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to azathioprine, and is particularly useful if they have associated haemolytic anemia. There is reasonable Grade B evidence for the use of cyclosporin A, mycophenolate, and rituximab as alternate immunosuppressive options. Mycophenolate produces a response in about a quarter to a half of all patients and is well tolerated by the majority of patients. 28 It should be remembered, however, that suppression of the immune system can predispose patients to infection, which is a major cause of death in ITP patients. 29,30 The long term use of immune suppressive agents, particularly in patients who have failed splenectomy, is an especial risk. Rituximab In 2001, Stasi et al. reported for the first time in an observational study the efficacy of rituximab in adults with chronic ITP. 31 A number of other studies have confirmed the efficacy of rituximab in patients with ITP. In 2007 Arnold et al. published a meta-analysis combining some of these studies including at least five patients treated. 32 The overall response rate (platelet count >50×10 9 /L) correct was estimated to be 60%, with an overall complete response rate (platelet count >15×10 9 /L) correct of approximately 46%. The study by Cooper et al. in 2004 33 showed that rituximab could be equally effective both pre-splenectomy and postsplenectomy. The better the initial response was, the longer the response was. The only factor correlated with a lower likelihood of response was the duration of ITP. The multicentre prospective French study of Godeau et al. 34 in chronic ITP (over 6 months’ duration) showed similar results and after 2 years of follow-up, the overall response rate was 33%. The study by Zaja in Italy 35 was a prospective, randomized comparison between a single course of dexamethasone 40 mg/m 2 correct for four consecutive days and dexamethasone followed by rituximab 375 mg/m 2 weekly for 4 weeks. The study in previously untreated patients showed a rate of sustained response (platelet count >50×10 9 /L at 6 months) of 63% in the dexamethasone plus rituximab arm compared with only 36% in the dexamethasone arm. After a median follow-up of 20 months, approximately 75% of the initial responders in both arms had a lasting response. All these studies used rituximab at a conventional dose of 375 mg/m 2 . Other studies from Italy and the UK 36,37 suggest that a lower dosage of rituximab (i.e., 100 mg weekly for 4 weeks) can be sufficient to achieve a response in the ITP setting. No serious adverse events were reported in the initial studies in ITP. However, infusion reactions are not infrequent, and both serum sickness and hypogammaglobulinemia have been reported. 34 More recently, there has been concern about the possible induction of progressive multifocal leucoencephalopathy (PML), an opportunistic infection of the brain, which is fatal in almost 100% of cases. A review of adverse events associated with rituximab 38 reported 57 cases of PML in patients treated with rituximab; the majority of these patients had been treated for a lymphoma, whereas only a few had autoimmune disorders, including two with ITP. Most of these patients had received not only rituximab but also chemotherapy or long-term corticosteroids London, United Kingdom, June 9-12, 2011 and/or immunosuppressives. The role of rituximab, therefore, is not clearly established at this time. In the past 5 years, a registry has been set up by rheumatologists in France looking at the safety of rituximab in rheumatoid arthritis outside a clinical trial setting. 39 This registry has included more than 1000 patients, some of whom have received up to eight courses of rituximab over years. The overall incidence of infection was slightly higher than the one reported in clinical trials was, reflecting that some patients treated with rituximab would have not been not included in clinical trials because of comorbidities, but not a single case of PML has been reported. Overall, 5% of patients acquired secondary hypogammaglobulinemia. Splenectomy Splenectomy has proved an effective therapy in the management of primary ITP, with a systematic review of 135 reported series from 1966 to 2004 finding a complete response (CR), defined by a platelet count of at least 150 x 10 9 /L and 30 days or longer on no treatment, in 66% of patients. 40 However, the procedure is not without risk, including intra-abdominal hemorrhage, 41 thromboembolic events, 42 and overwhelming postsplenectomy infections (OPSI). 43 Although the risks of these complications in patients with primary ITP is estimated to be low, 44 when coupled with the risk of failure to achieve CR in one-third of patients, limited data on long-term relapse risk, and increasing awareness of the pathogenic heterogeneity of the disease, 45–47 they provide sufficient impetus to investigate potential pre-operative predictive variables of response. A number of such clinical predictors have been suggested, including i) response to corticosteroid and IVIg therapies; ii) platelet turnover; iii) platelet lifespan; iv) patient age; v) duration of disease; vi) platelet-bound immunoglobulin; and vii) site of platelet destruction as determined by radionuclide labeling techniques. In a systematic review of the effectiveness of splenectomy among adult patients with primary ITP, Kojouri et al. report inconclusive evidence in support of this last variable. 