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TRM was higher for patients who received a transplant from a 1- or 2-antigen mismatched related donor compared to an HLA-identical sibling. 7 Since donor-derived T-lymphocytes in the graft are the major cause of GVHD in allogeneic SCT, various attempts were made to deplete T-cells from BM prior to infusion. The first ex vivo T-cell depleted bone marrow transplants (BMT) using soybean agglutinin and rosette formation with sheep red blood cells were performed in children with immunodeficiency syndromes. 8 Subsequently, Henslee–Downey and colleagues used intensive total body irradiation (TBI) based myeloablative preparative regimens with partial in vitro T-cell depletion of haploidentical BM using anti-CD3 antibodies (T10B9 or OKT-3) with a 1–1.5 log reduction of T-cells and posttransplant pharmacological GVHD prophylaxis. 9 In this large series of 201 patients, 98% engrafted with 5-year cumulative incidences of relapse and TRM of 31% and 51%, respectively. The cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 13% and 15%, respectively. An encouraging survival probability of 20% was seen in patients with advanced hematological malignancies. Challenges of haploidentical transplantation Based on the initial experience using unmanipulated or partially T-cell depleted bone marrow and fully ablative conditioning regimens, the major challenges in haploidentical stem cell transplantation turned out to be and still are: (i) the prevention of severe acute and chronic GVHD; (ii) the reduction of the risk of graft rejection; (iii) the acceleration of the delayed immunoreconstitution associated with a high incidence of severe and often lethal infectious complications; and (iv) the implementation of strategies for the selection of the best mismatched donor in terms of natural killer (NK) cell alloreactivity and post-transplant cellular therapeutic strategies to prevent the risk of relapse. Approaches to overcoming these challenges Megadose transplantation of positively selected CD34+ stem cells The ‘megadose’ concept was first described by Reisner et al. in animal models of haploidentical transplantation. 10 It is based on the observation that the transplantation of large numbers of purified hematopoietic stem cells can overcome the HLA barrier of haploidentical transplantation due to the presence of ‘veto’ cells within the CD34+ selected population. 11,12 To translate this concept into a clinical setting, Aversa et al. devised a strategy for the combination of BMderived CD34+ stem cells and CD34+ stem cells purified from granulocyte colony-stimulating factor (G- CSF)-mobilized peripheral blood stem cells (PBSC) from haploidentical donors using soybean agglutinin and Erosetting. 13 With this graft-engineering strategy, a 3 log reduction in T-cells was achieved and large numbers of CD34+ stem cells with a low number of graft-contaminating T-cells were transplanted. Primary engraftment was achieved in 16/17 patients with end-stage London, United Kingdom, June 9-12, 2011 leukemia. In the absence of any pharmacological GVHD prophylaxis, severe acute GVHD occurred in only one patient and no cases of chronic GVHD were observed. In a subsequent study, the same group then used positively selected CD34+ stem cells from leukapheresis as the sole source of stem cells with a higher degree of Tcell depletion (4 logs) following a preparative regimen composed of TBI, thiotepa, fludarabine, and anti-thymocyte globulin (ATG). The median number of transplanted CD34+ stem cells was 10x10 6 /kg recipient body weight, and the number of co-transplanted CD3+ Tcells was only 2 x 10 4 /kg. The engraftment rate was 95%, and severe GVHD was not seen even in the absence of any pharmacological GVHD prophylaxis. 14 However, due to the delayed immune reconstitution associated with this approach, there was a high rate of infectious complications, and infections were the leading cause of death and the main contributors to a TRM rate of 40%. The clinical introduction of a semi-automated device for the positive selection of highly purified CD34+ stem cells and the high degree of indirect depletion of T-cells and B-cells to 4.5–5 log and more than 3 log, respectively, 15 led investigators to evaluate haploidentical transplantation using ‘megadoses’ of highly purified CD34+ stem cells in patients with a variety of diseases. With this extensive T-cell depletion, almost no GVHD was seen even in the absence of any pharmacological GVHD prophylaxis and due to the indirect B-cell depletion associated with CD34+ selection, post-transplant EBVrelated lymphoproliferative disorders were also absent in both pediatric 16 and adult patients. 17 Similar results were reported from other investigators using mostly TBI-based myeloablative preparative regimens followed by the transplantation of large numbers of highly purified CD34+ peripheral stem cells without any additional GVHD prophylaxis. 