prevention of central line associated bloodstream infections in critical care units. Curr Opin Pediatr. 2011; 23(1):85-90. PubMed|https://doi.org/10.1097/MOP.0b013e328341d1da|Google Scholar
  342. Checkley W, White AC, Jaganath D. A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium. Lancet Infect Dis. 2015; 15(1):85-94. PubMed|https://doi.org/10.1016/S1473-3099(14)70772-8|Google Scholar
  343. Nuti F, Civitelli F, Cucchiara S. Long-term safety of immunomodulators in pediatric inflammatory diseases. Paediatr Drugs. 2014; 16(5):343-352. PubMed|https://doi.org/10.1007/s40272-014-0084-2|Google Scholar
  344. Zhang SX. Enhancing molecular approaches for diagnosis of fungal infections. Future Microbiol. 2013; 8(12):1599-1611. PubMed|https://doi.org/10.2217/fmb.13.120|Google Scholar
  345. Wojtowicz A, Bochud PY. Host genetics of invasive Aspergillus and Candida infections. Seminars in Immunopathology. 2015; 37(2):173-186. PubMed|https://doi.org/10.1007/s00281-014-0468-y|Google Scholar
  346. Bochud PY, Chien JW, Marr KA. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008; 359(17):1766-1777. PubMed|https://doi.org/10.1056/NEJMoa0802629|Google Scholar
  347. Cunha C, Di Ianni M, Bozza S. Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood. 2010; 116(24):5394-5402. PubMed|https://doi.org/10.1182/blood-2010-04-279307|Google Scholar
  348. Cunha C, Aversa F, Lacerda JF. Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med. 2014; 370(5):421-432. PubMed|https://doi.org/10.1056/NEJMoa1211161|Google Scholar
  349. Ferwerda B, Ferwerda G, Plantinga TS. Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med. 2009; 361(18):1760-1767. PubMed|https://doi.org/10.1056/NEJMoa0901053|Google Scholar
  350. Wöjtowicz A, Lecompte TD, Bibert S. PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant. Universite & EPFL: Lausanne; 2015. Google Scholar
  351. De Lima M, Porter DL, Battiwalla M. Proceedings from the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation: part III. Prevention and treatment of relapse after allogeneic transplantation. Biol Blood Marrow Transplant. 2014; 20:4-13. PubMed|https://doi.org/10.1016/j.bbmt.2013.08.012|Google Scholar
  352. Martelli MF, Di Ianni M, Ruggeri L. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014; 124(4):638-644. PubMed|https://doi.org/10.1182/blood-2014-03-564401|Google Scholar
  353. Schmid C, Schleuning M, Schwerdtfeger R. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006; 108(3):1092-1099. PubMed|https://doi.org/10.1182/blood-2005-10-4165|Google Scholar
  354. Damaj G, Mohty M, Robin M. Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloab-lative conditioning for patients with myelodysplastic syndrome: a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire. Biol Blood Marrow Transplant. 2014; 20(9):1349-1355. PubMed|https://doi.org/10.1016/j.bbmt.2014.05.010|Google Scholar
  355. Cruz CR, Micklethwaite KP, Savoldo B. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood. 2013; 122:2965-2973. PubMed|https://doi.org/10.1182/blood-2013-06-506741|Google Scholar
  356. Bargou R, Leo E, Zugmaier G. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008; 321(5891):974-977. PubMed|https://doi.org/10.1126/science.1158545|Google Scholar
  357. Topp MS, Gökbuget N, Zugmaier G. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hemato-logic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014; 32(36):4134-4140. PubMed|https://doi.org/10.1200/JCO.2014.56.3247|Google Scholar
