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ody has been involved in DHTR. 37 The (C)ce S has been associated with a partial c in one case, in which an antic was isolated from a mixture of antibodies. 38 In all reported cases, the “allo” feature may be questioned when many serological manipulations have been performed to isolate the antibody. Of greater concern are the rare phenotypes encoded by (C)ce S and the RN when they are present at the homozygous state. The RN/RN background encodes RH: 32,-46 and the (C)ce S /(C)ce S background encodes the RH:-34. Both these phenotypes, plus the RH:-18 phenotype and the homozygous partial e are real issues in the management of transfu- London, United Kingdom, June 9-12, 2011 Figure 2. The RHCE alleles encoding CE variants in individuals of African descent are represented. The antibodies prone by the variant and their clinical significance are indicated when documented in published reports. 1 The anti-C was found after DHTR. Then the real involvement cannot be proved, as the antibody was not eluted from the transfused RBCs. sion in SCD patients. They are known to prone alloimmunization, and supply is very rare. Therefore, alternative treatments, such as bone marrow graft, should be always discussed, balancing the risk of DHTR and the risk of the graft procedure. The low incidence RH antigens Substitutions on the Rh polypetides can encode antigens with missing epitopes as described in the partial situation, but can also cause creation of new epitopes. These new epitopes can induce production of allo-antibodies in a carrier who does not present the abnormali- Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 377 |
16 th Congress of the European Hematology Association ty. These new epitopes are called “low incidence antigens” relatively to their low incidence in the Caucasian reference population. In the Black population, some of them are frequently expressed, such as the RH20 (VS) antigen, encoded by the RHCE*ce S allele. Considering that this antigen is expressed in about 40% of individuals of African descent, a VS-negative SCD patient receiving blood from a donor with the same ethnic background can be exposed and get immunized to VS. Whether these antigens are immunogenic and clinically significant is also a real issue. Data are lacking on the subject. Antibodies against VS are not detected by the screening test because in most cases, RBC tests do not express VS. Then, it is quite difficult to evaluate the occurrence of immunization in case of mismatch. A prospective study on occurrence of immunization against VS with determination by DNA analysis of VS in both donors and recipients would be required to evaluate the risk, and decide whether a prevention strategy is necessary. The other described low incidence antigens in the RH blood group are linked to low incidence variants. Therefore, it is not likely that exposition of SCD patients occur frequently. It remains that a case of DHTR has been reported in a SCD patient who received RBCs from a partial DIVa donor who expressed the associated Go a low frequency antigen. 39 In cases of DHTR without detectable antibodies, the possibility of the involvement of antibodies against a low incidence antigen have always to be questioned, but is difficult to demonstrate. Many low incidence antigens are described in Blacks: the RH32 encoded by the RN haplotype, the DAK encoded by DIIIa, DOL, and RN. 40,41 Clinical significance of the antibodies linked to RH variants in SCD (Figures 1 and 2) For all the RH variants, the main question in case of occurrence of an antibody is finally its clinical significance. In the published cases, few “variant”’ situations have caused transfusion fatalities. They have been mainly encountered in patients lacking the Hr S and RH46 high incidence antigen. We described two fatal cases with the DAR-ceAR haplotype at the homozygous state in SCD patients. They produced both anti-RH18 and anti-D. 32 Those cases have pointed out the need to store RH:-18 RBCs in the frozen rare bank. Other fatal cases with anti-Hr S and anti-RH46 were described in the eighties. 42 Clinical significance has been shown for an anti-c developed by an African American woman with ce S (340) at the homozygous state. 36 For the other variants, except the anti-Goa case, there is no published data on the occurrence of DHTR with demonstration of the responsibility of an antibody prone by a partial in the carrier or prone by another low incidence antigen in the donor. In some published cases of DHTR, some antibodies prone by variants are developed in a mixture of antibodies and are sometimes detected following the DHTR. 5,37,43,44 Within eight cases of DHTR in SCD children, we found one partial C (encoded by a RN) patient who experienced DHTR with production of anti-C at distance of the episode 45 Data are dramatically lacking regarding the involvement of variants in DHTR. One reason could be the rarity of the situation. It is specially the case for the anti-e like antibodies produced by e variant carriers. In some severe cases of DHTR in SCD, many patients are being identified who have developed red cell auto-antibodies. It is possible that in some cases, the auto antibodies have been mislabeled because the laboratory could not perform molecular analysis to type for variants. It is important that the biologist keep in mind that an auto-anti-e or a pan agglutinin could be a real allo antibody linked to variants carried by the patient. Therefore, the reasons for the absence of data regarding occurrence of DHTR in RH variant patients can be the absence of careful laboratory evaluation in case of DHTR, but can also be a low clinical relevance of variants. Considering the second reason, what would be the point to detect variants and to take into account the associated antibodies if only few of them reveal a clinical relevance? This question is a real issue as many costly tools are developed to type RH variants, and management of transfusion in a variant carrier can be very tricky. However, if not directly involved in DHTR, variants could eventually promote allo-immunization to clinically significant antibodies (Fy, Jk, S) or to auto-antibodies that can compromise their clinical care. Some authors defend the hypothesis that occurrence of one antibody is a risk factor for the occurrence of many more antibodies. 8 Zimring et al. proposed an interesting hypothesis in which non exofacial polymorphisms (NEPs) contribute to the immunogenicity of blood group antigens, and provide a mechanism by which transfusion can lead to anti- RBC auto-antibodies. 46 Many of the RH variants encountered in individuals of African descent have NEPs. Other intriguing questions about RH variants and SCD transfusion In case of investigation of anti-e like antibody in SCD transfused patients, in our experience and in experiences of others, it happens that DNA analysis shows the presence of an altered allele, frequently the ce S allele or the (C)ce S haplotype, and in trans a normal ce or Ce allele. 