18–22 All these studies in both pediatric and adult patients have in common delayed immune reconstitution, which was associated with a high incidence of severe and lethal infections. In an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Group for Blood and Marrow Transplant (EBMT), of the outcome of 102 children with ALL in remission receiving haploidentical transplants with CD34+ positively selected stem cells, the impacts of the number of transplanted CD34+ stem cells and the transplant center size (in terms of number of haploidentical transplants performed per year) were demonstrated. 23 Patients who received more than 12.4 x 10 6 /kg CD34+ positively selected stem cells had a leukemia-free survival (LFS) of 35±7% compared with 17±6% in patients who received less than 12.4 x 10 6 /kg. Patients who received their transplant at a larger transplant center had a LFS of 39±7% compared with the LFS of 15±6% in patients transplanted in smaller centers. In a survey of adult patients with high risk acute leukemia in remission at transplantation who received positively selected CD34+ stem cells, the LFS for patients with AML in CR1, more than or equal to CR2 or advanced disease were 48±10 %, 21±%, and 1±1%, respectively. The LFS for patients with ALL in CR1, more than or equal to CR2 and advanced disease were 13±%, 30±8%, and 7±5%, respectively. 24 A reduced Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 65 |
16 th Congress of the European Hematology Association intensity conditioning regimen was employed in 28 adult patients with advanced hematological malignancies who were transplanted with haploidentical CD34+ positively selected stem cells. 25 Engraftment was achieved in 78% of the patients, and the toxicity was mostly infections. The co-transplantation of ex vivoexpanded donor-derived mesenchymal stem cells together with CD34+ positively selected stem cells accelerated lymphocyte recovery and reduced the risk of graft failure in pediatric patients. 26 Transplantation of negatively T-cell depleted stem cells Depletion of CD3+/CD19+ lymphocytes While initial attempts to deplete T-cells from BM resulted only in 1–1.5 log reduction of T-cells, semiautomated devices for the concomitant depletion of Tand B-lymphocytes to prevent GVHD and post-transplant EBV-associated lymphoproliferative disease, respectively, allow the effective depletion of CD3+ and CD19+ lymphocytes (CD3/19 depletion) from mobilized peripheral stem cell grafts. 27 The T-cell depletion with this method (3.5–4 log) is less than compared with the CD34+ positive selection method (4.5–5 log). In contrast to the CD34+ positive selection method, large numbers of NK-cells, monocytes, dendritic cells, and other myeloid cells are retained in the graft. In the first clinical study, 20 children with hematological malignancies were transplanted with CD3depleted PBSC following a TBI-based myeloablative preparative regimen. 28 Of 19 evaluable patients, all engrafted. Six patients (30%) died from TRM and 4 patients (20%) from disease recurrence. Ten patients (50%) are alive and well. A subsequent pediatric study was performed in 25 patients with advanced refractory hematological malignancies (n=9) or patients with relapse after a previous standard myeloablative transplantation (n=16). 29 Since these patients were considered to be at high risk of TRM with a myeloablative preparative regimen, a less intensive non TBI-based conditioning regimen consisting of fludarabine (200 mg/m²), thiotepa (10 mg/kg), melphalan (120 mg/m²), and the anti-CD3 antibody OKT-3 was employed. Two of three patients who did not engraft were rescued by another transplant from their original donor, and one patient had early disease progression without donor engraftment. The cumulative incidences of grade II-IV and grade III-IV GVHD were 44% and 8%, respectively. The cumulative incidence of chronic GVHD was 28%. Thirteen patients died of disease recurrence and four from TRM. No lethal viral infections were seen. Eight patients remain alive with a performance score greater than or equal to 90%. In a comparative analysis of the immune reconstitution in these two cohorts of patients, a much faster recovery of thymopoiesis, as determined by the rapid increase of T-cell receptor excision circles (TREC), and a rapid return of the T-cell receptor repertoire were seen in the patients who received a non TBI-based less intensive preparative regimen compared with the patients who received myeloablative TBI. 30 Additional studies were initiated in pediatric and adult patients using the less intensive non TBI-based preparative regimen, consisting of fludarabine (160 mg/m²), thiotepa (10 mg/kg), melphalan (140 mg/m²), and OKT-3. 31 In a study of 38 pediatric patients, primary engraftment was seen in 83%. The major cause of graft failure was rejection. However, after reconditioning and a second transplant with CD3/19 depleted PBSC from the other haploidentical parental donor, 32 engraftment was finally obtained in 98% of the patients. Most importantly, only 1 out of the 38 patients died from TRM. Acute GVHD grade 0-I, II, and III-IV were seen in 73%, 24%, and 3% of the patients respectively. In a recent update, Pfeiffer et al. reported an event-free survival of 51% for children with acute leukemia who were in morphological remission at time of transplantation. 33 In a study in adult patients, a similar approach was used with the same preparative regimen. 