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The Oncologist, Vol. 13, No. 6, 645-654, June 2008; doi:10.1634/theoncologist.2008-0057
© 2008 AlphaMed Press

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Leukemias

Is There an Entity of Chemically Induced BCR-ABL–Positive Chronic Myelogenous Leukemia?

Marshall A. Lichtman

University of Rochester Medical Center, Rochester, New York, USA

Key Words. Myelogenous leukemia • Secondary leukemia • Radiation • Chemotherapy • Benzene • Chromosomes

Correspondence: Marshall A. Lichtman, M.D., University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA. Telephone: 585-275-2205; Fax: 585-271-1876; e-mail: mal{at}urmc.rochester.edu

Received March 10, 2008; accepted for publication April 29, 2008.

Disclosure: No potential conflicts of interest were reported by the author, planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Causes of AML and...
 Chromosome and Genic Damage...
 Radiation and Acute and...
 Chemotherapy and Acute and...
 Benzene and Acute and...
 Summary
 References
 
After completing this course, the reader will be able to:

  1. Distinguish the exogenous causes of acute and chronic myelogenous leukemia.
  2. Discuss the evidence establishing the exogenous causes of secondary leukemia.
  3. Describe the relationship of radiation and chemical exposure to the risk of developing specific subtypes of leukemia.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Causes of AML and...
 Chromosome and Genic Damage...
 Radiation and Acute and...
 Chemotherapy and Acute and...
 Benzene and Acute and...
 Summary
 References
 
Advances in the therapy of malignancy have been accompanied by an increased frequency of cases of secondary acute myelogenous leukemia and related clonal cytopenias and oligoblastic (subacute) myelogenous leukemia (myelodysplastic syndromes). The acute myelogenous leukemia incidence can be increased by high-dose acute ionizing radiation exposure, alkylating agents, topoisomerase II inhibitors, possibly other DNA-damaging therapeutic agents, heavy, prolonged cigarette smoking, and high dose-time exposure to benzene, the latter less frequently seen in industrialized countries with worksite regulations. Acute myelogenous leukemia and myelodysplastic syndromes may result from innumerable primary types of chromosome damage. In the case of chronic myelogenous leukemia, a specific break in chromosome bands 9q34 and 22q11 must occur to result in the causal fusion oncogene (BCR-ABL). A review of 11 studies of the chromosomal abnormalities found in presumptive cases of cytotoxic therapy–induced leukemia and of 40 studies of the subtypes of leukemia that occur following cytotoxic therapy for other cancers has not provided evidence of an increased risk for chemically induced BCR-ABL–positive chronic myelogenous leukemia. Studies of the effects of alkylating agents, topoisomerase inhibitors, and benzene on chromosomes of hematopoietic cells in vitro, coupled with the aforementioned epidemiological studies of secondary leukemia after cytotoxic therapy or of persons exposed to high dose-time concentrations of benzene in the workplace, do not indicate a relationship among chemical exposure, injury to chromosome bands 9q34 and 22q11, and an increased risk for BCR-ABL–positive chronic myelogenous leukemia.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Causes of AML and...
 Chromosome and Genic Damage...
 Radiation and Acute and...
 Chemotherapy and Acute and...
 Benzene and Acute and...
 Summary
 References
 
Patients with newly diagnosed cancer often pose the question, "What have I eaten, drunk, inhaled, or otherwise encountered that caused my cancer?" In the substantial proportion of human cancers in which tobacco smoking is a predisposing factor, the answer is apparent. In the case of leukemia, a highly morbid group of diseases for which an external cause is evident only uncommonly, the answer to that question is usually "nothing." The disease usually appears to be the result of inherent cellular misadventures: naturally occurring mutations of cells, aberrancy in DNA repair mechanisms intrinsic to the cell, epigenetic factors, perhaps predisposing gene polymorphisms, and, occasionally, inherited germline predisposition genes.

Acute myelogenous leukemia (AML) secondary to cytotoxic exposures was uncommon in the first 60 years of the twentieth century and limited to exaggerated exposures to benzene in the workplace until the widespread application of chemotherapy for cancer developed in the 1960s. With the increased variety of DNA-damaging therapeutic agents and the increased intensity of treatment for many malignancies, secondary AML or myelodysplastic syndrome (MDS) has been a growing problem and has resulted in a distressing frequency of Pyrrhic victories in the treatment of cancer. Secondary leukemia cannot be differentiated from leukemia occurring de novo in an individual case. Epidemiological approaches are used to conclude that the risk for AML/MDS is elevated in a population of patients, often with another cancer, treated with DNA-damaging therapy, or workers exposed to benzene, when compared with an unexposed population with similar demographic characteristics. Some of the patients who develop AML/MDS after benzene exposure or cytotoxic therapy have de novo disease, making correlations of findings (e.g., cytogenetics) in presumptive cases of secondary leukemia imprecise. There is no evidence, not unexpectedly, that benzene or cytotoxic therapy reduces the risk for de novo AML/MDS.