9,47 From an immunology standpoint, there is no reason for the patient to produce an anti-e alloantibody. In other words, the anti-e like antibody cannot be considered as an allo antibody in a case of heterozygous abnormality compensated by a normal haplotype in trans. One case has been recently described in which the result of DNA analysis has contributed to hematopoietic stem cell transplantation. 48 The patient produced anti-e like antibody but carried only one (C)ce S . The authors concluded to an allo antibody despite a normal Dce haplotype in trans, based on serological absorption studies. It remains that this antibody did not induce DHTR in the child, and disappeared during the bone marrow graft procedure. This case points out the real need to implement, not only a register for allo-immunization but also a register for clinically significant antibodies. In this time of development of DNA analysis, it became a real issue to define the features of a significant antibody in SCD patients, especially those linked to RH variants. The second tricky situation is when the patient is found with a heterozygous composite background, the two different variants alleles encoding a known partial | 378 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)
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H e m a t o l o g y E d u c a t i o
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Copyright Information ©2011 by Eur
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Editorial Board Education Book Edit
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Acute lymphoblastic leukemia 1-8 Th
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S. Schnell P. Van Vlierberghe A. Fe
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lineage cells, and in differentiati
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FLT3 mutations The FMS-like tyrosin
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44. Bar-Eli M, Ahuja H, Foti A, Cli
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J.M. Rowe 1,2 C. Ganzel 1 1 Shaare
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treated on the MRC UKALL XII/ECOG29
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asparaginase (PEG), where the Esche
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or higher. It is, however, importan
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25. Bruggemann M, Schrauder A, Raff
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lymphoblastic leukemia: prospective
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such as high white blood cell count
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doxorubicine, there was a trend tow
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of the aging process with respect t
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K.L. Rice 1 M. Buzzai 2 J. Altman 1
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ing FLT3-ITD, wild-type NPM1, or bo
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ciated with gene activation, via th
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leukemia with inv(16) and t(8;21):
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99. Parsons DW, Jones S, Zhang X, e
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abnormalities, some of which are al
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file. 27,31 Thus, the double gene-m
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karyotype represents a distinct gen
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Table 1. Meta-analysis of 23 random
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A recent study by the Center for In
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Patients with HLA-matched related o
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After allogeneic HSCT, an autologou
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A. Bacigalupo Ospedale San Martino,
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Table 2. The effect of HLA mismatch
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References 1. Petersdorf EW, Malkki
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neutrophil and platelet recovery an
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Figure 2. One Year-Overall Survival
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infused on day 21. No serious adver
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W, et al. Effect of graft source on
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TRM was higher for patients who rec
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following a myeloablative preparati
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effect. Surprisingly, none of the p
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nancies. Bone Marrow Transplant. 20
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J.G. Gilles Center for Molecular an
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14C12 was humanized by grafting VH
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Table 1. VWD Classification. VWD Su
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Figure 1. Missense mutations found
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associated with an increased bleedi
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49. Brown SA, Eldridge A, Collins P
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leed. These issues are especially i
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estored function. 43,44 A phase I t
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years’ experience of prophylactic
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J.A. Burger Department of Leukemia,
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chemotaxis, migration across vascul
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Regulatory T cells (T reg), identif
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16. Burger JA, Ghia P, Rosenwald A,
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TE, Nowakowski GS, et al. CD49d exp
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andomized trial demonstrating impro
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Conclusions Chemoimmunotherapy has
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with multiple comorbidities (≥ 2)
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ment was finished in all 100 patien
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Table 2. Treatment recommendation f
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34. Ferrajoli A. The combination of
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to be the source of additional gene
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potential to prevent LSCs from acce
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ABL1 confirms that eradication of d
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65. Fiskus W, Pranpat M, Balasis M,
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alive after 10 years. 11 Hence, CCy
