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

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Treatment strategies in germinal center B cell DLBCL While GCB DLBCL has a better prognosis than ABC DLBCL, upwards of 30% are not cured. The resistance of GCB DLBCL to curative treatment may relate to the effect of BCL-6 on cell growth and survival. 31,32 BCL-6 is an important modulator of B cell development in the germinal center, and its transcriptional silencing is required for exit of the B cell from the germinal center. BCL-6 suppresses genes that are involved in lymphocyte activation, differentiation, cell cycle arrest, and include p21 and p27Kip1, and DNA damage response genes, p53 and ATR. 31 In GCB DLBCL, chromosomal translocations affecting the BCL-6 locus juxtapose heterologous promoters from the partner chromosome with intact BCL-6 coding sequences, leading to deregulated expression of BCL-6; additionally, BCL-6 can be altered by multiple somatic mutations. These mutations/translocations in BCL-6 enhance its inhibitory effect on the apoptotic stress response and promote proliferation, both of which are associated with treatment failure. 31,33-36 These results suggest that BCL-6 is an important target for GCB DLBCL. Inhibitors targeting the BCL-6 BTB domain protein interaction have shown efficacy in vitro. 20 Targeting other BCL-6 domains or using histone deacetylase inhibitors to overcome BCL-6 repression of p53 and cell cycle inhibitory proteins may also be potentially useful, and are under investigation. 20 An interesting and potentially important observation is the effect of topoisomerase II inhibition on BCL-6 levels. It has been shown that the topoisomerase II inhibitor etoposide leads to down regulation of BCL-6 expression by ubiquitin-mediated protein degradation and possibly through transcriptional inhibition. 37 This may partially account for the in vitro finding that sustained exposure of tumor cells to etoposide and low-dose doxorubicin promote the p53-p21 pathway and activates the checkpoint kinase (Chk2), effects that are inhibited in cells engineered to over-express BCL-6. 38,39 This raises the possibility that inhibition of topoisomerase II may be particularly important in GCB DLBCL. In this regard, the German high-grade lymphoma study group showed that the addition of etoposide to CHOP (CHOEP) significantly improved the event-free survival of younger but not older patients with untreated DLBCL. 40,41 The higher frequency of GCB DLBCL in younger compared to older patients may explain why the benefit of etoposide was only found in the study of patients under 60 years and not over 60 years. 9,40,41 Interestingly, the positive effect of including etoposide in CHOEP was lost when rituximab was added (R- CHOPE). 42 However, this may reflect the overall salutary effect of rituximab on the outcome of DLBCL, including both GCB and ABC DLBCL, and not a specific effect on BCL-6. The association between topoisomerase II inhibition and inhibition of BCL-6 raises the hypothesis of whether regimens that highly inhibit topoisomerase II would be more effective in GCB DLBCL, even in the setting of rituximab. To help address this hypothesis, we turned to the DA-EPOCH-(R) regimen, which was designed to inhibit topoisomerase II through several London, United Kingdom, June 9-12, 2011 strategies: 1. Incorporates two topoisomerase II inhibitors, etoposide and doxorubicin; 2. Optimizes topoisomerase II inhibition through a prolonged 96hour infusion; 3. Maximizes steady state concentrations through pharmacodynamic dose adjustment. 43 To help address this question, we analyzed the outcome of GCB DLBCL in two trials of DA-EPOCH-R in previously untreated GCB DLBCL. In one trial of 33 patients with HIV+ DLBCL, we observed a 95% EFS at a 5-year median follow-up in those with GCB DLBCL. 44 In another study of 75 patients, performed by the Cancer and Leukemia Group B cooperative group (CALGB), patients with GCB DLBCL achieved a 100% EFS at a 5year median follow-up (Hsi and Wilson et al., unpublished observations). 