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ently results in a less than 5% cumulative incidence of CNS relapse at 5 years (from 0.8% to 5%). 14 How to treat initial CNS involvement or CNS relapse? 1. CNS3 pts This problem has been evoked in the previous section (see also “Table 5”). The importance of the systemic treatment for these patients must be emphasized again, particularly in protocols trying to omit irradiation. As an example, the CNS 3 pts, treated without CNS irradiation in the EORTC 58881, received either 9 or 10 courses of HD MTX (5 g/m 2 ), depending on their other riskcriteria. 21 Their prognosis in that trial conducted in the beginning of the 1990s did not differ from the one of the CNS1 pts (8 year EFS 68.3 % versus 69.7%). 21 Also, in the DCOG ALL-9 study, considering CNS3 as a highrisk criterion per se, a 5-year EFS of 67% was observed, with an overall survival of 80%. 33 These results compare favorably to those of the BFM-95 (5-year EFS: 50%), obtained with the use of a 18gy cranial irradiation after 4 courses of HD-MTX (5 g/m 2 ). 5 2. CNS relapse As CNS relapses are rare and first line treatments are evolving, no gold standard exists. A recent study from the UKALL MRC group, reviewing the outcome of 5,564 children with ALL, treated from 1985 to 2001, has shown a marked trend towards a decrease in combined relapses, with a progressive shift towards later relapses (≥ 30 months). 59 Although isolated relapses declined, the proportional incidence and timing of relapses remained unchanged. CNS relapses in the UK MRC studies thus represent 18% of all relapses and are very early relapses (i.e. CR1 < 18 months) in roughly 37% of the cases. 59 The main points to be considered when tailoring the treatment of a child with CNS relapseare the length of first remission (less than 18 months or not), the immunophenotype (T-cell ALL versus BCP-ALL), the characteristics of the CNS relapse (isolated or combined), the presence of minimal disease in the marrow, and a history of previous CNS irradiation. An additional prognostic factor found in B-lineage ALL is the NCI classification, with standard-risk NCI patients having the best prognosis after an isolated CNS relapse (even if there is some correlation between length of CR1 and NCI risk). 58,59 Due to this heterogeneity, to small numbers and sometimes to a long recruitment period, it is not surprising to find variable outcomes across the studies (Table 6). 58-63 Some common principles can nevertheless be accepted: – To delay cranial or cranio-spinal irradiation for 6 to 12 months allows initial intensification of systemic chemotherapy. This has led to second EFS rates of 70% to 80% in children with isolated CNS relapse. 58,61,62 – To reduce as much as possible the dose of irradiation, investigators of the Children’s Oncology Group have proposed that patients with an initial remission duration of
16 th Congress of the European Hematology Association References 1. Evans AE, Gilbert ES, Zandstra R. The increasing incidence of central nervous system leukemia in children. (Children’s Cancer Study Group A). Cancer 1970 Aug;26(2):404-9. 2. Lange B, Bostrom B, Cherlow JM, Sensel MG, La MK, Rackoff W, et al. Double-delayed intensification improves event free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood 2002;99:825-33. 3. Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood 2003;101:3809-17. 4. Hutchinson RJ, Gaynon PS, Sather H, Bertolone SJ, Cooper HA, Tannous R et al. Intensification of therapy for children with lower-risk acute lymphoblastic leukemia: long-term follow-up of patients treated on Children’s Cancer Group Trial 1881. J Clin Oncol. 2003;21: 790-97. 5. Bürger B, Zimmermann M, Mann G, Kühl J, Löning L, Riehm H, et al. Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia : significance of low leukocyte counts significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol. 2003 Jan 15;21(2):184-8. 6. Blaney SM, Poplack DG, Godwin K, McCully CL, Murphy R, Balis FM, et al. Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol. 1995;13:177-79. 7. Odom LF, Wilson H, Cullen J, Bank J, Blake M, Jamieson B, et al. Significance of blasts in low-cell-count cerebrospinal fluid specimens from children with acute lymphoblastic leukemia. Cancer. 1990 Oct 15;66(8):1748-54. 8. Renshaw AA, Hughes JH, Wang E, Haja J, Wilbur D, Henry MR, et al. Cytopathology Resource Committee, College of American Pathologists. Leukemia/lymphoma in cerebrospinal fluid: distinguishing between cases that performed well and poorly in the College of American Pathologists Interlaboratory Comparison Program in Non-gynecologic Cytology. Arch Pathol Lab Med. 2006 Dec;130(12):1762-5. 9. Bromberg JEC, Breems DA, Kraan J, Bikker G, van der Holt B, Smitt PS, et al. CSF flow cytometry greatly improves diagnostic accuracy in CNS hematologic malignancies. Neurology 2007;68:1674-1679. 10. Scrideli CA, Queiroz RP, Takayanagui OM, Bernardes JE, Tone LG. Polymerase chain reaction on cerebrospinal fluid cells in suspected leptomeningeal involvement in childhood acute lymphoblastic leukemia: comparison to cytomorphological analysis. Diagn Mol Pathol. 2003 Sep;12(3):124-7. 11. Scrideli CA, Queiroz RP, Takayanagui OM, Bernardes JE, Melo EV, Tone LG, et al. Molecular diagnosis of leukemic cerebrospinal fluid cells in children with newly diagnosed acute lymphoblastic leukemia. Haematologica. 2004 Aug;89(8):1013-5. 12. Pine SR, Yin C, Matloub YH, Sabaawy HE, Sandoval C, Levendoglu-Tugal O, et al. Detection of central nervous system leukemia in children with acute lymphoblastic leukemia by real-time polymerase chain reaction. J Mol Diagn. 2005 Feb;7(1):127-32. 13. Sayed D, Badrawy H, Ali AM, Shaker S. Immuno - phenotyping and immunoglobulin heavy chain gene rearrangement analysis in cerebrospinal fluid of pediatric patients with acute lymphoblastic leukemia. Leuk Res. 2009 May;33(5):655-61. 14. Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol. 2008 Mar;9(3):257-68. 15. Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007 Jul 21;370(9583): 240-50. 16. Aricò M, Valsecchi MG, Camitta B, Schrappe M, Chessells J, Baruchel A, et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med. 2000 Apr 6;342(14): 998-1006. 17. Nachman JB, Heerema NA, Sather H, Camitta B, Forestier E, Harrison CJ, et al. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood. 2007 Aug 15;110(4):1112-5. 18. Mahmoud HH, Rivera GK, Hancock ML, Krance RA, Kun LE, Behm FG, et al. Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med. 1993 Jul 29; 329(5): 314-9 19. Gilchrist GS, Tubergen DG, Sather HN, Coccia PF, O’Brien RT, Waskerwitz MJ, et al. Low numbers of CSF blasts at diagnosis do not predict for the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: a Children’s Cancer Group report. J Clin Oncol. 1994 Dec;12(12):2594-600. 20. Pui CH, Campana D, Pei D, et al.: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360(26):2730-41. 21. Sirvent N, Suciu S, Rialland X, Millot F, Benoit Y, Plantaz D, et al. Prognostic significance of the initial cerebro-spinal fluid (CSF) involvement of children with acute lymphoblastic leukaemia (ALL) treated without cranial irradiation: results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group study 58881. Eur J Cancer. 2011 Jan;47(2):239-47. 22. Gajjar A, Harrison PL, Sandlund JT, et al. Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 2000;96(10): 3381-4. 23. Dutch Childhood Oncology Group, te Loo DM, Kamps WA, van der Does-van den Ber A, van Wering ER, de Graaf SS. Prognostic significance of blasts in the cerebrospinal fluid without pleiocytosis or a traumatic lumbar puncture in children with acute lymphoblastic leukemia: experience of the Dutch Childhood Oncology Group. J Clin Oncol. 2006 May 20;24(15):2332-6. 24. Hasegawa D, Manabe A, Ohara A, Kikuchi A, Koh K, Kiyo - kawa N, et al. The Tokyo Children’s Cancer Study Group. The utility of performing the initial lumbar puncture on day 8 in remission induction therapy for childhood acute lymphoblastic leukemia: TCCSG L99-15 study. Pediatr Blood Cancer. 2011 Jan 19. 25. Conter V, Schrappe M, Aricó M, Reiter A, Rizzari C, Dördelmann M, et al. Role of cranial radiotherapy for childhood T-cell acute lymphoblastic leukemia with high WBC count and good response to prednisone. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin- Frankfurt-Münster groups. J Clin Oncol. 1997;15(8):2786-91. 26. Jeha S, Pei D, Raimondi SC, Onciu M, Campana D, Cheng C, et al. Increased risk for CNS relapse in pre-B cell leukemia with the t(1;19)/TCF3-PBX1. Leukemia 2009 Aug;23(8):1406- 9. 27. Cario G, Izraeli S, Teichert A, Rhein P, Skokowa J, Möricke A, et al. High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the CNS. J Clin Oncol. 2007 Oct 20;25(30):4813-20. 28. Rocha JC, Cheng C, Liu W, Kishi S, Das S, Cook EH, et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood. 2005 Jun 15;105(12):4752-8. 29. Stanulla M, Schäffeler E, Arens S, Rathmann A, Schrauder A, Welte K, et al. GSTP1 and MDR1 genotypes and central nervous system relapse in childhood acute lymphoblastic leukemia. Int J Hematol. 2005 Jan;81(1):39-44. 30. Buonamici S, Trimarchi T, Ruocco MG, Reavie L, Cathelin S, Mar BG, et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature. 2009 Jun 18;459 (7249):1000-4. 31. Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM | 308 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)
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H e m a t o l o g y E d u c a t i o
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Copyright Information ©2011 by Eur
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Editorial Board Education Book Edit
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Acute lymphoblastic leukemia 1-8 Th
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S. Schnell P. Van Vlierberghe A. Fe
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lineage cells, and in differentiati
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FLT3 mutations The FMS-like tyrosin
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44. Bar-Eli M, Ahuja H, Foti A, Cli
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J.M. Rowe 1,2 C. Ganzel 1 1 Shaare
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treated on the MRC UKALL XII/ECOG29
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asparaginase (PEG), where the Esche
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or higher. It is, however, importan
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25. Bruggemann M, Schrauder A, Raff
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lymphoblastic leukemia: prospective
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such as high white blood cell count
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doxorubicine, there was a trend tow
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of the aging process with respect t
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K.L. Rice 1 M. Buzzai 2 J. Altman 1
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ing FLT3-ITD, wild-type NPM1, or bo
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ciated with gene activation, via th
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leukemia with inv(16) and t(8;21):
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99. Parsons DW, Jones S, Zhang X, e
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abnormalities, some of which are al
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file. 27,31 Thus, the double gene-m
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karyotype represents a distinct gen
