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134 Chapter 9 · General Approach to the Therapy of Adult Acute Lymphoblastic Leukemia zumab may therefore provide additional benefit to patients with particularly T-cell leukemias or lymphomas. The group at M.D. Anderson has started to incorporate alemtuzumab in the hyper-CVAD induction program for patients with relapsed or refractory T-cell hematopoietic malignancies. The CALGB is testing alemtuzumab in the setting of postremission therapy for those patients whose lymphoblasts were CD52-positive at diagnosis [8]. In another randomized CALGB study, anti- B4bR (anti-CD19 monoclonal antibody conjugated to blocked ricin) during minimal residual disease showed little additional clinical evidence [21]. Imatinib is increasingly explored in Philadelphia chromosome-positive ALL. Thomas et al. pioneered imatinib-chemotherapy combinations in previously untreated patients [22]. Imatinib is added at a dose of 400 mg/day for the first 14 days of each of the eight induction/consolidation courses of the hyper-CVAD regimen which is followed by 1 year of maintenance with imatinib at 600 mg orally daily. Of 15 patients who have been treated with active disease (11 with de novo ALL and four who were primary failures following nonimatinib containing induction therapy), all achieved CR. Ten patients underwent allogeneic stem cell transplantation within a median of 3.5 months. Among 10 patients who did not undergo transplant, five remain in continuous CR for a median of 20 months. The German ALL study group (GMALL) is conducting a randomized phase II study of induction therapy with imatinib versus standard induction chemotherapy in patients > 55 years with Philadelphia chromosome-positive ALL [23]. In a preliminary update, all patients treated with imatinib induction achieved CR whereas two patients assigned to chemotherapy induction failed and were crossed over to the imatinib arm. It is hoped that accumulating experience resulting from these and other regimens will establish the role of in kinase situs in Philadelphia chromosome-positive ALL and set a new standard of care for these patients. A number of other novel agents are investigated in relapsed in refractory disease states and include new nucleoside analogs (clofarabine, nelarabine), liposomal agents (liposomal vincristine), or hypomethylating agents (decitabine). 9.4 Conclusion ALL is a heterogeneous disease where ALL subsets are characterized by distinct clinical, biological, and thus prognostic features. In addition to developing novel therapies, adapting these therapies according to the risk profile of individual patients has become a main focus in ALL treatment in recent years [24]. Traditional risk factors such as age, white blood cell count, time to response, or cytogenetic abnormalities have shown to influence outcome. More recently, assessment of minimal residual disease has emerged as a tool to gauge individual response following achievement of a complete remission. The GMALL study group is prospectively monitoring minimal residual disease of patients during induction and early consolidation and has started to stratify patients according to residual disease levels at day 71 as low-, high-, or intermediate risk for relapse. The goal of these further refinements is clear: (i) identification of patients who should be transplanted in first CR; (ii) adjustments of intensity during consolidation; and (iii) possible modifications in the intensity and duration of maintenance therapy. ALL therapy in adults has stepped out of the shadows from its pediatric role model. Even though battling the odds seems more cumbersome in adults, important progress has been made to combine an increasing understanding of the biology of adult ALL with the development of novel therapies and the accumulating experience of the clinical behavior of ALL during therapy. ALL therapy has become a complex endeavor and will be even more so in the future. The following articles in this section will provide a far more in-depth description of this progress and create an outlook at state-of-the art therapy in this intriguing disease. References 1. Kantarjian HM, O’Brien S, Smith TL, et al. (2000) Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 18:547–561 2. Larson RA, Dodge RK, Burns CP, et al. (1995) A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 8811. Blood 85:2025–2037 3. Durrant IJ, Richards, SM, Prentice HG, et al. (2000) The Medical Research Council trials in adult acute lymphocytic leukemia. Hem Onc Clin North Am 14:1327–1352
a References 135 4. Gökbuget N, Hoelzer D. (2002) Recent approaches in acute lymphoblastic leukemia in adults. Rev Clin Exp Hematol 6:114– 141 5. Jones B, Freeman AI, Shuster JJ, et al. (1991) Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia. Med Pediatr Oncol 19:269–275 6. Bostrom BC, Sensel MR, Sather HN, et al. (2003) 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 101:3809–3817 7. Todeschini G, Tecchio C, Meneghini V, et al. (1998) Estimated 6year event-free survival of 55% in 60 consecutive adult acute lymphoblastic leukemia patients treated with an intensive phase II protocol on high induction dose of daunorubicin. Leukemia 12:144–148 8. Larson RA.(2004) The US trials in adult acute lymphoblastic leukemia. Ann Hematol 83(Suppl 1):S127–128 9. Weiss M, Maslak P, Feldman E, et al. (1996) Cytarabine with high dose mitoxantrone induces rapid complete remissions in adult acute lymphoblastic leukemia (ALL) without the use of vincristine or prednisone. J Clin Oncol 14:2480–2485 10. Weiss M (2001) Induction therapyof adult acute lymphocytic leukemia without the use of vincristine or prednisone. Hem Onc Clin North Am 15:1–7 11. Larson RA, Dodge RK, Linker CA, et al. (1998) A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 92:1556–1564 12. Hoelzer D. (1996) Acute lymphoblastic leukemia: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87:495–508 13. Thomas D, Cortes J, O’Brien S, et al. (1999) Hyper-CVAD program in Burkitt’s-type adult acute lymphoblastic leukemia. J Clin Oncol 17:2461–2470 14. Thiebault A, Vernant JP, Degos L, et al. (2000) Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87. Hem Onc Clin North Am 14:1353–1366 15. Rowe JM, Richards