34 Twentynine high risk patients were transplanted and 9/29 patients are alive. The TRM in the first 100 days was 20% and 12 patients relapsed. The immune reconstitution was analyzed in 28 adult patients who received a haploidentical CD3/19-depleted graft. T-cell reconstitution was delayed with a median of 70 CD4+ T-cells/µl on day +100 post-transplant, whereas the NK cell recovery was fast reaching normal values at day +20. 35 Depletion of TcRab+/CD19+ lymphocytes Compared with CD34+ positive selection, the number of graft-contaminating T-cells is approximately 10fold higher in CD3/19-depleted grafts, requiring shortterm post-transplant immunosuppression with mycophenolate mofetil (MMF). 36 A more effective approach for the negative depletion of T-cells is the recently described negative depletion of T-cell receptor (TcR) ab+ T-lymphocytes from mobilized peripheral stem cell grafts. 37 With this method, a T-cell reduction of 4.5–5 log can be achieved, which is comparable with CD34+ positive selection. This approach retains NK cells, monocytes, dendritic cells, and gδ+ T-lymphocytes in the graft. gδ+ T-lymphocytes are non-alloreactive lymphocytes with important anti-infectious and antitumor properties (for review, see 38 ), which might have an impact on the outcome of haploidentical transplantation. In this context, it has been reported that gδ+ T-cells can exert an anti-leukemic effect in partially mismatched HSCT. 39 In this retrospective analysis, patients with a high gδ T-cell count post-transplant had a better 5-year survival than those with normal or low counts (70.8 vs. 19.6%, p=0.0001), while no difference in the incidence of GVHD was observed. The first clinical experience in children undergoing haploidentical transplantation of TcRab/CD19-depleted T-cells are promising with a rapid donor engraftment, a rapid expansion of gδ+ T-lymphocytes, and a rapid immune reconstitution with a median time to reach 100 CD3+ T-cells of 34 days (own unpublished observations). Transplantation of T-cell replete bone marrow and/or peripheral stem cells The use of T-cell replete BM or PBSCs relies either on the composition of the graft, on intensive pharmacological prophylaxis for GVHD, or on the in-vivo T-cell depletion of the donor-derived T-cells after infusion of the graft using polyclonal antithymocyte globulin (ATG) or monoclonal antibodies (Alemtuzumab). Huang et al. combined G-CSF-primed BM and unmanipulated PBSC | 66 | 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
Page 24 and 25: or higher. It is, however, importan
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Page 28 and 29: lymphoblastic leukemia: prospective
Page 30 and 31: such as high white blood cell count
Page 32 and 33: doxorubicine, there was a trend tow
Page 34 and 35: of the aging process with respect t
Page 36 and 37: K.L. Rice 1 M. Buzzai 2 J. Altman 1
Page 38 and 39: ing FLT3-ITD, wild-type NPM1, or bo
Page 40 and 41: ciated with gene activation, via th
Page 42 and 43: leukemia with inv(16) and t(8;21):
Page 44 and 45: 99. Parsons DW, Jones S, Zhang X, e
Page 46 and 47: abnormalities, some of which are al
Page 48 and 49: file. 27,31 Thus, the double gene-m
Page 50 and 51: karyotype represents a distinct gen
Page 52 and 53: Table 1. Meta-analysis of 23 random
Page 54 and 55: A recent study by the Center for In
Page 56 and 57: Patients with HLA-matched related o
Page 58 and 59: After allogeneic HSCT, an autologou
Page 60 and 61: A. Bacigalupo Ospedale San Martino,
Page 62 and 63: Table 2. The effect of HLA mismatch
Page 64 and 65: References 1. Petersdorf EW, Malkki
Page 66 and 67: neutrophil and platelet recovery an
Page 68 and 69: Figure 2. One Year-Overall Survival
Page 70 and 71: infused on day 21. No serious adver
Page 72 and 73: W, et al. Effect of graft source on
Page 76 and 77: following a myeloablative preparati
Page 78 and 79: effect. Surprisingly, none of the p
Page 80 and 81: nancies. Bone Marrow Transplant. 20
Page 82 and 83: J.G. Gilles Center for Molecular an
Page 84 and 85: 14C12 was humanized by grafting VH
Page 86 and 87: Table 1. VWD Classification. VWD Su
Page 88 and 89: Figure 1. Missense mutations found
Page 90 and 91: associated with an increased bleedi
Page 92 and 93: 49. Brown SA, Eldridge A, Collins P
Page 94 and 95: leed. These issues are especially i
Page 96 and 97: estored function. 43,44 A phase I t
Page 98 and 99: years’ experience of prophylactic
Page 100 and 101: J.A. Burger Department of Leukemia,
Page 102 and 103: chemotaxis, migration across vascul
Page 104 and 105: Regulatory T cells (T reg), identif
Page 106 and 107: 16. Burger JA, Ghia P, Rosenwald A,
Page 108 and 109: TE, Nowakowski GS, et al. CD49d exp
Page 110 and 111: andomized trial demonstrating impro
Page 112 and 113: Conclusions Chemoimmunotherapy has
Page 114 and 115: with multiple comorbidities (≥ 2)
Page 116 and 117: ment was finished in all 100 patien
Page 118 and 119: Table 2. Treatment recommendation f
Page 120 and 121: 34. Ferrajoli A. The combination of
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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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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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