Acute Leukemias - Republican Scientific Medical Library

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4 Chapter 1 · Therapy of AML CBF AML where it produced average cure rates in excess of 50%. In the normal karyotype group, IDAC and HDAC were equivalent, with each superior to standard doses, i.e., those in 3+7. In the worse-prognosis group any differences among HDAC, IDAC, and standard doses were small relative to the poor outcome observed with all three doses. NCRI data suggest that similar results can be obtained in CBF AML with IDAC as with HDAC [10], leading to an NCRI trial randomizing between these 2 doses. 1.2.6 Beyond Cytogenetics Although cytogenetic findings remain the most important prognostic factor in AML, there is considerable variability in outcome particularly within the intermediate and favorable groups. The presence of (a) secondary AML, (b) “white blood cell index,” (c) “secondary” chromosome abnormalities superimposed on the primary abnormalities noted above, and (d) molecular abnormalities such as gene mutations and deregulated gene expression are useful in unravelling this heterogeneity. The poorer outcome in secondary rather than in de novo AML is well known and appears independent of the association between secondary AML and worseprognosis cytogenetics [15]. Nguyen et al. for the French AML Intergroup found that relapse-free survival in patients with t (8;21) given IDAC (or an allogeneic transplant) varied as a function of a “white blood cell index” defined as [WBC ´% marrow blasts]/100 [16]. Longterm RFS was > 75% with an index < 2.5, 60% with an index 2.5–20, and 30% with an index > 20. In general, the presence of secondary chromosome abnormalities has little affect on prognosis. However, the German AML Intergroup and Cancer and Leukemia Group B (CALGB) have shown that trisomy 22 improves relapse-free survival in inv [16] AML [17, 18], while the German group has also shown that a missing Y chromosome is associated with shorter survival t(8;21) [17]. Of more general interest, mutations in receptor tyrosine kinases (RTK), such as KIT, and in RAS genes have been found in 25% of cases of inv 16 AML and in 10% of cases of t(8;21) AML; KIT mutations appear associated with an inferior prognosis [19–22]. Given its frequency, the normal karyotype group is the one in which prognostic heterogeneity is most problematic. Such patients often have molecular abnormalities involving FLT3, NPM1, CEBPA, MLL, RAS, BAALC, or EVI,1. Internal tandem duplications (ITD) within the juxtamembrane domain of the RTK FLT3 occur in 28–34% of patients with normal karyotype AML and are consistently associated with a significantly inferior outcome [23–27]. An additional 10–15% of these patients have mutations within the activation loop of the second tyrosine kinase domain (TKD) [25, 26, 28, 29]. A recent meta-analysis suggests that FLT3 TKD mutations also negatively affect RFS, although the British NCRI group has recently reported a favorable effect [30, 31]. The most common somatic gene alterations in AML are mutations in the nucleophosmin (NPM1) gene, resulting in cytoplasmic rather than nuclear localization of the NPM1 protein. NPM1 mutations have been reported in 48–64% of normal karyotype AML [32–36]. Recent studies have found that overall survival (OS) and relapse-free survival (RFS) are significantly better in NPM1+/FLT3 ITD– patients contrasted with NPM1– and NPM1+/FLT3 ITD + patients [32–36]. NRAS/KRAS mutations occur in approximately 18% of normal karyotype AML [37]. Although no consistent prognostic effect has yet been shown, there may be such an effect after accounting for mutations in other genes, such as dominant negative mutations in the transcription factor CEBPA and partial tandem duplications (PTD) in the MLL1 gene, which occur in 15– 18% and 8–11% of normal karyotype cases, respectively. CEBPA mutations are associated with superior OS and RFS [38–40], while MLL1 mutations predict for inferior RFS without significant effect on OS [41– 44]. A significant negative prognostic effect on these two outcomes has also been reported in cases with aberrant overexpression of BAALC, a gene that is physiologically expressed in brain tissue and in hematopoietic progenitor cells [45, 46]. Genome-wide gene expression profiling based on DNA microarrays has provided additional prognostic information [47–49]. In particular, hierarchical clustering has identified two normal karyotype-predominant classes that differed in OS, and a gene expression predictor emerged as the strongest prognostic factor in multivariate analysis. These findings have been validated prospectively in an independent data set [50]. Table 1.2, based on outcome in younger adults given anthracycline + IDAC/HDAC, provides a prognostic system combining genetic and cytogenetic information. The value of cytogenetics in predicting RFS can also be enhanced by incorporating information regarding response to induction therapy [51].
a 1.2 · Standard Therapy 5 Table 1.2. Approximate 3-year event-free survival probabilities based on cytogenetic and molecular findings in younger adults treated with anthracycline + IDAC/ HDAC Group EFS >75% t(8;21) with WBC index 20 or with kit mutation t(9;11) Normal karyotype and NPM1–/FLT3 ITD– Normal karyotype and NPM1+ or –/ FLT3 ITD+ Normal karyotype and MLL1 PTD+ EFS
Page 1 and 2: E.H. Estey · S.H. Faderl · H. M.
Page 3 and 4: E. H. Estey Department of Leukemia
Page 5 and 6: VI Table of Contents 14 Philadelphi
Page 7 and 8: VIII Contributors S. H. Faderl Depa
Page 9 and 10: X Contributors D. Wartenberg Depart
Page 11 and 12: Therapy of AML Elihu Estey Contents
Page 13: a 1.2 · Standard Therapy 3 Table 1
Page 17 and 18: a 1.2 · Standard Therapy 7 tween G
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Page 27 and 28: a References 17 19. Care RS, Valk P
Page 29 and 30: a References 19 6-thioguanine in th
Page 31 and 32: Acute Myeloid Leukemia: Epidemiolog
Page 33 and 34: a 3.1 · Epidemiology 49 3.1.4 Gend
Page 35 and 36: a 3.2 · Etiology 51 part of the in
Page 37 and 38: a 3.2 · Etiology 53 for the develo
Page 39 and 40: a References 55 38. Crane MM, Stom
Page 41 and 42: Relapsed and Refractory Acute Myelo
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Page 45 and 46: a 4.3 · Treatment of Relapsed and
Page 47 and 48: a 4.4 · Hematopoietic Stem Cell Tr
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Page 55 and 56: a References 71 The ability of immu
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Page 61 and 62: Part II - Acute Lymphoblastic Leuke
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80 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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Acute Lymphoblastic Leukemia: Clini
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a 7.3 · Diagnosis 111 or neoplasti
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a 7.3 · Diagnosis 113 Fig. 7.2. Hi
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a 7.3 · Diagnosis 115 The vast maj
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a References 117 dren: Biologic bas
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General Approach to the Therapy of
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a 9.3 · New Agents 133 dose methot
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a References 135 4. Gökbuget N, Ho
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138 Chapter 10 · Recent Clinical T
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146 Chapter 11 · Conventional Ther
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ALL Therapy: Review of the MD Ander
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a 12.2 · The Hyper-CVAD Regimen in
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a 12.3 · Subset-Specific Approache
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Treatment of Adult ALL According to
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a 13.2 · Therapy for Younger (15-6
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a 13.3 · Therapy of Ph/BCR-ABL-Pos
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a 13.5 · Prognostic Factors 173 13
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a References 175 Only patients with
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Philadelphia Chromosome-Positive Ac
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a 14.2 · Molecular Biology of the
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a 14.3 · Treatment of Ph+ ALL 181
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a 14.4 · Hematopoietic Stem Cell T
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a References 185 2. Kurzrock R, Sht
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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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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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