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TE, Nowakowski GS, et al. CD49d expression is an independent predictor of overall survival in patients with chronic lymphocytic leukaemia: a prognostic parameter with therapeutic potential. Br J Haematol. 2008 Mar;140(5):537-46. 97. Spaargaren M, Beuling EA, Rurup ML, Meijer HP, Klok MD, Middendorp S, et al. The B cell antigen receptor controls integrin activity through Btk and PLCgamma2. J Exp Med. 2003 Nov 17;198(10):1539-50. 98. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010 Apr 1;115(13):2578-85. 99. Burger JA, O’Brien S, Fowler N, Advani R, Sharman JP, Furman RR, et al. The Bruton’s Tyrosine Kinase Inhibitor, PCI-32765, Is Well Tolerated and Demonstrates Promising Clinical Activity In Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): An Update on Ongoing Phase 1 Studies. Blood. 2010 November 19, 2010; 116(21):32a. 100. Furman RR, Byrd JC, Brown JR, Coutre SE, Benson DM, Jr., Wagner-Johnston ND, et al. CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110{delta}, Demonstrates Clinical Activity and Pharmacodynamic Effects In Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Blood. 2010 November 19, 2010;116(21):31a. 101. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al. The Bruton tyrosine kinase inhibitor PCI- London, United Kingdom, June 9-12, 2011 32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proce Natl Acad Sci U S A. Jul 20;107(29):13075-80. 102. Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, et al. CAL-101, a p110{delta} selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011 Jan 13;117(2):591-4. 103. de Gorter DJ, Beuling EA, Kersseboom R, Middendorp S, van Gils JM, Hendriks RW, et al. Bruton’s tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007 Jan;26(1):93-104. 104. Majid A, Lin TT, Best G, Fishlock K, Hewamana S, Pratt G, et al. CD49d is an independent prognostic marker that is associated with CXCR4 expression in CLL. Leuk Res. 2010 Nov 17. 105. Eistere W, Hilbe W, Stauder R, Bechter O, Fend F, Thaler J. An aggressive subtype of B-CLL is characterized by strong CD44 expression and lack of CD11c. Br J Haematol. 1996 Jun;93(3): 661-9. 106. Redondo-Munoz J, Ugarte-Berzal E, Garcia-Marco JA, del Cerro MH, Van den Steen PE, Opdenakker G, et al. Alpha4beta1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells. Blood. 2008 Jul 1;112(1): 169-78. 107. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006 Mar 1;107(5):1761-7. Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 99 |
J.G. Gribben Barts Cancer Institute, Barts and The London School of Medicine, Queen Mary University of London, United Kingdom Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:100-103 Chronic lymphocytic leukemia Updating treatment of chronic lymphocytic leukemia Introduction The clinical course of chronic lymphocytic leukemia (CLL) is extremely heterogeneous. Some patients will live for decades and never require treatment, while others require immediate treatment1 . A major focus of research has been to try to identify those clinical and biological factors that influence the clinical course to help determine whether patients will have indolent disease or rapid progression, and which patients will respond best to which treatment2 . High risk features predictive of disease progression include deletion (del) 17p and del 11q, IgVH unmutated status, use of the IGHV3-21 gene segment, and expression of either ZAP70 or CD38. It remains a major challenge to understand how these biomarkers can be used in clinical practice and whether the detection of “high-risk” features will alter treatment offered. Therefore, assessment of the impact of these biomarkers remains a vital component of research studies. Treatment of CLL The results of clinical trials in previously untreated CLL have demonstrated major advances over the last decade. The best outcomes have been reported with chemoimmunotherapy, the most active combination described being the three drug regimen of fludarabine, cyclophosphamide, and rituximab (FCR). Phase II clinical studies at the MD Anderson Cancer Center evaluated FCR in previously untreated, 3-4 as well as in treated patients 5 . In a series of 300 previously untreated patients, overall response rate (ORR) was 95%, with 72% achieving complete remission (CR) CR, 7% complete remission with incomplete bone marrow recovery (Cri), 10% nodular partial response (PR) and 6% PR and at a 6 year median follow-up, overall survival (OS) was 77% and progression free survival (PFS) 51%. 4 Importantly, these findings were confirmed A B S T R A C T Over the past decade there have been tremendous advances in the treatment of chronic lymphocytic leukemia (CLL), with the goal of therapy no longer being just to palliate symptoms, but now to achieve complete remission and improve survival. Front line chemo-immunotherapy approaches now offer prolonged survival. However, novel treatment approaches are required for those patients who do not respond or relapse following this therapy, as well as for those who are too frail to tolerate these approaches. Numerous novel agents are being developed and their role in the frontline treatment of frail patients or those who relapse after previous treatment is being explored in ongoing clinical trials. in a phase III clinical trial demonstrating the advantage of chemo-immunotherapy. The German CLL Study Group (GCLLSG) CLL8 randomized clinical trial demonstrated a significant improvement in response rates, duration of response, and overall survival with FCR compared with FC. 6 Although this clearly represents a major advance, many patients with CLL are not suitable candidates for FCR therapy and for this population, new approaches are needed. Notwithstanding, the improved results with first line therapy in fit patients with CLL, the disease remains incurable, and CLL patients are destined to relapse after primary treatment. The management of relapsed CLL patients is dependent upon age, performance status, previous therapy, response, and duration of response to therapy. The goal of therapy, whether palliative or aggressive, must also be weighed into the decision when deciding on the next line of treatment. With many potential treatments available in clinical trials, the sequence of treatments and the timing of procedures, such as stem cell transplantation (SCT), remain questions being addressed in clinical trials. With improvement in therapy, as some groups respond better to newer treatment combinations, it is likely that the prognostic significance of some of these parameters will change. Of particular significance is the detection of cases with del 17p. These patients have poor outcomes using even optimal chemo-immunotherapy approaches, and novel agents are required for this group of patients. Presently, alemtuzumab alone or in combination is a reasonable option for patients with del 17p or p53 mutations, since this agent has been shown to have efficacy in this patient population. 7 Novel agents in clinical trials Bendamustine is a potent alkylating agent widely used in Germany and approved for use in CLL in the USA in 2008 based on a | 100 | 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
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 74 and 75: TRM was higher for patients who rec
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 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
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 128 and 129: 65. Fiskus W, Pranpat M, Balasis M,
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
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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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