H e m a t o lo g y E d u c a t io n - European Hematology Association

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W. Wilson National Cancer Institute, Bethesda, MD, USA Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:199-209 Diffuse large B-cell lymphoma Diffuse large B cell lymphoma: treatment decisions based on molecular features Pathological classification Conceptual therapeutic advances are highly dependent on biologically-based pathological classifications. The National Cancer Institute’s Working Formulation, which was in use in the United States until the early 1990’s, categorized lymphomas according to their morphology and clinical behavior, and lacked a biological foundation. 1 In contrast, the Kiel Classification, which was used in Europe, was the first to employ a biological foundation. 2 However, it was not until the Revised European-American Lymphoid (REAL) classification, published in 1994, that a clinical-biological foundation was incorporated into the classification of lymphomas. 3 Since then, major genetic and biological insights have been incorporated into the diagnostic criteria codified in the World Health Organization (WHO) classification of tumors of the lymphoid tissues. 4 This evolution in classification is the direct result of insights into the molecular pathogenesis of lymphoma, including the identification of “hallmark” genetic abnormalities, and has led to the discovery of driver pathways and clinical testing of targeted therapy. 5,6 The classification of diffuse large B cell lymphoma (DLBCL) has been among the greatest beneficiaries of these biological advances. While it has long been recognized that DLBCL is clinically and biologically diverse, it had been difficult to readily subdi- A B S T R A C T The treatment of diffuse large B cell lymphoma (DLBCL) in the last two decades has heralded an era of increasing exploration of therapies derived from improved biologic understanding of tumors and tumor-host interactions. The focus of drug discovery has moved from identifying classical cytotoxic agents to molecules that target specific pathways involved in signal transduction, apoptosis, and differentiation, among others. These efforts have been greatly aided by insights into the structure of proteins and the ability to design specific inhibitors using small molecules or monoclonal antibodies. The discovery of new signaling pathways through gene expression profiling (GEP) and RNA interference screens that are critical to lymphomagenesis has produced an array of new targets for the treatment of lymphomas. Specifically, GEP has revealed that DLBCL consists of at least three major subtypes: germinal center B cell-like (GCB), activated B cell-like (ABC) and primary mediastinal B cell (PMBL) DLBCL, which derive from B cells at different states of differentiation and with unique molecular pathogenesis. ABC DLBCL shows high expression of target genes of the NF-κB/Rel family of transcription factors, and may benefit from NF-κB inhibition. In GCB DLBCL, studies raise the hypothesis that inhibition of the BCL-6 transcription factor may be therapeutically important, whereas PMBL, like its biological cousin nodular sclerosis Hodgkin’s lymphoma, may benefit from dose intensity approaches and inhibition of the Janus Kinases. vide it into distinct disease entities because of overlapping morphology and pathogenetic features. 7 As a result, treatment strategies have primarily depended on clinical features such as stage, age and the International Prognostic Index (IPI) score. 8 Large scale gene expression profiling (GEP) and mutational analysis, however, has led to the recognition of new subtypes of DLBCL. Though still retaining the histological description of a neoplasm of large B lymphoid cells with a diffuse growth pattern, DLBCL can now be subdivided into diseases that arise from B cells at different stages of differentiation with distinctive molecular and clinical characteristics. 4 Thus, when considering treatment, either in the research or clinical setting, it is essential to understand these pathobiological distinctions. This educational review will focus primarily on three distinct subtypes of DLBCL in which molecular, diagnostic and therapeutic advances have been made. Molecular pathology of germinal center B cell and activated B cell DLBCL Presently, DLBCL is divided into four major groupings within the WHO, which are further divided along molecular, pathological and/or clinical grounds. Of these, the most common group is DLBCL not otherwise specified (NOS) that is further subdivided into the germinal center B cell-like Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 199 |
16 th Congress of the European Hematology Association (GCB) and activated B cell-like (ABC) molecular subgroups by GEP (Figure 1A). 9,10 In the initial GEP studies of DLBCL, arrays were performed on follicular lymphoma, CLL, lymphoma and leukemia cell lines, and normal lymphocyte subpopulations obtained under a variety of activation conditions to provide a comparative basis for analysis of DLBCL gene expression. 11 Genes associated with cellular proliferation showed a Figure 1. Diagnosis and outcome of DLBCL subtypes by gene expression profiling subtypes. A. Heat map showing expression of genes that discriminate between the GCB and ABC subtypes of DLBCL. Genes associated with the microenvironment, which have prognostic significance, are clustered into stromal 1 and 2 signatures. The stromal-1 signature genes are associated with extracellular matrix deposition and histiocytic infiltration and the stromal-2 signature genes are associated with increased tumor blood vessel density. B. Kaplan-Meier estimates of progression free and overall survival are shown according to GCB or ABC DLBCL subtype in patients treated with R-CHOP based therapy. Median follow-up is approximately 2 years. | 200 | 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
Page 158 and 159: Currently the epistatic relationshi
Page 160 and 161: R. Küppers Institute of Cell Biolo
Page 162 and 163: Figure 1. TNFAIP3 mutation in HL ce
Page 164 and 165: Figure 2. HRS cells and their precu
Page 166 and 167: Hansmann ML, et al. Detection of cl
Page 168 and 169: fying patients for whom different a
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Page 172 and 173: 12. Noordijk EM, Carde P, Dupouy N,