   CAUSES OF AML AND MDS
Top
 Learning Objectives
 Abstract
 Introduction
 Causes of AML and...
Chromosome and Genic Damage...
 Radiation and Acute and...
 Chemotherapy and Acute and...
 Benzene and Acute and...
 Summary
 References
 
Exaggerated exposure to ionizing radiation [1–5], intensive therapy with certain chemotherapeutic drugs, notably, but probably not exclusively, the alkylating agents and topoisomerase II inhibitors [6, 7], high dose-time exposures to benzene (e.g., ≥40 ppm-years) [8–11], usually in an unregulated industrial setting, and heavy and prolonged cigarette smoking [12, 13] are documented causes of AML and the clonal cytopenias and oligoblastic myelogenous leukemias (MDS). Their causal relationship has been established by numerous studies, showing consistent results, temporality, and a dose–response relationship, and accepted by experts in the field, as is evident by their inclusion as causes of AML and MDS in authoritative textbooks and scientific journal articles, and by judgments of independent health agencies, such as the International Agency for Research on Cancer of the World Health Organization and the U.S. Public Health Service. These relationships satisfy Austin Bradford Hill's recommendations on determining disease causation related to exogenous factors [14].


   CHROMOSOME AND GENIC DAMAGE ASSOCIATED WITH ACUTE AND CHRONIC MYELOGENOUS LEUKEMIA
Top
 Learning Objectives
 Abstract
 Introduction
 Causes of AML and...
 Chromosome and Genic Damage...
Radiation and Acute and...
 Chemotherapy and Acute and...
 Benzene and Acute and...
 Summary
 References
 
The special case of chronic myelogenous leukemia (CML) is the topic of this commentary. In contrast to AML and MDS, which are genetically diverse in that numerous different genetic abnormalities have been linked to their onset, CML is homogeneous in that the BCR-ABL oncogene is the sole genetic lesion that permits the development of that disease phenotype in about 99% of cases. Thus, AML is associated (often causally) with abnormalities of any chromosome (many different genes), including unbalanced structural abnormalities, such as loss of part or all of chromosome 5 or 7, numerical abnormalities, such as an additional chromosome 8 (trisomy 8), or balanced structural abnormalities, such as translocation between chromosomes 8 and 21, 15 and 17, or between chromosome 11 and many other chromosome partners, or any one of numerous other abnormalities involving other chromosomes (genes) [15], as can occur de novo or be induced by ionizing radiation and/or DNA-damaging chemotherapeutic agents [6, 7].

In the case of CML, an inducing agent must result in the BCR-ABL oncogene, always the product of the fusion of breakpoints at a certain band of chromosome 9, in the ABL gene, with certain breakpoints on chromosome 22, in the BCR gene. The fusion gene must transcribe, and the fusion messenger RNABCR-ABL must translate the oncogenic BCR-ABL protein. These specific events are required, by definition, for BCR-ABL-positive CML to occur. Logically, one could estimate that the induction of CML by an incitant chemical should be far less frequent than the induction of AML, given the vastly more frequent DNA lesions that can induce AML, whereas CML will not occur unless the incitant can result in a BCR-ABL fusion oncogene.


   RADIATION AND ACUTE AND CHRONIC MYELOGENOUS LEUKEMIA
Top
 Learning Objectives
 Abstract
 Introduction
 Causes of AML and...
 Chromosome and Genic Damage...
 Radiation and Acute and...
Chemotherapy and Acute and...
 Benzene and Acute and...
 Summary
 References
 