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Table 1. Meta-analysis of 23 random
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A recent study by the Center for In
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Patients with HLA-matched related o
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After allogeneic HSCT, an autologou
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A. Bacigalupo Ospedale San Martino,
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Table 2. The effect of HLA mismatch
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References 1. Petersdorf EW, Malkki
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neutrophil and platelet recovery an
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Figure 2. One Year-Overall Survival
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infused on day 21. No serious adver
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W, et al. Effect of graft source on
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TRM was higher for patients who rec
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following a myeloablative preparati
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effect. Surprisingly, none of the p
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nancies. Bone Marrow Transplant. 20
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J.G. Gilles Center for Molecular an
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14C12 was humanized by grafting VH
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Table 1. VWD Classification. VWD Su
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Figure 1. Missense mutations found
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associated with an increased bleedi
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49. Brown SA, Eldridge A, Collins P
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leed. These issues are especially i
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estored function. 43,44 A phase I t
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years’ experience of prophylactic
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J.A. Burger Department of Leukemia,
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chemotaxis, migration across vascul
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Regulatory T cells (T reg), identif
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16. Burger JA, Ghia P, Rosenwald A,
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TE, Nowakowski GS, et al. CD49d exp
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andomized trial demonstrating impro
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Conclusions Chemoimmunotherapy has
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with multiple comorbidities (≥ 2)
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ment was finished in all 100 patien
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Table 2. Treatment recommendation f
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34. Ferrajoli A. The combination of
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to be the source of additional gene
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potential to prevent LSCs from acce
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ABL1 confirms that eradication of d
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65. Fiskus W, Pranpat M, Balasis M,
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alive after 10 years. 11 Hence, CCy
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each arm). A minimal change in myel
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Any discussion about the definition
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H. Kantarjian J. Cortes Leukemia De
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59%; the CCyR rate was 44%. Among p
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ern era of BCR-ABL1 tyrosine kinase
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the hematopoietic system, 10 nor in
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over the period of 6 weeks, demonst
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Data on clonal changes in the blood
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2006 Feb 1;107(3):924-30. 41. Liang
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demonstrated that changes in osteob
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“Mafia” transgenic mice in whic
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68. Coetzee T, Fujita N, Dupree J,
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ization. In WASP deficiency, lympho
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Currently the epistatic relationshi
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R. Küppers Institute of Cell Biolo
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Figure 1. TNFAIP3 mutation in HL ce
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Figure 2. HRS cells and their precu
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Hansmann ML, et al. Detection of cl
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fying patients for whom different a
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prognosis HL, whilst those with res
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12. Noordijk EM, Carde P, Dupouy N,
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A. Sureda Consultant in Haematology
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Figure 1. Long-term outcome of pati
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from a MRD and 18 from MUDs. All pa
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Parker PM, Stein AS, et al. High-do
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R. Stasi Department of Haematology,
