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31. Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021-30. 32. Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, et al. Maintenance therapy with thalidomide improves survival in multiple myeloma patients. Blood. 2006; 15:3289-94. 33. Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27:1788-93. 34. Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010;115:1113-20. 35. Attal M, Cristini C, Marit G, Caillot D, Facon T, Hullin C, et al. Lenalidomide maintenance after transplantation for myeloma. J Clinl Oncol. 2010;28(15): 8018a. 36. McCarthy PL, Owzar K, Anderson KC, Hofmeister CC, Hassoun H, Hurd DD, et al. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104. J Clin Oncol. 2010;28(15):8017a. 37. Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138:176-85. 38. van Rhee F, Szymonifka J, Anaissie E, Nair B, Waheed S, Alsayed Y, et al. Total therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy. Blood. 2010;116:1220-7. 39. Moreau P, Hulin C, Facon T. Frontline treatment of multiple myeloma in elderly patients. Blood Rev. 2008;22:303-9. 40. Alexanian R, Haut A, Khan AU, Lane M, McKelvey EM, Migliore PJ, et al. Treatment for multiple myeloma. Combination chemotherapy with different dose regimens. JAMA. 1969;208: 1680-5. 41. Myeloma Trialists’Collaborative Group. Combination chemotherapy versus melphalan and prednisone as treatment for multiple myeloma: an overview of 6633 patients from 27 randomized trials. J Clin Oncol. 1998;16:3832-42. 42. Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006;107:1292-8. 43. Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006;367:825-31. 44. Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM99-06): a randomised trial. Lancet. 2007;370:1209-18. 45. Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C, et al. Efficacy of melphalan and prednisone plus thalido- London, United Kingdom, June 9-12, 2011 mide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27: 3664-70. 46. Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, et al. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010;116:1405-12. 47. Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, et al. Phase III study of the value of thalidomide added to Melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 study. J Clin Oncol. 2010;28:3160-6. 48. Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N, et al. Addition of thalidomide to oral Melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011; 86:16-22. 49. Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1 / 2 study. Blood 2006; 108:2165-72. 50. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-17. 51. Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11:934-41. 52. Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28:5101-9. 53. Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. J Clin Oncol. 2007;25:4459-65. 54. Antonio Palumbo, Michel Delforge, John Catalano, Roman Hajek, Martin Kropff, Maria Teresa Petrucci, et al. A phase 3 evaluating the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients > 65 years with newly diagnosed multiple myeloma: continuous use of lenalidomide vs fixed-duration regimens. Blood (ASH Annual Meeting Abstracts) Nov 2010;116:622a. 55. Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, et al. Combination therapy with lenalidomide plus dexamethasone for newly diagnosed myeloma. Blood. 2005;106:4050-3. 56. Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010; 11:29-37. Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 293 |
H. Hasle Department of Paediatrics, Aarhus University Hospital Skejby, Denmark Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:294-301 Pediatric hematology Diagnosis and management of childhood myelodysplastic syndrome and juvenile myelomonocytic leukemia Introduction Myelodysplastic and myeloproliferative disorders are rare in children and in many aspects different from the diseases in adults, requiring a pediatric approach to their diagnosis and management. 1-2 Contemporary classification includes three main groups; myelodysplastic syndrome (MDS), juvenile myelomonocytic leukaemia (JMML), and the myeloid leukemias of Down syndrome (ML-DS). MDS is the only one of the main subgroups in children that has a partial overlap with the spectrum of disease in adults. However, there are significant differences between MDS in children and adults (Table 1). There is no sharp age distinction between adult and childhood MDS, and young adults with MDS share many of the features of childhood MDS and may benefit from similar management aiming at curing the patient with MDS, which is often not realistic in adults. There are very few protocol-based studies on pediatric MDS. Most studies on MDS and JMML have been performed by the European Working Group of MDS in childhood (EWOG-MDS) (www.ewogmds.org). 3-8 Classification The WHO classification from 2001 9 recognized JMML, previously termed juvenile chronic myeloid leukaemia (JCML) or chronic myelomonocytic leukaemia (CMML), as a separate entity, but the classification of MDS did not acknowledge the special features of MDS in children. A pedi- A B S T R A C T Myelodysplastic and myeloproliferative disorders are rare in children. Contemporary classification includes three main groups: myelodysplastic syndrome (MDS), juvenile myelomonocytic leukemia (JMML), and the myeloid leukemias of Down syndrome (ML-DS). Separating MDS from AML may be a challenge and biological features rather than an arbitrary cutoff in blast count may be more important in distinguishing MDS from AML. The presence of genetic aberrations in the Ras signal transduction pathway in most patients with JMML has contributed major insight into the pathogenesis of JMML and facilitates the diagnosis. Hematopoietic stem cell transplantation is the treatment of choice for MDS and JMML. Reduced AML therapy is very successful in ML-DS. JMML in infants with Noonan syndrome often regresses spontaneously. atric approach to the WHO classification separated myelodysplastic and myeloproliferative disorders in children into three main groups: JMML, MDS, and ML-DS (Table 2). 