Acute Leukemias - Republican Scientific Medical Library

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a 5.3 · Etiology 85 tern of ALL diagnosis or symptoms. Karimi and Yarmohammadi found a late fall, early winter peak in Iran, Sorensen et al. [138] a fall peak in Denmark, Higgins et al. [44], Westerbeek et al. [157] and Badrinath et al. [7] summer peaks in Europe, and Ross and colleagues [123] a summer peak in the northern USA, with approximately a 7.5% excess over the mean in July and August. This suggests a possible link to allergic and infections processes in the summer that may trigger the ALL disease process, although further research is needed to more precisely define this effect. 5.3.2 Physical Factors 5.3.2.1 Ionizing Radiation The importance of ionizing radiation as an etiologic agent for leukemia and other lymphohematopoeitic cancers has been known since the early 1900s from studies of radiologists [8]. However, the most compelling evidence for this association has come from studies of survivors of the atomic bomb blasts in Hiroshima and Nagasaki [107] and patients treated for ankylosing spondylitis [20]. For both of these types of exposures, leukemias (other than chronic lymphocytic) were noted as early as 3 years after exposure, with peak incidence occurring 5–10 years after exposure, and additional cases were diagnosed even 30 years after exposure [60]. For ankylosing spondylitis, the strongest effect was for AML rather than ALL. There also is evidence for leukemia risk associated with occupational exposure to ionizing radiation among those involved with the nuclear industry [75]. Studies of military personnel on maneuvers at a nuclear bomb test showed statistically elevated leukemia incidence and mortality [96], as do the most recent studies of workers at other nuclear facilities. A review and pooled analysis of nuclear worker studies conducted by the International Agency for Research on Cancer (IARC) found statistically significant excess relative risks for leukemia excluding chronic lymphocytic leukemia [14]. The leukemia exposure-response effect was consistent with but smaller than the values estimated from the studies atomic bomb survivors reported in the BEIR V report from the National Research Council [97]. Studies of workers at naval nuclear shipyards are inconsistent, while studies of fallout from bomb testing showed small increases in cases of leukemia [33], particularly acute leukemias among children, although the interpretations of these data vary [67, 82, 84, 143]. Prenatal exposures are also a concern. In the 1950s, a British study showed that radiography of a pregnant woman’s abdomen increased the child’s risk of leukemia by about 50% [144]. While this relationship is believed to be causal, few women today undergo this type of diagnostic testing, making this a nonissue, at least in terms of public health impact. Studies of prenatal exposure from atomic bomb blasts did not show increased risk, nor did studies of children of atomic bomb survivors who were not exposed prenatally [160]. However, those exposed prenatally may have higher risks as adults [159, 161]. Concern about leukemia risk from ionizing radiation also arose in the early 1980s from an apparent cluster among children living in close proximity to the Sellafield nuclear fuels reprocessing plant in Seascale, England. Initial studies suggested that residential proximity to the plant, and paternal employment at the plant were risk factors [30–32]. Further studies, however, did not confirm either risk factor [10, 50, 70, 86, 149]. Kinlen suggested that this situation supports his population mixing theory [58]. Another suggested physical environmental cause of leukemia is radionuclides in water and air. For example, ingestion of radium-containing groundwater in an ecologic study conducted in Florida showed an association with leukemia [80]. Subsequent studies seeking to clarify this issue provided limited support [6, 17, 29]. Studies examining inhaled radon found an increased risk of leukemia, through the hypothesized mechanism of irradiation to the bone marrow. This association was shown in ecologic studies but not other studies, and thus is unlikely to be etiologic [71]. 5.3.2.2 Nonionizing Radiation Concern also has been raised over the apparent elevated leukemia incidence among children and workers exposed to electric and magnetic fields (EMF) [49, 98, 100]. The risk was first documented in a case-control study of children who had lived in homes with high magnetic fields [156], and the results were replicated in many subsequent population-based studies [22, 79, 131]. Some studies did not show this association [28, 76, 148]. As yet, no mechanism for this risk has been established. Prompted by positive results in these studies,
