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

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65. Fiskus W, Pranpat M, Balasis M, Bali P, Estrella V, Kumaraswamy S, et al. Cotreatment with vorinostat (suberoylanilide hydroxamic acid) enhances activity of dasatinib (BMS-354825) against imatinib mesylate-sensitive or imatinib mesylate-resistant chronic myelogenous leukemia cells. Clin Cancer Res. 2006 Oct 1;12(19):5869-78. 66. Fiskus W, Pranpat M, Bali P, Balasis M, Kumaraswamy S, Boyapalle S, et al. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Blood. 2006 Jul 15;108(2):645-52. 67. Nimmanapalli R, Fuino L, Bali P, Gasparetto M, Glozak M, Tao London, United Kingdom, June 9-12, 2011 J, et al. Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or - refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res. 2003 Aug 15;63(16):5126-35. 68. Zhang B, Strauss AC, Chu S, Li M, Ho Y, Shiang KD, et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell. 2010 May 18;17(5):427-42. 69. Sengupta A, Arnett J, Dunn S, Williams DA, Cancelas JA. Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo. Blood. 2010 Jul 8;116(1):81-4. Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 119 |
A. Hochhaus Universitätsklinikum Jena, Klinik für Innere Medizin II, Abteilung Hämatologie und internistische Onkologie, Jena, Germany Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:120-126 Chronic myeloid leukemia Management of newly diagnosed chronic myeloid leukemia patients Introduction The evolution in the understanding of the biology of chronic myeloid leukemia (CML) that eventually translated into the development of specific, highly effective therapy is unparalleled in oncology. In 1960, a minute G-chromosome was identified in patients with CML. 1 In 1973, the abnormality was more specifically described as a balanced translocation between chromosomes 9 and 22, 2 with the formation of a chimeric gene, BCR-ABL1 3 that translates into a protein with increased and dysregulated tyrosine kinase activity. 4 The realization of the critical role this protein plays in the pathogenesis of CML 5 led to a search for specific inhibitors and resulted in the development of imatinib. 6 After a series of clinical trials, imatinib became standard therapy in CML. The IRIS trial in which patients with CML in chronic phase (CP) were randomized to receive imatinib or interferon alpha (IFNa) plus ara-C established imatinib as the standard therapy. 7 With 8 years of follow-up on this study, the results are outstanding. A complete cytogenetic response (CCyR) was achieved in 83% of patients, with a projected 8-year eventfree survival (EFS) of 81% and overall survival of 85%. 8 In this trial, 17% of patients never achieved CCyR, approximately 15% achieved CCyR but eventually lost it, and nearly 5% were intolerant to imatinib. Thus, approximately one-third of all patients did not have an acceptable outcome. Following the lead of imatinib development, second-generation tyrosine kinase A B S T R A C T The BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib has been the standard first-line therapy for chronic myeloid leukemia (CML) for almost 10 years. High-dose imatinib and imatinib in combination with interferon alpha are options to increase the efficacy of TKI therapy. Dasatinib and nilotinib, two newer drugs with higher potency than imatinib against BCR-ABL1 and activity against most imatinibresistant BCR-ABL1 mutations, have each shown superior efficacy compared with imatinib for firstline treatment of chronic-phase CML in randomized phase 3 trials. With 18–24 months follow-up time, no differences in overall survival were observed between imatinib and the second generation drugs. Available data suggest no differences in efficacy between dasatinib and nilotinib. Compared with imatinib, dasatinib is associated with higher rates of pleural effusion and thrombocytopenia, but lower rates of edema, gastrointestinal, or musculoskeletal adverse effects, and rash. Nilotinib is associated with higher rates of dermatologic toxicity and biochemical abnormalities associated with hepatic and pancreatic toxicity compared with imatinib, but lower rates of edema, gastrointestinal adverse effects, muscle spasms, and neutropenia. New studies are in preparation or ongoing to test the option to cure CML with novel TKI alone or in combination. inhibitors (TKI) were created shortly after imatinib failure began to be identified. An initial important step was the identification of mutations in the tyrosine kinase domain as the most common mechanism of resistance. 9 This was soon followed by the development of new agents with higher binding affinity to BCR-ABL1, even in the presence of most known mutants. Two of these agents, dasatinib and nilotinib, have been most extensively studied. The excellent results obtained with imatinib when used as initial therapy and the availability of effective salvage therapy redefined the CML treatment algorithm. Nearly all patients are offered therapy with imatinib or a second generation TKI at diagnosis and for those with failure to therapy. 10 an alternative TKI is indicated. With this approach, the median survival for CML patients will probably exceed 20 years. Still, as we understand the disease better and improve the outcome of patients, we have uncovered new challenges and important questions that demand attention. What should we aim for in chronic myeloid leukemia therapy? For many years, IFNa was the standard therapy for CML (besides allogenic stem cell transplantation) as it induced cytogenetic remissions in a significant number of patients. Importantly, it was established that patients that achieved CCyR had a significant improvement in survival, with 78% | 120 | 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
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
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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
Page 122 and 123: to be the source of additional gene
Page 124 and 125: potential to prevent LSCs from acce
Page 126 and 127: ABL1 confirms that eradication of d
Page 130 and 131: alive after 10 years. 11 Hence, CCy
Page 132 and 133: each arm). A minimal change in myel
Page 134 and 135: Any discussion about the definition
Page 136 and 137: H. Kantarjian J. Cortes Leukemia De
Page 138 and 139: 59%; the CCyR rate was 44%. Among p
Page 140 and 141: ern era of BCR-ABL1 tyrosine kinase
Page 142 and 143: the hematopoietic system, 10 nor in
Page 144 and 145: over the period of 6 weeks, demonst
Page 146 and 147: Data on clonal changes in the blood
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
Page 170 and 171: prognosis HL, whilst those with res
Page 172 and 173: 12. Noordijk EM, Carde P, Dupouy N,
Page 174 and 175: A. Sureda Consultant in Haematology
Page 176 and 177: Figure 1. Long-term outcome of pati
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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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