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each arm). A minimal change in myel
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Any discussion about the definition
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H. Kantarjian J. Cortes Leukemia De
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59%; the CCyR rate was 44%. Among p
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ern era of BCR-ABL1 tyrosine kinase
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the hematopoietic system, 10 nor in
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over the period of 6 weeks, demonst
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Data on clonal changes in the blood
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2006 Feb 1;107(3):924-30. 41. Liang
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demonstrated that changes in osteob
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“Mafia” transgenic mice in whic
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68. Coetzee T, Fujita N, Dupree J,
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ization. In WASP deficiency, lympho
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Currently the epistatic relationshi
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R. Küppers Institute of Cell Biolo
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Figure 1. TNFAIP3 mutation in HL ce
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Figure 2. HRS cells and their precu
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Hansmann ML, et al. Detection of cl
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fying patients for whom different a
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prognosis HL, whilst those with res
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12. Noordijk EM, Carde P, Dupouy N,
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A. Sureda Consultant in Haematology
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Figure 1. Long-term outcome of pati
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from a MRD and 18 from MUDs. All pa
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Parker PM, Stein AS, et al. High-do
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R. Stasi Department of Haematology,
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common variants in the regulatory r
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against the TPO receptor (cMpl). 61
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W.B. Mitchell A.A. Miller J.B. Buss
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platelet counts and/or bleeding. Th
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Mpl. Cell. 1994;77(7):1117-24. 6. d
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ity and mortality associated with t
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to azathioprine, and is particularl
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stemming from antibodies against PE
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L. Pasqualucci Institute for Cancer
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cation of molecularly distinct subg
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of cases) 46 and amplifications of
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gene alterations in B cell lymphoma
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W. Wilson National Cancer Institute
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clear distinction among the lymphom
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Treatment strategies in germinal ce
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in ABC DLBCL (Hernandez et al., 201
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DLBCL that mostly occurs in young p
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phoma. J Clin Oncol. 2005;23:5347-5
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Table 1. Diffuse Large B cell Lymph
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sion/relapse are similar to those i
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intensive therapy with curative int
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A. Karsan Genome Sciences Centre an
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Balanced translocations In contrast
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some arm 5q have also been implicat
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(H3K27) methyltransferase, and is a
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38. Starczynowski DT, Morin R, McPh
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G. Garcia-Manero Department of Leuk
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trial evaluating different doses an
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acid. 62 The second was a large mul
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Borthakur G, et al. Cause of death
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P. Krishnamurthy 1 G.J. Mufti 1,2 1
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etween 1995 and 2005. 11 Five hundr
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London, United Kingdom, June 9-12,
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attainment of FDC post DLI. Interes
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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
Page 336 and 337: example, improving blood viscosity
Page 338 and 339: 92(9):1266-7. 36. Bensinger TA, Gil
Page 340 and 341: London, United Kingdom, June 9-12,
Page 342 and 343: port have also been used. 5 Combina
Page 344 and 345: Wingard JR, Young J-AH, Boeckh MJ.
Page 346 and 347: K. Rezvani 1 J. Barrett 2 1 Haemato
Page 348 and 349: include the childhood infectious il
Page 350 and 351: Summary Patients undergoing hematop
Page 352 and 353: Table 1. Key issues. In a retrospec
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Page 358 and 359: T.M. Hackeng Department of Biochemi
Page 360 and 361: and inhibits FVIIa, and that the se
Page 362 and 363: Figure 4. Regulation of coagulation
Page 364 and 365: T. Baglin Department of Haematology
Page 366 and 367: Figure 1. Illustration of alternati
Page 368 and 369: compared with 3.5% in patients with
Page 370 and 371: 49. Hron G, Kollars M, Binder BR, E
Page 372 and 373: Women receiving vitamin K antagonis
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Page 376 and 377: eral morbidity and mortality. 17-21
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Page 380 and 381: Goals of future murine studies incl
Page 382 and 383: F. Noizat-Pirenne C. Tournamille Et
Page 384 and 385: phenotype. 26 In 2010, we investiga
Page 388 and 389: antigen. Cases can be encountered d
Page 390 and 391: S.R. Sloan Harvard Medical School &
Page 392 and 393: We also analyzed patient databases
Page 394 and 395: Index of authors Altman J. 27 Bacig
Page 396 and 397: Cornelissen J. Affiliations to disc
Page 398 and 399: GlaxoSmithKline (Research Support;
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