45,46 These studies suggest that DA- EPOCH-R may be particularly effective in GCB DLBCL, in part due to its effective inhibition of topoisomerase II and BCL-6. Treatment strategies in activated B cell DLBCL As discussed above, studies show that ABC DLBCLs are characterized by constitutive activity of NF-κB, which activates genes associated with survival and proliferation and has an inferior clinical outcome. To help assess if NF-κB is a clinically useful target, Dunleavy et al. undertook a “proof of principle” clinical study to test whether inhibition of NF-κB might sensitize ABC but not GCB DLBCL to chemotherapy (Figure 3A and 3B). 47,48 Based on in vitro evidence that bortezomib, a proteasome inhibitor, blocked degradation of phosphorylated IκBa and consequently inhibited NF-κB activity in ABC DLBCL cell lines (data not shown), bortezomib was combined with DA-EPOCH in patients with relapsed/refractory DLBCL. 49-51 Tumor tissue was analyzed by gene expression profiling and/or immunohistochemistry to identify molecular DLBCL subtypes (figure 3A). As a control, they showed that relapsed/refractory ABC and GCB DLBCL have equally poor survivals following upfront chemotherapy. Bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated a significantly higher response (83% versus 13%; P = 0.0004) and median overall survival (10.8 versus 3.4 months; P = 0.0026) in ABC compared to GCB DLBCL, respectively, as shown in Figure 3B. These results suggest bortezomib enhances the activity of chemotherapy in ABC but not GCB DLBCL, and provide a rational therapeutic approach based on genetically distinct DLBCL subtypes. 52 In another recent study, bortezomib was combined with R-CHOP in patients with previously untreated DLBCL to assess its toxicity and efficacy in ABC DLBCL subtype. 53 In this study of 40 patients with DLBCL, patients achieved a PFS of 64% at 2-years, and there was no difference among patients with GCB and ABC DLBCL, suggesting that bortezomib overcame the adverse prognostic effective of the ABC DLBCL subtype. Based on these studies, a randomized study of R-CHOP ± bortezomib in untreated patients with ABC DLBCL is ongoing (Pyramid Study). A recent study suggests that lenalidomide, an immune modulatory agent, may also be preferentially effective Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 203 |
16 th Congress of the European Hematology Association Figure 3. Clinical treatment paradigm. Patients initially received bortezomib alone at 1.3 mg/m 2 on days 1, 4, 8 and 11 every 21 days (Part A) unless they had disease which the investigators judged to required immediate chemotherapy such as impending or ongoing organ compromise; these patients only received Part B. Patients with progressive disease on Part A received bortezomib with DA-EPOCH (Part B). Of 31 DLBCL cases analyzed by GEP, 16 were excluded due to ineligible subtype by classification or did not receive Part A, leaving 5 ABC and 10 GCB cases eligible for analysis of outcome. Of 24 paraffin embedded tumor biopsies analyzed by immunohistochemistry, 12 each were categorized as GCB and ABC (non-GCB) type. 28 By combining both methods, cases were identified as GCB in 15 and ABC in 12 and included in the analysis of outcome with Part B. B. Response and overall survival of 27 patients with de novo GCB or ABC DLBCL who received DA-EPOCH-B. Overall survival of patients with ABC or GCB DLBCL showed a median survival of 10.8 and 3.4 months, respectively (P = 0.0026). Patients with ABC DLBCL also had a significantly higher complete and overall response rate compared to patients with GCB DLBCL. | 204 | 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
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
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Page 170 and 171: prognosis HL, whilst those with res
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
Page 196 and 197: to azathioprine, and is particularl
Page 198 and 199: stemming from antibodies against PE
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
Page 208 and 209: W. Wilson National Cancer Institute
Page 210 and 211: clear distinction among the lymphom
Page 214 and 215: in ABC DLBCL (Hernandez et al., 201
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
Page 252 and 253: myelodysplastic syndromes is associ
Page 254 and 255: ubiquitous chaperone that promotes
Page 256 and 257: was thought that they are linked to
Page 258 and 259: pathologic induction of miR-28 in M
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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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