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174 Chapter 13 · Treatment of Adult ALL According to Protocols of the German Multicenter Study Group for Adult ALL (GMALL) of the ETS transcription factor ERG, which has an incidence of 50% within T-ALL, is associated with an inferior survival in T-ALL. The prognostic relevance was confirmed in a multivariate analysis together with immunophenotype (early/mature), presence of HOX11L2 and absence of HOX11. Most importantly, within thymic T-ALL high ERG and HOX11L2 were confirmed as adverse prognostic factors [34]. The overexpression of ERG was then correlated to the overexpression of the BAALC gene, which is present in 25% of adult T-ALL cases. The latter is also correlated with inferior prognosis. The prognostic significance of BAALC increased if combined with ERG. Patients with low BAALC/low ERG had a favorable prognosis compared to an unfavorable prognosis in patients with high BAALC/high ERG [35]. 13.5.3 MRD Analysis The GMALL central laboratory for MRD analysis has demonstrated in a large patient cohort that persistence of MRD above 10 –4 until week 16 (after consolidation 1), which is observed in 25% of the patients, confers a very poor prognosis with a relapse rate above 90%. On the other hand, there is a small proportion of patients (10%) who decline rapidly below 10 –4 at day 11 and day 24 (after induction 1). These patients have an excellent prognosis. In the remaining patients the relapse rate was nearly 50% [36]. Thanks to the frequent MRD analyses during first year of therapy, it was possible to identify molecular re- Table 13.3. MRD-based stratification in GMALL study 07/03 MRD risk group Day 71 a MRD low risk (MRD-LR) 10 –4 MRD intermediate risk (MRD-IMR) MRD evaluation not possible Technical prerequisites not fulfilled c Inconclusive course of MRD lapses in patients who had already achieved a molecular remission. If the MRD level increased during the second year to more than 10 –4 , 89% of the patients relapsed. As a result of this study molecular relapse is treated in the GMALL trials similarly to cytologic relapse and identifies patients for salvage therapy and SCT [37]. Based on these findings, the ongoing GMALL trial 07/2003 comprises a risk stratification based on MRD analysis in patients with SR according to conventional factors. Patients with high level of MRD after consolidation I (> 10 –4 ) were allocated to a MRD-HR group and to SCT in first CR. Patients with low level of MRD after induction and consolidation I were defined as MRD low risk and received no maintenance therapy. The remaining patients (MRD intermediate risk) with inconclusive course of MRD or technical problems were scheduled for intensified maintenance (Table 13.3). According to an interim analysis of MRD risk stratification at month 12 in 98 SR patients, the risk groups according to MRD were distributed as follows: MRD-LR 36%, MRD-HR 9%, and MRD-IMR 55%. The major reasons for allocation to MRD-IMR were lack of a second marker (58%), insufficient sensitivity (51%), and inconclusive course of MRD (28%). Most patients in the MRD-IMR group had, however, combinations of several reasons. Further treatment after MRD risk stratification was evaluable in 88 patients. In nearly all MRD-LR patients therapy was stopped. The relapse risk (RR) in this cohort was so far 20–30%. In MRD-HR less than half of the patients could receive SCT. In several cases the relapses occurred shortly after the end of the first year of therapy and before the MRD results were available. Week 16 until week 52 b and Always 10 –4 Negative in week 52 Molecular relapse Increase of MRD above 10 –4 later than week 16 after previous negative status a after induction, before first consolidation b during consolidation c –4 Technical prerequisites: At least 2 clone-specific markers, minimum sensitivity of 10 material from decisive time-points available
a References 175 Only patients with immediate SCT remained relapse free in the MRD-HR group. In MRD-IMR half of the patients received intensified maintenance. In this group the RR was overall also around 20–30% with lowest RR for intensified maintenance and highest RR for premature stop of therapy. Unexpectedly the MRD-IMR group was large (> 50%) partly due to strict quality standards for MRD evaluation as mandatory for a prospective study. Further characterization of this subgroup also by other means e.g. gene profiling is attempted. Overall the interim results demonstrate that the treatment recommendations for the MRD risk groups are reasonable although the relapse rate was higher than expected. Nevertheless the major question is still whether the intermediate risk group can be reduced and whether any type of treatment de-escalation is justified in adult ALL [38]. 13.5.4 Development of Risk Models in the GMALL Studies The risk model for adult ALL first described for study 01/81 [2] was continuously developed in subsequent trials (Fig. 13.4). It is important to note that in the meantime prognostic factors are different for B-precursor and T-ALL and individualized factors such as course of MRD are added. Furthermore, although increasing age is one of the most significant adverse prognostic features, it is not included in the risk stratification. The aim of risk stratification is to identify patients who could benefit from SCT and since outcome of SCT also decreases with age, it is not an adequate feature for this purpose. 