Extensive skin cancer as a result of excessive exposure to the fluoroscope occurred in Thomas Edison's laboratory assistant. This case was purportedly the first known death from radiation-induced cancer in 1904 (9 years after Wilhelm Konrad Roentgen's discovery of x-rays). Van Jagie described the first case of leukemia in a physician, associated with exposure to x-rays in the Berliner Klinische Wochenschrift in 1911 [2]. Although suspicion grew about the noxious effects of chronic radiation exposure, for example, in physicians repeatedly exposed to their own x-ray procedures with inadequate shielding, it required the extensive epidemiological studies conducted by the Atomic Bomb Casualty Commission in Japan after World War II to provide conclusive evidence for the leukemogenic effect of acute, high-dose ionizing radiation exposure [1, 2]. The occurrence of AML and CML (and acute lymphocytic leukemia [ALL]) was increased in survivors of the atomic bomb detonations in Hiroshima and Nagasaki within 1,500 meters of the hypocenter of the detonation. Whereas 15% of the cases in Nagasaki were CML, 44% of the cases in Hiroshima were CML [16]. The significant difference in CML occurrence— Nagasaki, 6 cases and Hiroshima, 51 cases—has been explained by a similar difference in background frequency of CML in each city [1], although the different background has not been explained. AML frequency was similar between the two cities.

The causal link of AML and CML to ionizing radiation exposure was reinforced by studies of the effects of therapeutic x-radiation and {gamma}-radiation. In the case of irradiated patients with ankylosing spondylitis, 19% of subsequent leukemia cases were CML [17], and in the case of patients irradiated for cervical cancer, 29% of leukemia cases were CML [4]. About 10% of cases of leukemia each year in the U.S. are CML [18], and about 13% of cases in East Asia are CML [19]. These observations have suggested that CML may be more likely to occur after acute, high-dose radiation exposure than other types of leukemia. In part, this difference may be explained by the absence of a relationship of radiation exposure to the incidence of chronic lymphocytic leukemia (CLL). It was initially thought that an inherent lack of susceptibility to CLL in the Japanese population [2, 20, 21] might explain the absence of an increase in its incidence after exposure to the atomic bomb blasts. However, several subsequent studies in Western populations have indicated that the DNA damage induced by ionizing radiation does not result in an increased incidence of CLL [3, 4, 17, 22]. Indeed, currently, radiobiologists neglect CLL when studying radiation-induced leukemogenesis [23]. If CLL is removed from the total cases of leukemia each year, CML represents about 17% of the (potentially radiation-inducible) new cases of leukemia per year in the U.S.

Biological plausibility was added to the compelling epidemiological evidence for radiation-induced CML by the demonstration that the BCR-ABL oncogene could result from high-dose x-irradiation or {gamma}-irradiation (50–100 Gy) of cell lines in culture and the subsequent transcription of BCR-ABL message in such cells [24, 25]. HL-60 cells and KG1 cells shown not to harbor the BCR-ABL gene, using sensitive techniques, were induced to form the characteristic b2a2 or b3a2 fusion genes prevalent in cases of CML. Studies, also, have indicated a nonrandom geographical arrangement of chromosomes in G0 or cycling lymphocytes, HL-60 cells, or marrow cells, resulting in a more proximate physical relationship between chromosomes 9 and 22, which may facilitate a 9:22 translocation [26, 27]. Theoretical models of radiation-induced BCR-ABL translocations provide hypothetical frequencies of the lifetime incidence of CML at lower acute radiation dose exposures (<1.0 Gy) [28, 29].

The increasing use of high radiation–dose imaging, such as computed tomography (CT), coronary artery imaging, and thallium scanning, has raised questions about the leukemogenicity of these modalities when used repeatedly in the same individual. An abdominal CT scan results, on average, in an absorbed dose of about 10 milliSieverts (mSv), according to the U.S. Food and Drug Administration Center for Devices and Radiological Health: twice that much if done with and without contrast material. In the studies of the Japanese exposed to acute radiation from the atomic bombs, radiation-related, excess relative risk of cancer mortality occurred with exposures of 5–20 mSv [30]. A mitigating factor in the exposure to multiple CT examinations (increasingly common) or other high radiation–dose imaging procedures is the episodic exposure (in effect fractional delivery) [31]; but, contrariwise, the potential increased risk to the exposed fetus and younger child has been reported [32, 33]. The infrequency of radiation-induced CML in patients treated for malignancy is likely related to the use of fractionated radiation doses, efforts to spare the marrow, where possible, and, perhaps, the reduction or elimination of radiation therapy in situations in which multidrug chemotherapy has become the treatment of choice.


   CHEMOTHERAPY AND ACUTE AND CHRONIC MYELOGENOUS LEUKEMIA
Top
 Learning Objectives
 Abstract
 Introduction
 Causes of AML and...
 Chromosome and Genic Damage...
 Radiation and Acute and...
 Chemotherapy and Acute and...
Benzene and Acute and...
 Summary
 References
 
The relationship of exposure of patients with solid tumors or lymphoma to cytotoxic therapy and the subsequent increased risk of AML and MDS has been reported repeatedly [5, 6, 34–36].

