Acute Leukemias - Republican Scientific Medical Library

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172 Chapter 13 · Treatment of Adult ALL According to Protocols of the German Multicenter Study Group for Adult ALL (GMALL) bone marrow and blood [12] and thereby MRD evaluation provided an excellent method for response evaluation. In younger patients (55 years), a GMALL pilot trial for elderly ALL showed a very poor response rate in Ph+ ALL (19%) [15]. Therefore, the GMALL group started a randomized trial for elderly Ph+ ALL comparing induction chemotherapy with imatinib only (600 mg) with a dose-reduced chemotherapy induction. After induction all patients received imatinib together with consolidation chemotherapy. The CR rate was 93% for the imatinib induction compared to 54% with chemotherapy. However, LFS and survival were similar in both arms due to a high rate of relapse [16], and only one third of the patients achieved a molecular CR. Most probably pre-existing or developing resistance to imatinib is a major problem. With gene expression analysis it was demonstrated that resistance to imatinib is associated with a set of 56 differentially expressed genes [17]. A high proportion of patients develop resistance mutations in the TK domain at relapse (90%) and in a considerable proportion these mutations are already present at diagnosis (40%) [18]. These results may help to predict response to imatinib and other TK inhibitors. Also a less genotoxic chemotherapy in combination with imatinib or other TKinhibitors will be evaluated in the next GMALL studies for Ph+ ALL. 13.4 Studies for Mature B-ALL and High-Grade B-Cell Non-Hodgkin’s Lymphomas Major advances in the treatment of mature B-ALL were achieved by innovative childhood B-ALL studies with short, intensive cycles including high doses of fractionated CP and HDM in combination with conventional drugs. The GMALL study group developed such a regimen in two consecutive trials as described previously. Both protocols were based on six short, intensive and alternating cycles at 21-day intervals (ABABAB) with differences in the dose of HDM (0.5 g/m 2 in study B- NHL83 and 1.5 g/m 2 in study B-NHL86) [19]. A significant improvement with a CR rate of 63% and 74%, respectively, was obtained and the CCR rate increased from 53% in study B-NHL83 to 71% in study B-NHL86 [19]. 13.4.1 B-NHL90 Protocol In the protocol B-NHL90 the dose level for M was doubled to 3 g/m 2 (patients
a 13.5 · Prognostic Factors 173 13.4.2 B-ALL/NHL 2002 Protocol More than 80% of patients with mature B-ALL show a CD20-positive phenotype. Therefore, in the subsequent trial two major changes of the protocol were implemented: (1) introduction of rituximab before each of the six chemotherapy cycles followed by two consolidation doses of rituximab, and (2) implementation of a HDACand HDM-based cycle C in younger patients (< 55 years) changing the schedule to ABCABC. The dose of M was reduced to 1.5 g/m 2 . Older patients received a dose-reduced version of the schedule without cycle C. According to an interim analysis in 53 patients who had completed the first two cycles, CR was achieved after only two cycles (AB) in 10/11 B-ALL patients (91%). In 26 Burkitt’s NHL patients, the response rate (15 CR/10 PR) after two cycles was 96%. Fifty out of 53 patients were alive after a median follow-up of 137 days. Rituximab was administered without excess toxicity. The survival rate was improved significantly to approximately 90% in younger patients with B- ALL, in BuNHL, and other B-NHL. In older patients with B-ALL, mortality is not negligible, and more frequent relapses are observed [21]. It was also demonstrated that the protocol is applicable in HIV-positive patients with B-ALL or Burkitt’s lymphoma [22]. In the future, the reduction of toxicity, namely mucositis, and further improvement of outcome in older patients with mature B-ALL will be the focus of the study group. 13.5 Prognostic Factors Central diagnostic review in all patients including morphology/cytochemistry, immunophenotyping, cytogenetics, molecular genetics, and eventually MRD made a major contribution to the identification of prognostic factors in the GMALL studies. 13.5.1 Immunophenotyping The refined classification according to surface and intracytoplasmatic markers of ALL blasts by flow cytometry contributed to a better characterization of ALL subtypes, their specific clinical and biologic features, and revealed their prognostic relevance [4, 23–25]. In the GMALL, immunophenotype contributes substantially to the prognostic model and also to treatment stratifica- tion, e.g., application of rituximab in all CD20-positive patients. In an early paper, prethymic phenotype (cyCD3+, CD2–, sCD3–) was identified as a poor prognostic feature [26] and the unfavorable outcome of mature T-ALL was detected later [5, 27]. Therefore, early and mature T-ALL is now considered a high-risk subgroup and patients are candidates for SCT in first CR. The prognostic relevance of phenotype rules out all other prognostic factors including WBC > 100 000/ll. Similar observations have been made for early Blineage ALL (also referred to as pro B-ALL, CD10-negative ALL). This subtype was associated with an inferior prognosis in GMALL studies [4]. In study 04/89, an improved outcome was observed for early B-lineage ALL patients treated according to the high-risk protocol with either HDAC consolidation or allogeneic SCT [28]. More recently it was demonstrated that CD10-negative pre-B- ALL has a similarly unfavorable outcome as pro-B-ALL [29]. 13.5.2 Cytogenetic and Molecular Analysis t(9;22) or the corresponding BCR-ABL fusion transcript is the most frequent aberration in adult ALL. In the GMALL trials, initial detection and follow-up for MRD are performed by central laboratories [30], and prospective analysis of MRD has a major impact on treatment decisions. Recently, the presence of a fusion gene NUP214-ABL1 also conferring increased TK activity was also detected in 4% of the T-ALL patients. This may represent a target for therapy with TK-inhibitors [31]. Quantitative analysis of MRD is also established for t(4;11) and the corresponding fusion gene ALL1- AF4 [32]. More recently, the GMALL group has focussed on the application of gene expression analysis in T-ALL. For the GMALL studies, the most important question is whether new adverse prognostic factors can be identified within the favorable subgroup of thymic T-ALL in order to select additional patients who could benefit from SCT in first CR. It was demonstrated that overexpression of the HOX11 oncogene confers a favorable prognosis but is mostly confined to thymic T-ALL. Within thymic T-ALL it did not show prognostic relevance. HOX11L2 overexpression is a rare feature that is observed in 10% of T-ALL cases and identifies within thymic T-ALL patients with poor prognosis [33]. Furthermore, it was demonstrated that high expression
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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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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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224 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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264 Chapter 21 · Central Nervous S
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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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