86 Chapter 5 · <strong>Acute</strong> Lymphoblastic Leukemia: Epidemiology and Etiology a series of occupational mortality studies were undertaken of workers in electrical, electronic, and telecommunications occupations and ham radio operators and showed increased risks for ALL, AML, CML, and CLL occurring inconsistently across studies [24, 92, 93, 130, 147]. The interpretation of these studies remains controversial. Because no viable mechanism has been postulated for nonionizing radiation to cause leukemia, there is much controversy over the definition of relevant exposure and interpretation of results, although only magnetic fields rather than electrical fields are implicated. Exposure metrics under consideration include peak, average, time-weighted average, and variability measures, although the data from different studies are contradictory. Many weight-of-evidence reviews have been conducted to summarize subjectively the available data. Two recent expert panel reviews of the EMF issue were conducted in the USA [98, 100] and one in Europe [49]. While the first [98], under the sponsorship of the National Academy of Sciences, using a consensus process, reported that “no conclusive and consistent evidence shows that exposures to residential electric and magnetic fields produce cancer [our emphasis],” they also asserted that “an association between residential wiring configurations . . . and childhood leukemia persists in multiple studies . . .” The second panel [100], convened by the National Institute of Environmental Health Sciences (NIEHS), using a majority rule process, concluded that “ELF EMF are possibly carcinogenic to humans (Group 2B).” This was based principally on “the results of studies on childhood leukemia in residential environments and on CLL [chronic lymphocytic leukemia] in adults in occupational settings.” In addition, the participants stated that the in vitro and mechanistic data provide weak support based on studies at very high levels of exposures (>100 lT). The third expert panel [49], convened by IARC, also using a majority rule process, also concluded that ELF EMF exposures are possibly carcinogenic to humans (Group 2B). In addition to those data-based, albeit subjective, reviews, a variety of meta-analyses and pooled analyses were conducted to summarize this body of literature analytically. In a meta-analysis, the investigator extracts results from published papers and combines them statistically to provide an average risk estimate for the set of studies as a whole. In a pooled analysis, the investigator obtains the original, individual subject data for a set of studies and then combines them statistically to provide an average risk estimate for the set of studies as a whole while adjusting for confounding variables for individual subjects and differences among the study characteristics. Pooled analyses are believed to be more reliable than meta-analyses. A meta-analysis of occupational studies [55] did not find consistent results regarding the risk of leukemia. The most recent meta-analyses for residential exposures to children [151] reported that the risk for leukemia was elevated and marginally statistically significant, particularly at the higher exposure cutpoints. There was some evidence that supported an exposure-response gradient. Two pooled analyses of childhood leukemia reported statistically significant elevated risks at the highest exposure categories [3, 41]. There still is much controversy over exposure to EMFs as a cause of cancer, with the excess risk suggested by the combined studies for exposures 4 times greater than background being in the range of 50– 100%. However, there is added concern because exposures are ubiquitous, there are no truly unexposed comparison groups, and residential exposures rarely can be greater than 50 times background, while occupational exposures, although typically only short-term, on rare occasion can reach 1000 to 40000 times background. A study of children with ALL found that event-free survival varied across different levels of EMF exposure (events were defined as incomplete remission following therapy, leukemia relapse, secondary cancers, or deaths from any cause) [25]. After adjusting for risk group and socioeconomic status, the authors reported elevated risks of any event (Hazard Ratio = 1.9) including mortality (Hazard Ratio=4.5) among those exposed to higher magnetic fields (> 0.3 lT vs. < 0.1 lT). The robustness of the study results was limited by small sample sizes. 5.3.3 Chemical Factors 5.3.3.1 Solvents Workers in a variety of occupations, such as the leather, shoe, rubber, and printing industries, are exposed to benzene, and studies have reported increased risks of leukemia. Although exposure to benzene has been shown to cause leukemia, most studies have reported excesses of AML rather than ALL [60], with one exception [4]. There also has been concern that exposure to other solvents may cause leukemia, although most data
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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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Page 41 and 42: Relapsed and Refractory Acute Myelo
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Page 55 and 56: a References 71 The ability of immu
Page 57 and 58: a References 73 39. Vogler WR, McCa
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Page 61 and 62: Part II - Acute Lymphoblastic Leuke
Page 63 and 64: 78 Chapter 5 · Acute Lymphoblastic
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Page 79 and 80: Molecular Biology and Genetics Meir
Page 81 and 82: a 6.3 · Structural Aberrations 97
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Page 87 and 88: a References 103 clear that homozyg
Page 89 and 90: a References 105 53. Chim CS, Tam C
Page 91 and 92: a References 107 122. Lennard L, Li
Page 93 and 94: Diagnosis of Acute Lymphoblastic Le
Page 95 and 96: a 8.3 · Cytochemistry and Immunoph
Page 97 and 98: a 8.5 · Cytogenetic and Molecular
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Page 103 and 104: a References 129 47. Kita K, Shirak
Page 105 and 106: Acute Lymphoblastic Leukemia: Clini
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Page 115 and 116: General Approach to the Therapy of
Page 117 and 118: a 9.3 · New Agents 133 dose methot
Page 119 and 120: 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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