1 MDS is subdivided into refractory cytopenia of childhood (RCC), RAEB and RAEB-T. The change in nomenclature from RA to RCC reflects that anemia is not a prerequisite for the diagnosis. 4 The revised WHO classification from 2008 10 keeps JMML separate and recognizes ML-DS and RCC as unique groups. Children with more than 2% blasts in the peripheral blood (PB) or 5% in the bone marrow (BM) are classified as RAEB using the same criteria as in adults. RAEB-T is kept for selected patients but it is emphasized that the diagnosis cannot rely on a single blast count but must be a comprehensive evaluation of clinical features, natural course, morphology, immunophenotype, and cytogenetics. Epidemiology Combined population-based data from Denmark and British Columbia (BC) in Canada showed an annual incidence of MDS of 1.8 and of JMML of 1.2 per mil lion children, corresponding to a total of 6% of all hematological malignan cies in children (Table 3). 11-12 Data from the UK suggest a lower incidence of MDS of 0.8/mil lion (Table 3). 13 The male/female distribution in pediatric MDS is equal, with a median age at presentation of 6.8 years. 11-14 This is in contrast to the male predominance in JMML and a median age at presentation of 1.8 years. 15 Down syndrome has been reported in 25% of those with a morphologic diagnosis of MDS but is no longer included in the | 294 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)
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H e m a t o l o g y E d u c a t i o
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Copyright Information ©2011 by Eur
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Editorial Board Education Book Edit
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Acute lymphoblastic leukemia 1-8 Th
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S. Schnell P. Van Vlierberghe A. Fe
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lineage cells, and in differentiati
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FLT3 mutations The FMS-like tyrosin
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44. Bar-Eli M, Ahuja H, Foti A, Cli
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J.M. Rowe 1,2 C. Ganzel 1 1 Shaare
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treated on the MRC UKALL XII/ECOG29
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asparaginase (PEG), where the Esche
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or higher. It is, however, importan
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25. Bruggemann M, Schrauder A, Raff
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lymphoblastic leukemia: prospective
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such as high white blood cell count
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doxorubicine, there was a trend tow
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of the aging process with respect t
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K.L. Rice 1 M. Buzzai 2 J. Altman 1
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ing FLT3-ITD, wild-type NPM1, or bo
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ciated with gene activation, via th
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leukemia with inv(16) and t(8;21):
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99. Parsons DW, Jones S, Zhang X, e
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abnormalities, some of which are al
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file. 27,31 Thus, the double gene-m
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karyotype represents a distinct gen
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Table 1. Meta-analysis of 23 random
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A recent study by the Center for In
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Patients with HLA-matched related o
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After allogeneic HSCT, an autologou
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A. Bacigalupo Ospedale San Martino,
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Table 2. The effect of HLA mismatch
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References 1. Petersdorf EW, Malkki
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neutrophil and platelet recovery an
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Figure 2. One Year-Overall Survival
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infused on day 21. No serious adver
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W, et al. Effect of graft source on
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TRM was higher for patients who rec
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following a myeloablative preparati
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effect. Surprisingly, none of the p
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nancies. Bone Marrow Transplant. 20
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J.G. Gilles Center for Molecular an
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14C12 was humanized by grafting VH
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Table 1. VWD Classification. VWD Su
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Figure 1. Missense mutations found
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associated with an increased bleedi
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49. Brown SA, Eldridge A, Collins P