  358. Ghorashian S, Veliça P, Chua I. CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor. J Immunol. 2015; 194(3):1080-1089. PubMed|https://doi.org/10.4049/jimmunol.1401703|Google Scholar
  359. Van Loenen MM, Hagedoorn RS, de Boer R, Frederik Falkenburg JH, Heemskerk MH. Extracellular domains of CD8α and CD8ß subunits are sufficient for HLA class I restricted helper functions of TCR-engineered CD4+ T cells. PLoS One. 2013; 8(5):e65212. PubMed|https://doi.org/10.1371/journal.pone.0065212|Google Scholar
  360. Feucht J, Opherk K, Lang P. Adoptive T-cell therapy with hexon-specific THELPER-1 cells as a treatment for refractory adenovirus infection after HSCT. Blood. 2015; 125(12):1986-1994. PubMed|https://doi.org/10.1182/blood-2014-06-573725|Google Scholar
  361. Walter D, Lier A, Geiselhart A. Exit from dormancy provokes DNA-damage-induced attrition in hematopoietic stem cells. Nature. 2015; 520(7548):549-552. PubMed|https://doi.org/10.1038/nature14131|Google Scholar
  362. Sun J, Ramos A, Chapman B. Clonal dynamics of native hematopoiesis. Nature. 2014; 514(7522):322-327. PubMed|https://doi.org/10.1038/nature13824|Google Scholar
  363. Etzrodt M, Endele M, Schroeder T. Quantitative single-cell approaches to stem cell research. Cell Stem Cell. 2014; 15(5):546-558. PubMed|https://doi.org/10.1016/j.stem.2014.10.015|Google Scholar
  364. Shepard KA, Talib S. Bottlenecks in Deriving Definitive Hematopoietic Stem Cells From Human Pluripotent Stem Cells: A CIRM Mini-Symposium and Workshop Report. Stem Cells Transl Med. 2014; 3(7):775-781. PubMed|https://doi.org/10.5966/sctm.2014-0104|Google Scholar
  365. Graf T, Enver T. Forcing cells to change lineages. Nature. 2009; 462(7273):587-594. PubMed|https://doi.org/10.1038/nature08533|Google Scholar
  366. Cathomen T, Ehl S. Translating the genomic revolution - targeted genome editing in primates. N Engl J Med. 2014; 370(24):2342-2345. PubMed|https://doi.org/10.1056/NEJMcibr1403629|Google Scholar
  367. Genovese P, Schiroli G, Escobar G. Targeted genome editing in human repopulating hematopoietic stem cells. Nature. 2014; 510(7504):235-240. PubMed|https://doi.org/10.1038/nature13420|Google Scholar
  368. Dominici M, Le Blanc K, Mueller I. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8(4):315-317. PubMed|https://doi.org/10.1080/14653240600855905|Google Scholar
  369. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013; 13(4):392-402. PubMed|https://doi.org/10.1016/j.stem.2013.09.006|Google Scholar
  370. Sauer AV, Di Lorenzo B, Carriglio N, Aiuti A. Progress in gene therapy for primary immunodeficiencies using lentiviral vectors. Curr Opin Allergy Clin Immunol. 2014; 14(6):527-534. PubMed|https://doi.org/10.1097/ACI.0000000000000114|Google Scholar
  371. Naldini L. Ex vivo gene transfer and correction for cell-based therapies. Nat Rev Genet. 2011; 12(5):301-315. PubMed|https://doi.org/10.1038/nrg2985|Google Scholar
  372. Cieri N, Mastaglio S, Oliveira G, Casucci M, Bondanza A, Bonini C. Adoptive immunotherapy with genetically modified lymphocytes in allogeneic stem cell transplantation. Immunol Rev. 2014; 257(1):165-180. PubMed|https://doi.org/10.1111/imr.12130|Google Scholar

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Vol. 101 No. 2 (2016): February, 2016 : Opinion Article
 
DOI
https://doi.org/10.3324/haematol.2015.136739
Pubmed
26819058
Pubmed Central
PMC4938336
 
Published
2016-02-01
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Ferrata Storti Foundation, Pavia, Italy
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0390-6078
Online ISSN
1592-8721
 

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