13.6 Future Risk Stratification and Treatment Concepts for Adult ALL Risk and subtype adjusted treatment strategies led in the GMALL studies to considerable improvement of outcome in mature B-ALL, T-ALL and Ph-positive ALL but to a lesser extent in B-precursor ALL. Future concepts will integrate a variety of additional factors thereby resulting in a more complex, flexible and patient specific treatment approach [39]. These approaches include: 4 Subgroup adjusted treatment e.g. for mature B-ALL and Burkitt’s NHL 4 Age adapted treatment e.g. specific protocols for elderly fit, elderly frail and adolescent patients. 4 Individualized treatment e.g. according to MRD, drug resistance or TK domain mutations 4 Risk adapted indications for SCT 4 Targeted therapies e.g. with kinase inhibitors in Ph+ ALL, monoclonal antibodies and other new drugs e.g. subtype specific therapy in T-ALL 4 Evaluation of new cytostatic drugs Beside these sophisticated approaches a better adherence to protocols, support of patients to improve their compliance and documentation of compliance would be warranted. Treatment should be done at experienced centers and closer cooperation between internal medicine and pediatrics including cooperative studies is attempted. References 1. Gökbuget N, Hoelzer D, Arnold R, et al. (2000) Treatment of adult ALL according to the protocols of the German Multicenter Study Group for Adult ALL (GMALL). Hemat/Oncol Clin North Am 14:1307–1325 2. Hoelzer D, Thiel E, Löffler H, et al. (1984) Intensified therapy in acute lymphoblastic and acute undifferentiated leukemia in adults. Blood 64:38–47 3. Hoelzer D, Thiel E, Ludwig WD, et al. (1993) Follow-up of the first two successive German multicentre trials for adult ALL (01/81 and 02/84). German Adult ALL Study Group. Leukemia 7(Suppl 2):S130–S134 4. Hoelzer D, Thiel E, Löffler H, et al. (1988) Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71:123–131 5. Gökbuget N, Arnold R, Buechner TH, et al. (2001) Intensification of induction and consolidation improves only subgroups of adult ALL: Analysis of 1200 patients in GMALL study 05/93. Blood 98:802a(abstr) 6. Gökbuget N, Baur K-H, Beck J, et al. (2005) Dexamethasone dose and schedule significantly influences remission rate and toxicity of induction therapy in adult acute lymphoblastic leukemia (ALL): Results of the GMALL pilot trial 06/99 [abstract]. Blood 106:1832 7. Arnold R, Bunjes D, Ehninger G, et al. (2002) Allogeneic stem cell transplantation from HLA-identical sibling donor in high risk ALL patients is less effective than transplantation from unrelated donors. Blood 100:77a (abstr 279) 8. Kiehl MG, Kraut L, Schwerdtfeger R, et al. (2004) Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: No difference in related compared with unrelated transplant in first complete remission. J Clin Oncol 22:2816–2825
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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 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 4.3 · Treatment of Relapsed and
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a 4.4 · Hematopoietic Stem Cell Tr
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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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Part II - Acute Lymphoblastic Leuke
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78 Chapter 5 · Acute Lymphoblastic
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Molecular Biology and Genetics Meir
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a 6.3 · Structural Aberrations 97
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a 6.3 · Structural Aberrations 99
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a 6.5 · Molecular Aberrations 101
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a References 103 clear that homozyg
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a References 105 53. Chim CS, Tam C
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a References 107 122. Lennard L, Li
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Diagnosis of Acute Lymphoblastic Le
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a 8.3 · Cytochemistry and Immunoph
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a 8.5 · Cytogenetic and Molecular
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a 8.5 · Cytogenetic and Molecular
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a References 127 including the reti
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a References 129 47. Kita K, Shirak
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226 Chapter 17 · The Role of Allog
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228 Chapter 17 · The Role of Allog
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230 Chapter 18 · The Role of Autol
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238 Chapter 19 · Novel Therapies i
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248 Chapter 20 · Minimal Residual
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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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