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leed. These issues are especially i
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estored function. 43,44 A phase I t
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years’ experience of prophylactic
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J.A. Burger Department of Leukemia,
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chemotaxis, migration across vascul
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Regulatory T cells (T reg), identif
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16. Burger JA, Ghia P, Rosenwald A,
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TE, Nowakowski GS, et al. CD49d exp
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andomized trial demonstrating impro
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Conclusions Chemoimmunotherapy has
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with multiple comorbidities (≥ 2)
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ment was finished in all 100 patien
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Table 2. Treatment recommendation f
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34. Ferrajoli A. The combination of
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to be the source of additional gene
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potential to prevent LSCs from acce
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ABL1 confirms that eradication of d
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65. Fiskus W, Pranpat M, Balasis M,
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alive after 10 years. 11 Hence, CCy
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each arm). A minimal change in myel
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Any discussion about the definition
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H. Kantarjian J. Cortes Leukemia De
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59%; the CCyR rate was 44%. Among p
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ern era of BCR-ABL1 tyrosine kinase
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the hematopoietic system, 10 nor in
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over the period of 6 weeks, demonst
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Data on clonal changes in the blood
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2006 Feb 1;107(3):924-30. 41. Liang
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demonstrated that changes in osteob
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“Mafia” transgenic mice in whic
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68. Coetzee T, Fujita N, Dupree J,
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ization. In WASP deficiency, lympho
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Currently the epistatic relationshi
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R. Küppers Institute of Cell Biolo
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Figure 1. TNFAIP3 mutation in HL ce
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Figure 2. HRS cells and their precu
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Hansmann ML, et al. Detection of cl
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fying patients for whom different a
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prognosis HL, whilst those with res
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12. Noordijk EM, Carde P, Dupouy N,
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A. Sureda Consultant in Haematology
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Figure 1. Long-term outcome of pati
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from a MRD and 18 from MUDs. All pa
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Parker PM, Stein AS, et al. High-do
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R. Stasi Department of Haematology,
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common variants in the regulatory r
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against the TPO receptor (cMpl). 61
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W.B. Mitchell A.A. Miller J.B. Buss
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platelet counts and/or bleeding. Th
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Mpl. Cell. 1994;77(7):1117-24. 6. d
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ity and mortality associated with t
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to azathioprine, and is particularl
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stemming from antibodies against PE
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L. Pasqualucci Institute for Cancer
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cation of molecularly distinct subg
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of cases) 46 and amplifications of
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gene alterations in B cell lymphoma
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W. Wilson National Cancer Institute
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clear distinction among the lymphom
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Treatment strategies in germinal ce
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in ABC DLBCL (Hernandez et al., 201
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DLBCL that mostly occurs in young p
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phoma. J Clin Oncol. 2005;23:5347-5
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Table 1. Diffuse Large B cell Lymph
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sion/relapse are similar to those i
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intensive therapy with curative int