The results of 11 studies of cytogenetic findings of relatively large numbers of patients with presumptive secondary leukemia, usually occurring in a patient after treatment with cytotoxic therapy for a first malignancy, are shown in Table 1[37–47]. Of 983 patients with secondary leukemia so studied, two had malignant cells with t(9q34;22q11) and with a phenotype of CML. One patient was irradiated after surgery for breast cancer, but received no chemotherapy. The other received, postoperatively, 2 years of three-drug therapy for ovarian carcinoma and developed CML 10.5 years later (Table 1). The frequency of BCR-ABL–positive CML of about 1 in 500 is far below an expected frequency of occurrence of secondary CML, assuming an AML:CML ratio similar to that of the diseases developing de novo (about 2.6:1). The data in Table 1 were generated from "convenience" samples and may not be representative of the population at risk. In addition, one of the two cases of CML was not preceded by chemotherapy. These findings are complemented by studies shown in Table 2.


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  		Table 1. Studies of cytogenetic abnormalities in cases of presumptive secondary leukemia

 


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  		Table 2. Frequency of secondary leukemia in patients treated for cancer

 
Table 2 cites 40 studies in which the development of leukemia occurred after patients received chemotherapy plus radiation therapy or chemotherapy alone [45, 48–77]. Cases of CML have been reported infrequently in relationship to cytotoxic therapy. In nearly all cases in which CML has occurred subsequent to cytotoxic therapy, the patient groups under study had received either radiotherapy or radiotherapy and chemotherapy, not chemotherapy alone, as indicated in Table 2. For example, in a study of 376,825 women treated for breast cancer, a somewhat increased excess absolute risk (2.1; confidence interval, 1.3–2.9) of CML was interpreted as being related to radiation therapy and not to alkylating agents (Table 2, study 1). In a study of women with ovarian cancer, in which eight cases of CML occurred out of 32,251 patients followed, the frequency of cases of CML was not significantly different from the expected rate (Table 2, study 9); and, the patients were exposed to radiation therapy. In a study, noted in the footnote to Table 2, of 82,700 patients, 90 cases of leukemia were observed and seven had CML. In the latter case, each of those patients received radiation therapy. In the studies cited in Table 2, there was no instance in which the risk for CML was elevated significantly in a population exposed to chemotherapy alone, and it was elevated in only one of 22 studies in which radiation and chemotherapy were used conjointly. In the U.S., in 2007, the new cases of AML to CML were estimated to be 13,410 to 4,570, respectively, or a ratio of 2.9 to 1 [29]. In the patients treated with chemotherapy shown in Table 2, it was 164 to 1 (over the period of observation in these studies), whereas in patients whose treatment included chemotherapy and radiotherapy it was 741 to 178 or 4.2 to 1, over the period of observation in the studies cited in Table 2.

Nine cases of CML with t(9;22) identified in the patient's cells were reported in a small and heterogeneous population of patients treated with multiple cytotoxic agents for multiple diseases. Six of the nine cases received therapeutic radiation; in the five cases in which the dose was specified it was between 15 Gy and 40 Gy [78]. In an examination of secondary CML based on epidemiological studies following cancer treatment, no significant elevated relative risk for CML was found in eight studies of patients treated with either radiotherapy or chemotherapy and radiotherapy and the authors concluded that the evidence for CML secondary to cytotoxic therapy was unconvincing [79]. A comprehensive review of the matter of secondary CML was published in 1999, which included patients exposed to the atomic bomb detonations, therapeutic radiation, combined radiation therapy and chemotherapy, immunosuppression, and chemotherapy alone, and patients developing CML as a second malignancy without prior therapy [80]. Of the 287 cases of secondary CML identified from a search of the literature between 1950 and 1998, 12 were cases in which chemotherapy alone preceded the onset of the disease with an 18–50 months' latency. This finding represents, on average, one case reported every 4 years. These uncommon events do not permit the conclusion that cytotoxic therapy used in cancer treatment can increase the risk for CML, nor is there any basis for arriving at a relative risk for CML after chemotherapy. In a study that examined the literature over a similar period of time, nine cases of CML were uncovered that developed after another neoplasm without prior radiation or chemotherapy; five of the patients had surgery for their initial cancer [81]. The outstanding feature was older age, making the possibility of coincidence of the two neoplasms more likely. The frequency of nine cases without prior treatment over about the same interval as the 12 cases treated only with chemotherapy is not sufficiently different to be suggestive.