Page 174 and 175: A. Sureda Consultant in Haematology
Page 176 and 177: Figure 1. Long-term outcome of pati
Page 178 and 179: from a MRD and 18 from MUDs. All pa
Page 180 and 181: Parker PM, Stein AS, et al. High-do
Page 182 and 183: R. Stasi Department of Haematology,
Page 184 and 185: common variants in the regulatory r
Page 186 and 187: against the TPO receptor (cMpl). 61
Page 188 and 189: W.B. Mitchell A.A. Miller J.B. Buss
Page 190 and 191: platelet counts and/or bleeding. Th
Page 192 and 193: Mpl. Cell. 1994;77(7):1117-24. 6. d
Page 194 and 195: ity and mortality associated with t
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Page 200 and 201: L. Pasqualucci Institute for Cancer
Page 202 and 203: cation of molecularly distinct subg
Page 204 and 205: of cases) 46 and amplifications of
Page 206 and 207: gene alterations in B cell lymphoma
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Page 212 and 213: Treatment strategies in germinal ce
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Page 216 and 217: DLBCL that mostly occurs in young p
Page 218 and 219: phoma. J Clin Oncol. 2005;23:5347-5
Page 220 and 221: Table 1. Diffuse Large B cell Lymph
Page 222 and 223: sion/relapse are similar to those i
Page 224 and 225: intensive therapy with curative int
Page 226 and 227: A. Karsan Genome Sciences Centre an
Page 228 and 229: Balanced translocations In contrast
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Page 232 and 233: (H3K27) methyltransferase, and is a
Page 234 and 235: 38. Starczynowski DT, Morin R, McPh
Page 236 and 237: G. Garcia-Manero Department of Leuk
Page 238 and 239: trial evaluating different doses an
Page 240 and 241: acid. 62 The second was a large mul
Page 242 and 243: Borthakur G, et al. Cause of death
Page 244 and 245: P. Krishnamurthy 1 G.J. Mufti 1,2 1
Page 246 and 247: etween 1995 and 2005. 11 Five hundr
Page 248 and 249: London, United Kingdom, June 9-12,
Page 250 and 251: attainment of FDC post DLI. Interes
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Page 254 and 255: ubiquitous chaperone that promotes
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pathologic induction of miR-28 in M
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STATs. Second, levels of HP1 alpha
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72. Irandoust MI, Aarts LH, Roovers
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A.M. Vannucchi Section of Hematolog
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2,559 patients with a diagnosis of
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tant use of aspirin should be caref
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sions at this regard. Based on thes
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in bcr-abl-negative myeloproliferat
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Table 1. Prognostic scoring systems
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Figure 1. Current inhibitors of JAK
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Table 4. A risk-based approach to d
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the flexibility to be adjusted as t
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A. Vacca 1 D. Ribatti 2 1 Departmen
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neovessel building together with MM
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Mevastatin, a specific inhibitor of
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egression of tumor vessels, and app
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diagnosis does not require genetic
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Genetics prognostic tools should be
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sone induction improves outcome of
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Table 1. Conventional chemotherapy
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Novel agents given as consolidation
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dence of peripheral neuropathy, gas
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31. Barlogie B, Tricot G, Anaissie
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Table 1. Major differences between
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first line therapy have shown survi
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transplantation, 7,91 and generally
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methylation characterizes juvenile
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Table 1. Clinical signs of possible
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Table 4. Distribution of CSF involv
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ently results in a less than 5% cum
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90. German-Austrian-Swiss ALL-BFM S
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U. Nowak-Göttl 1 R. Junker 1 A. Kr
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Based on the data obtained from the
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59. Male C, Chait P, Ginsberg JS, e
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Table 1. Characteristic features of
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Table 2. Mutational spectrum of CDA
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megarakaryoblastic leukemia (AMKL)
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R.E. Ware Professor and Vice-Chairm
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protein, cytokines, and soluble adh
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example, improving blood viscosity
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92(9):1266-7. 36. Bensinger TA, Gil
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London, United Kingdom, June 9-12,
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port have also been used. 5 Combina
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Wingard JR, Young J-AH, Boeckh MJ.
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K. Rezvani 1 J. Barrett 2 1 Haemato
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include the childhood infectious il
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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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