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A. Karsan Genome Sciences Centre an
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Balanced translocations In contrast
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some arm 5q have also been implicat
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(H3K27) methyltransferase, and is a
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38. Starczynowski DT, Morin R, McPh
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G. Garcia-Manero Department of Leuk
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trial evaluating different doses an
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acid. 62 The second was a large mul
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Borthakur G, et al. Cause of death
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P. Krishnamurthy 1 G.J. Mufti 1,2 1
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etween 1995 and 2005. 11 Five hundr
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London, United Kingdom, June 9-12,
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attainment of FDC post DLI. Interes
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Page 258 and 259: pathologic induction of miR-28 in M
Page 260 and 261: STATs. Second, levels of HP1 alpha
Page 262 and 263: 72. Irandoust MI, Aarts LH, Roovers
Page 264 and 265: A.M. Vannucchi Section of Hematolog
Page 266 and 267: 2,559 patients with a diagnosis of
Page 268 and 269: tant use of aspirin should be caref
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Page 272 and 273: in bcr-abl-negative myeloproliferat
Page 274 and 275: Table 1. Prognostic scoring systems
Page 276 and 277: Figure 1. Current inhibitors of JAK
Page 278 and 279: Table 4. A risk-based approach to d
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Page 282 and 283: A. Vacca 1 D. Ribatti 2 1 Departmen
Page 284 and 285: neovessel building together with MM
Page 286 and 287: Mevastatin, a specific inhibitor of
Page 288 and 289: egression of tumor vessels, and app
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Page 292 and 293: Genetics prognostic tools should be
Page 294 and 295: sone induction improves outcome of
Page 296 and 297: Table 1. Conventional chemotherapy
Page 298 and 299: Novel agents given as consolidation
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Page 304 and 305: Table 1. Major differences between
Page 306 and 307: first line therapy have shown survi
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Page 310 and 311: methylation characterizes juvenile
Page 312 and 313: Table 1. Clinical signs of possible
Page 314 and 315: Table 4. Distribution of CSF involv
Page 316 and 317: ently results in a less than 5% cum
Page 318 and 319: 90. German-Austrian-Swiss ALL-BFM S
Page 320 and 321: U. Nowak-Göttl 1 R. Junker 1 A. Kr
Page 322 and 323: Based on the data obtained from the
Page 324 and 325: 59. Male C, Chait P, Ginsberg JS, e
Page 326 and 327: Table 1. Characteristic features of
Page 328 and 329: Table 2. Mutational spectrum of CDA
Page 330 and 331: megarakaryoblastic leukemia (AMKL)
Page 332 and 333: R.E. Ware Professor and Vice-Chairm
Page 334 and 335: protein, cytokines, and soluble adh
Page 336 and 337: example, improving blood viscosity
Page 338 and 339: 92(9):1266-7. 36. Bensinger TA, Gil
Page 340 and 341: London, United Kingdom, June 9-12,
Page 342 and 343: port have also been used. 5 Combina
Page 344 and 345: Wingard JR, Young J-AH, Boeckh MJ.
Page 346 and 347: K. Rezvani 1 J. Barrett 2 1 Haemato
Page 348 and 349: include the childhood infectious il
Page 350 and 351: Summary Patients undergoing hematop
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Table 1. Key issues. In a retrospec
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invasive method to assess iron over
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stitution but even with optimal sub
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T.M. Hackeng Department of Biochemi
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and inhibits FVIIa, and that the se
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Figure 4. Regulation of coagulation
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T. Baglin Department of Haematology
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Figure 1. Illustration of alternati
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compared with 3.5% in patients with
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49. Hron G, Kollars M, Binder BR, E
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Women receiving vitamin K antagonis
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molecular weight heparin as prophyl
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eral morbidity and mortality. 17-21
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the HOD construct. Furthermore, the
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Goals of future murine studies incl
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F. Noizat-Pirenne C. Tournamille Et
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phenotype. 26 In 2010, we investiga
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ody has been involved in DHTR. 37 T
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antigen. Cases can be encountered d
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S.R. Sloan Harvard Medical School &
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We also analyzed patient databases
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Index of authors Altman J. 27 Bacig
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Cornelissen J. Affiliations to disc
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GlaxoSmithKline (Research Support;
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