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each arm). A minimal change in myelosuppression rates was observed with additional 12 months followup. With a minimum follow-up of 24 months, only slight increases were observed in anemia (1% for both the nilotinib arms) and neutropenia (1% for each the nilotinib 400 mg BID and imatinib arms) compared with the 12-month minimum follow-up. Lipase and amylase elevation was rare and in most cases asymptomatic. Hyperglycemia occured significantly more often on nilotinib, whilst imatinib had the potential to reduce serum glucose levels. By 24-month, one patient in the imatinib arm had a QTcF greater than 500 msec but no patient in any of the nilotinib arms had a QTcF greater than 500 msec. No patient in the study had a decrease in left ventricular ejection fraction less than 45%. Discontinuations due to AEs occurred in 6% of patients on nilotinib 300 mg BID, 10% on nilotinib 400 mg BID, and 9% on imatinib. A total of 26 patients died (11 in the imatinib arm, 9 in the nilotinib 300 mg BID arm, and 6 in the nilotinib 400 mg QD arm). 34,35 Dasatinib. In the international phase 3 DASISION trial, dasatinib showed higher and faster rates of CCyR and MMR versus imatinib in patients with newly diagnosed CML-CP. Patients were randomized to receive dasatinib 100 mg once daily (n=259) or imatinib 400 mg QD (n=260). Primary endpoint was confirmed CCyR (cCCyR; CCyR on 2 consecutive evaluations) by 12 months. After a median of 18 months of therapy, 81% and 80% of patients remained on dasatinib and imatinib, respectively. Response rates were higher for dasatinib versus imsatinib, including cCCyR by 18 months (78% vs. 70%; p=0.037) and MMR (57% vs. 41%; p=0.0002). Thirteen percent versus 7% achieved a BCR-ABL1 level less than or equal to 0.0032% (CMR 4.5 ). Six (2.3%) versus 9 (3.5%) patients transformed to accelerated/blast phase on study, and 18-month progression-free survival rates were 94.9% versus 93.7%. Rates of grade 3/4 nonhematologic AEs were less than or equal to 1%. Pleural effusion were seen only with dasatinib (2% grade 1, 9% grade 2,
16 th Congress of the European Hematology Association rates have been associated with lower risk of transformation. In addition, population-based analysis have suggested that the rate of imatinib failure might be higher than reported in IRIS, 41,42 with a 5-year EFS of 63%. 41 With these results, the possible benefit of earlier responses could be magnified, provided these results can be reproduced in similar population-based analysis. Treatment discontinuation and operational cure Among the most intriguing clinical questions remaining in the management of CML is whether patients could eventually discontinue therapy and be cured. The current recommendation is to continue therapy indefinitely. Early attempts at treatment discontinuation among patients with CMR suggested that most patients relapsed. 43–45 However, some patients remained in remission and it was suggested that prior IFNa use could contribute to a sustained response. 43 As mentioned earlier, in the STIM trial, 59% of patients relapsed after treatment discontinuation. 18 Although longer follow-up is needed, the fact that approximately 40% of patients had not relapsed is a promising finding. An important task is to identify what characteristics make these patients remain in remission. In aiming for treatment discontinuation and cure for all patients, two goals should be accomplished. One is to make treatment discontinuation available to all patients. Only patients with sustained CMR for greater than or equal to 2 years were eligible for the STIM trial. How often patients treated with imatinib reach this milestone is unclear. A recent analysis suggested that, after a median follow-up of 79 months, only 32% of all imatinib-treated patients achieved sustained CMR, 17 but other studies have suggested that approximately two-thirds of patients may reach this hallmark. 15 One approach to increase the number of patient achieving CMR is the use of vaccines to trigger an anti-CML immune response. Several approaches have been reported, including a junction BCR-ABL1 peptide, 46 a proteinase-3-derived peptide (PR1), 47 heat-shock protein, 48 or GM-CSF-transfected K562 cells. 49 Although immune responses have been reported with all of them, the clinical results have been mixed. A study using the BCR-ABL1 junction peptide reported 41% of patients achieving CMR after vaccination. 50 The second important element is to develop approaches that decrease the probability of relapse after treatment discontinuation. In one study, patients received IFNa as they discontinued imatinib. Three patients achieved CMR after imatinib discontinuation and, after more than 2 years of follow-up, 75% of patients remained in remission. 51 Intriguingly, some patients did not relapse despite the persistence of low levels of BCR-ABL1 transcripts. Although preliminary, these results suggest that IFNa might aid in maintaining responses. Alternative strategies are looking at targets directed to the leukemic stem cell, such as inhibition of the Smo/Hedgehog pathway. 52 Trials with these agents have been initiated. However, for the moment, all patients should continue therapy indefinitely unless they are enrolled in clinical trials exploring treatment discontinuation. Toward the path to a cure: achievement and maintenance of CMR Several groups are assessing the discontinuation of TKIs following the achievement of sustained CMR. The STIM study, the most mature of its kind, prospectively assessed imatinib discontinuation in 100 CML patients in CMR 5 more than 2 years in duration. 18 n the interim analysis (median 17 months follow-up after imatinib discontinuation), 42 of 69 (61%) patients relapsed, with 98% of relapses occurring in the first 7 months following discontinuation of imatinib. At 12 months, the probability of persistent CMR was 41%. All patients who relapsed responded to reintroduction of imatinib, with 26 achieving sustained CMR. Interestingly, the kinetics of response in these patients was heterogeneous. Along with factors identified in a univariate analysis for prediction of relapse (Sokal score, gender, duration of imatinib therapy), perhaps the time to and duration of prior CMR might also influence the rate and kinetics of relapse in patients on discontinuation studies. Whatever the path to CMR, the ultimate goal should be to use the achievement and maintenance of CMR as a marker for allowing patients to stop TKI therapy, in the context of a clinical trial. Such a pan-European clinical study is currently in preparation by the ELN. The need for CMR definition and standardization With more patients likely to achieve CMR moving forward and with more treatment cessation studies to come, it is essential that standardized definitions of CMR are used. CMR is defined by the ELN as undetectable BCR-ABL1 mRNA transcripts by reverse transcriptase quantitative PCR (RQ-PCR) and/or nested PCR in two consecutive high-quality samples (sensitivity >10 4 ). 10 In laboratories with the most sensitive RQ- PCR techniques available, CMR typically constitutes confirmed and consistent undetectable BCR-ABL1 transcript levels with an assay sensitivity of 4-, 4.5- or 5-logs (CMR 4 , CMR 4.5 , or CMR 5 , respectively). DNA-based PCR of BCR-ABL1 has been evaluated previously to monitor patients for any detectable presence of the Philadelphia chromosome in cells that may not be actively expressing BCR-ABL1 mRNA. 53 This study found that a proportion of patients with undetectable transcript levels and RQ-PCR negativity demonstrated positivity for BCR-ABL1 via DNA-based PCR. This was presumably due to the presence of dormant CML stem cells expressing very low levels of BCR-ABL1 RNA below the limit of detection. The alternative was also observed in two patients, where patients were positive for BCR-ABL1 by RQ-PCR but demonstrated DNA negativity. These examples raise questions of assay sensitivity and sample quality, as well whether DNA and RNA samples should be required from the peripheral blood and bone marrow. Still, results from these studies suggest that DNA-PCR, coupled with traditional RQ-PCR, may provide additional information to help the clinician make an informed decision on therapeutic approaches for individual patients. | 124 | 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
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
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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 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
Page 178 and 179: from a MRD and 18 from MUDs. All pa
Page 180 and 181: 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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