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common variants in the regulatory r
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against the TPO receptor (cMpl). 61
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W.B. Mitchell A.A. Miller J.B. Buss
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platelet counts and/or bleeding. Th
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Mpl. Cell. 1994;77(7):1117-24. 6. d
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ity and mortality associated with t
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to azathioprine, and is particularl
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stemming from antibodies against PE
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L. Pasqualucci Institute for Cancer
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cation of molecularly distinct subg
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of cases) 46 and amplifications of
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gene alterations in B cell lymphoma
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W. Wilson National Cancer Institute
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clear distinction among the lymphom
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Treatment strategies in germinal ce
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in ABC DLBCL (Hernandez et al., 201
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DLBCL that mostly occurs in young p
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phoma. J Clin Oncol. 2005;23:5347-5
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Table 1. Diffuse Large B cell Lymph
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sion/relapse are similar to those i
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intensive therapy with curative int
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A. Karsan Genome Sciences Centre an
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Balanced translocations In contrast
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some arm 5q have also been implicat
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(H3K27) methyltransferase, and is a
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38. Starczynowski DT, Morin R, McPh
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G. Garcia-Manero Department of Leuk
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trial evaluating different doses an
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acid. 62 The second was a large mul
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Borthakur G, et al. Cause of death
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P. Krishnamurthy 1 G.J. Mufti 1,2 1
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etween 1995 and 2005. 11 Five hundr
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London, United Kingdom, June 9-12,
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attainment of FDC post DLI. Interes
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myelodysplastic syndromes is associ
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ubiquitous chaperone that promotes
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was thought that they are linked to
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pathologic induction of miR-28 in M
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STATs. Second, levels of HP1 alpha
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72. Irandoust MI, Aarts LH, Roovers
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A.M. Vannucchi Section of Hematolog
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Page 274 and 275: Table 1. Prognostic scoring systems
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Page 278 and 279: Table 4. A risk-based approach to d
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Page 296 and 297: Table 1. Conventional chemotherapy
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Page 302 and 303: 31. Barlogie B, Tricot G, Anaissie
Page 304 and 305: Table 1. Major differences between
Page 306 and 307: first line therapy have shown survi
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Page 312 and 313: Table 1. Clinical signs of possible
Page 314 and 315: Table 4. Distribution of CSF involv
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Page 320 and 321: U. Nowak-Göttl 1 R. Junker 1 A. Kr
Page 322 and 323: Based on the data obtained from the
Page 324 and 325: 59. Male C, Chait P, Ginsberg JS, e
Page 326 and 327: Table 1. Characteristic features of
Page 328 and 329: Table 2. Mutational spectrum of CDA
Page 330 and 331: megarakaryoblastic leukemia (AMKL)
Page 332 and 333: R.E. Ware Professor and Vice-Chairm
Page 334 and 335: protein, cytokines, and soluble adh
Page 336 and 337: example, improving blood viscosity
Page 338 and 339: 92(9):1266-7. 36. Bensinger TA, Gil
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Page 342 and 343: port have also been used. 5 Combina
Page 344 and 345: Wingard JR, Young J-AH, Boeckh MJ.
Page 346 and 347: K. Rezvani 1 J. Barrett 2 1 Haemato
Page 348 and 349: include the childhood infectious il
Page 350 and 351: Summary Patients undergoing hematop
Page 352 and 353: Table 1. Key issues. In a retrospec
Page 354 and 355: invasive method to assess iron over
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Page 358 and 359: T.M. Hackeng Department of Biochemi
Page 360 and 361: and inhibits FVIIa, and that the se
Page 362 and 363: Figure 4. Regulation of coagulation
Page 364 and 365: T. Baglin Department of Haematology
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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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