S, Burnett AK, et al. (2001) Favorable results of allogeneic bone marrow transplantation (BMT) for adults with Philadelphia (Ph)-chromosome-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR): Results from the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 98:481a 16. Childhood ALL Cooperative Group. (1996) Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: Overview of 42 trials involving 12000 randomized children. Lancet 347:1783–1788 17. Mandelli F, Annino L, Rotoli B (1996) The GIMEMA ALL 0183 trial: Analysis of 10-year follow-up. Br J Haematol 92:665–672 18. Thomas DA, Kantarjian HM (2001) Lymphoblastic lymphoma. Hem Onc Clin North Am 15:51–95 19. Thomas DA, Cortes J, O’Brien SM, et al. (2000) Significance of CD20 positivity in de novo acute lymphocytic leukemia (ALL). Blood 96:109a 20. Thomas DA, Cortes J, Giles FJ, et al. (2001) The modified hyper- CVAD regimen in newly diagnosed adult acute lymphoblastic leukemia (ALL). Blood 98:590a 21. Szatrowski TP, Dodge RK, Reynolds C, et al. (2003) Lineage specific treatment of adult patients with acute lymphoblastic leukemia in first remission with anti-B4-blocked ricin or high-dose cytarabine: Cancer and Leukemia Group B study 9311. Cancer 97:1471–1480 22. Thomas DA, Faderl S, Cortes J, et al. (2003) Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood [epub ahead of print] 23. Wassmann B, Gökbuget N, Scheuring UJ, et al. (2003) A randomized multicenter open label phase II study to determine the safety and efficacy of induction therapy with imatinib (Glivec, formerly STI571) in comparison with standard induction chemotherapy in elderly (>55 years) patients with Philadelphia chromosomepositive (Ph+/BCR-ABL+) acute lymphoblastic leukemia (ALL). Ann Hematol 82:716–720 24. Gökbuget N, Raff R, Brügge-Mann M, et al. (2004) Risk/MRD adapted GMALL trials in adult ALL. Ann Hematol 83(Suppl 1): S129–131
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E.H. Estey · S.H. Faderl · H. M.
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E. H. Estey Department of Leukemia
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VI Table of Contents 14 Philadelphi
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VIII Contributors S. H. Faderl Depa
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X Contributors D. Wartenberg Depart
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Therapy of AML Elihu Estey Contents
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a 1.2 · Standard Therapy 3 Table 1
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a 1.2 · Standard Therapy 5 Table 1
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a 1.2 · Standard Therapy 7 tween G
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a 1.2 · Standard Therapy 9 Fig. 1.
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a 1.2 · Standard Therapy 11 of tre
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a 1.2 · Standard Therapy 13 Table
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a 1.2 · Standard Therapy 15 permit
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a References 17 19. Care RS, Valk P
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a References 19 6-thioguanine in th
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Acute Myeloid Leukemia: Epidemiolog
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a 3.1 · Epidemiology 49 3.1.4 Gend
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a 3.2 · Etiology 51 part of the in
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a 3.2 · Etiology 53 for the develo
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a References 55 38. Crane MM, Stom
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Relapsed and Refractory Acute Myelo
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a 4.2 · Prognostic Factors in Pati
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a 4.3 · Treatment of Relapsed and
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a 4.4 · Hematopoietic Stem Cell Tr
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a 4.6 · Gemtuzumab Ozogamicin 65 T
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a 4.7 · Relapsed and Refractory Ac
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a 4.7 · Relapsed and Refractory Ac
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a References 71 The ability of immu
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a References 73 39. Vogler WR, McCa
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a References 75 95. Sievers EL, Lar
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Part II - Acute Lymphoblastic Leuke
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78 Chapter 5 · Acute Lymphoblastic
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80 Chapter 5 · Acute Lymphoblastic
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Page 79 and 80: Molecular Biology and Genetics Meir
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a References 187 56. Mori T, Manabe
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a References 189 acute lymphoblasti
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192 Chapter 15 · Burkitt’s Acute
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204 Chapter 16 · Treatment of Lymp
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216 Chapter 17 · The Role of Allog
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248 Chapter 20 · Minimal Residual
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276 Chapter 22 · Relapsed Acute Ly
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278 Chapter 22 · Relapsed Acute Ly
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Emergencies in Acute Lymphoblastic
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a 23.5 · Hyperleukocytosis 283 LA
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a 23.9 · Neurological Complication
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a References 287 29. Hingorani AD,
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Subject Index A aberrant methylatio
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a Subject Index 291 CREB, see enhan
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a Subject Index 293 MUD, see matche
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