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

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J.M. Rowe 1,2 C. Ganzel 1 1 Shaare Zedek Medical Center, Jerusalem, Israel; 2 Technion, Israel Institute of Technology, Haifa, Israel Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:9-19 Acute lymphoblastic leukemia Management of acute lymphoblastic leukemia in adults The treatment of adults with acute lymphoblastic leukemia (ALL) remains challenging. While there has been a gradual improvement in the overall results over the past 40 years, the long term survival from diagnosis for adults less than 60 years is still no more than 35–40%. The therapeutic options have increased over the past decade to include a better understanding of the indications for transplantation and a broadening of the number of patients who are eligible for such a procedure. New drugs, as well as potential targeted monoclonal antibodies, have opened up novel areas for study in the management of ALL. Sensitive techniques for the detection of minimal residual disease have also opened new strategies for post remission management. This paper will focus on the management of young adults, up to age 60 years, and will include both patients who are Philadelphia chromosome negative ALL, as well as those who are positive. Most of the discussion will focus on newly diagnosed patients. Prognostic factors At presentation It has long been realized that the management of patients with ALL is dependent on the prognostic factors at diagnosis. Patients with known very high risk features are often assigned different post remission strategies, even if the induction therapy is not always altered. Decisions regarding the appropriateness of bone marrow transplantation are also dependent on the prognostic factors at diagnosis. Over the past four decades, there has been a shift in the understanding of the prognostic factors such that morphology 1 and cytochemistry, 2 so dominant in the 1970s, have no prognostic significance nowadays. Even immunophenotyping, which was the dominant determining factor for several decades since the 1980s, is rapidly becoming less important for prognostication, even if its use remains crucial for the initial diagnosis, for the detection of minimal residual disease, and for the application of specific and targeted therapies. Thus, although B- and T-lineage patients are often treated differently, the level of maturity within B-lineage is no longer important for prognosis, 3,4 although among T-lineage patients, there appears to be a difference depending on the level of maturity. 5 At the same time, certain immunologic markers have been recognized as having significant prognostic impact, the most important of these being CD20, which, in several trials, has been reported among adults with B-lineage ALL to have a low complete remission rate and inferior overall survival. 6,7 While these historic prognostic factors clearly have relevance, they have now been mostly superseded by genetic and/or molecular markers leading to a changing paradigm, incorporating cytogenetics and molecular determinants 8 (Figure 1). The importance of immu no phenotyping for assigning specific targeted therapies against antigenic determinants for B or T-cell ALL, such as nelarabine, foro desine, or monoclonal antibodies, 9–11 will be fully discussed in the Therapy section. Age has withstood the test of time and remains the most important prognostic factor in ALL that is unlikely to be superseded by any of the new molecular determinants. Not only are there enormous differences in prognosis between childhood and adult ALL, but age also critically affects the prognosis within adult groups. Although most clinical studies have used an arbitrary cutoff of 35 or 40 years, 12–14 the prognostic significance of age, in fact, is a continuum between ages 20 and 60. 14 The prognostic classification in ALL, much like AML, is now moving rapidly towards cytogenetics and molecular markers. The Philadelphia chromosome, t(9;22) (q34;q11), remains the most frequent and clinically significant abnormality in adult ALL, with an incidence that increases with age, reaching 50% among older adults with B-lineage. 15 The importance of determining the presence of the Philadelphia chromosome at diagnosis, either by cytogenetics or by molecular detection of BCR-ABL, cannot be overstated, as the entire approach to such a patient is different (see Philadelphia chromosome-positive ALL section). Among patients who are Philadelphia chromosome-negative, management is also affected by cytogenetics (Table 1) and this categorization has a major impact on choosing the appropriate therapy for ALL. 16 In the past, due to the relative rarity of ALL in adults, the precise prognostic significance of many of the recurring cytogenetic abnormalities could not be determined due to the relatively small numbers. The analysis of cytogenetics among patients Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 9 |
16 th Congress of the European Hematology Association Figure 1. The evolving paradigm of prognostic factors for ALL in adults. Reproduced from Rowe et al, Br J Haematol, 2010, 150, 389-405; with permission. | 10 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)
Page 1 and 2: H e m a t o l o g y E d u c a t i o
Page 3 and 4: Copyright Information ©2011 by Eur
Page 5 and 6: Editorial Board Education Book Edit
Page 7 and 8: Acute lymphoblastic leukemia 1-8 Th
Page 10 and 11: S. Schnell P. Van Vlierberghe A. Fe
Page 12 and 13: lineage cells, and in differentiati
Page 14 and 15: FLT3 mutations The FMS-like tyrosin
Page 16 and 17: 44. Bar-Eli M, Ahuja H, Foti A, Cli
Page 20 and 21: treated on the MRC UKALL XII/ECOG29
Page 22 and 23: asparaginase (PEG), where the Esche
Page 24 and 25: or higher. It is, however, importan
Page 26 and 27: 25. Bruggemann M, Schrauder A, Raff
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
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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
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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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