40 However, past investigations into platelet sequestration studies have adopted heterogeneous methods and varied widely with regard to power. Utilizing patients with primary ITP who underwent 111 In-labelled, autologous platelet sequestration studies at Barts and The London NHS Trust between 1994 and 2008, we evaluated the effectiveness of sequestration site in predicting short, medium, and long-term surgical failure through multivariable logistic regression modeling. In total 256 patients with primary ITP underwent scanning, with 91 (35.5%) proceeding to splenectomy. Logistic regression revealed adjusted, statistically significant odds ratios (ORs) for surgical failure of 7.47 (95% CI, 1.89–29.43) at 1–3 months post-splenectomy, 4.85 (95% CI, 1.04– 22.54) at 6–12 months post-splenectomy, and 5.39 (95% CI, 1.34–21.65) at last follow-up (median: 3.8 years [range: 0.5–13.1 years]) in patients with mixed or hepatic versus purely or predominantly splenic platelet sequestration. These findings support adoption of a cautious approach to splenectomy in patients exhibiting mixed or hepatic sequestration. 48 Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 187 |
16 th Congress of the European Hematology Association Thrompopoietin receptor agonists Initially ITP was thought to be a disease of increased platelet destruction, which is why current standard treatments are either of a non-specific immunosuppressant nature or targeted solely at decreasing platelet destruction. Recent evidence suggests that suboptimal platelet production by suppression of megakaryocyte production and maturation may also have a role in ITP. Therefore, it was postulated that treatment aimed at increasing platelet production may provide an opportunity to improve outcomes in patients with this chronic disease. 49 Megakaryopoiesis and platelet production are gov- Table 1. Investigation of suspected ITP. Basic evaluation Tests in selected cases Tests of unproven benefit Patient history Antiphospholipid antibody (including ACL and Lupus) Glycoprotein-Specific Ab Family history Anti thyroid antibody and thyroid function Thrombopoitein Assay Physical examination Pregnancy test Reticulated platelet count Full blood count Antinuclear antibodies Indirect PaIgG Peripheral blood film Viral PCR for parvovirus and CMV Bleeding time Blood group (Rh) and reticulocyte count Platelet survival DAGT Serum complement levels Quantitative Ig measurement Bone marrow examination* H. pylori HIV and HCV Table 2. Summary of treatment options. Clinical situation Therapy option First line – Anti-D (initial treatment for newly diagnosed ITP) – Corticosteroids: dexamethasone, methylprednisolone, prednis(ol)one – IVIg Second line – Azathioprine – Cyclosporin A – Cyclophosphamide – Danazol – Dapsone – Mycophenolate mofetil – Rituximab – Splenectomy – TPO-receptor agonists – Vinca alkaloids Treatment for refractory ITP patients Category A: (patients failing first and second-line therapies) Treatment options with sufficient data – TPO-receptor agonists Category B: Treatment options with minimal data and considered to have potential for considerable toxicity – Campath-1H – Combination of first- and second-line therapies – Combination chemotherapy – Haemopoietic stem cell transplantation (HSCT) Modified from 7 erned by signaling through the Mpl receptor and the ligand for this receptor, known as thrombopoietin (TPO), has a pivotal role in the regulation of platelet production. Following the cloning of the molecule, two recombinant thrombopoietin molecules were developed: recombinant human thrombopoietin (rhTPO) and pegylated human recombinant megakaryocyte growth and development factor (PEG-rHuMGDF). These agents underwent extensive clinical testing for a range of thrombocytopenic disorders. The clinical development of these recombinant growth factors was halted in 1998 with reports that patients receiving PEG-rHuMGDF (which has significant sequence homology with endogenous TPO) developed severe thrombocytopenia | 188 | 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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Page 148 and 149: 2006 Feb 1;107(3):924-30. 41. Liang
Page 150 and 151: demonstrated that changes in osteob
Page 152 and 153: “Mafia” transgenic mice in whic
Page 154 and 155: 68. Coetzee T, Fujita N, Dupree J,
Page 156 and 157: 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
Page 208 and 209: W. Wilson National Cancer Institute
Page 210 and 211: clear distinction among the lymphom
Page 212 and 213: Treatment strategies in germinal ce
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
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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
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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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myelodysplastic syndromes is associ
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ubiquitous chaperone that promotes
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was thought that they are linked to
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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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