Studies of the sites at which alkylating agents interact with DNA have been made in vitro in hematopoietic cells or cell lines and, unlike radiation, have resulted in neither relevant breaks in chromosomes 9 or 22 [82–85] nor the formation of the BCR-ABL translocation. These exposures have induced chromosome abnormalities that parallel those abnormalities seen in AML secondary to alkylating agents; for example, damage to chromosome 5. Topoisomerase II inhibitors can result in an increase in secondary AML, usually as a result of the induction of translocations involving chromosome band 11q23 (MLL gene), as well as other cytogenetic alterations. In vitro study of the DNA topoisomerase II inhibitor etoposide resulted in the induction of MLL translocations in human CD34-positive and TK6 lymphoblastoid cells, a principal effect in the marrow cells of patients treated with this agent and its congeners [85, 86].


   BENZENE AND ACUTE AND CHRONIC MYELOGENOUS LEUKEMIA
Top
 Learning Objectives
 Abstract
 Introduction
 Causes of AML and...
 Chromosome and Genic Damage...
 Radiation and Acute and...
 Chemotherapy and Acute and...
 Benzene and Acute and...
Summary
 References
 
In 1928, the first reported case of acute leukemia in an Italian worker heavily exposed to benzene was published [87]. Numerous studies over the succeeding years have confirmed that three hematological diseases, aplastic anemia, AML, and MDS, can be the result of relatively high dose-time exposures to benzene, now uncommon in the First World, but a problem in developing countries without appropriate or enforced environmental work standards.

As the risks of benzene exposure became incontestable, the argument has moved to what level of benzene exposure is "safe." Although some believe that no level is safe, implying that any exposure is leukemogenic, several students of benzene toxicity accept the data from the "Ohio Pliofilm cohort," which indicates that exposures ≥40 ppm-years are required to identify an increase in the relative risk for AML over the rate in the general population [8–11]. This study has been particularly useful for the study of the risk of benzene exposure because no other potential hematopoietic toxin was present in the workplace. Also, although incomplete, there were considerable data on benzene air concentrations with which to estimate employee exposures. Repeated studies have used different methodologies to refine exposure estimates but the threshold exposure felt to be capable of leukemogenicity is >40 ppm-years. A detailed consideration of "thresholds" in the effects of genotoxic agents is beyond the boundary of this commentary [88]. One mentionable aspect is whether threshold measures of DNA effects in cells studied in vitro, such as adduct formation, can be transferable to the chemical concentration threshold for induction of leukemia in vivo, based on population studies, the latter being a far more complex outcome than the former. These considerations are further complicated by individuals who have polymorphisms that may influence detoxification or other processes such as DNA repair [89]. Individual proclivities as a result of polymorphic genes encoding detoxifying enzymes are also a consideration in the response to cytotoxic therapy [90, 91]. However, if secondary cases of CML are not evident, the latter issue is moot.

The relationship of benzene to the subtypes of leukemia has been examined and reviewed, and comprehensive studies considered in the aggregate do not find evidence to link prior benzene exposure to CML or to any major subtype of leukemia other than AML (and MDS) [87, 92–98].

Benzene is not considered genotoxic. Benzene metabolism takes place initially in the liver. The major liver metabolites of benzene are phenol and catechol. Hepatic metabolism converts phenol to hydroquinone and the latter is converted to 1,4-benzoquinone and semiquinone, which may be the most genotoxic metabolites of benzene [99]. The latter molecules may be generated in the marrow and undergo secondary oxidation as a result of peroxidases in marrow cells, producing both protein-bound and free products [100]. Phenol, also, has been shown to accentuate the genotoxic effects of the quinone derivatives (hydroquinone, 1,2,4-benzenetriol) in vitro. The metabolites of benzene that induce DNA damage, especially phenol, hydroxyquinone, 1,2,4-benzenetriol, and their metabolic products (e.g., 1,4-benzoquinone and semiquinone), are thought to act in a manner similar to alkylating agents [85, 99] and, perhaps, topoisomerase inhibitors [100, 101]. The benzene metabolite trans, trans-muconaldehyde, although genotoxic, is thought to be inactivated efficiently in the liver by glutathione and, thus, the active form is unlikely to reach the marrow in concentrations sufficient to injure hematopoietic cell chromosomes.

Exposure of blood lymphocytes or early-stage (CD34-positive) marrow hematopoietic cells to benzene metabolites has a propensity to induce injury to chromosomes 5, 7, and 8 (and also other chromosomes) [85, 99, 102–104]. Aneusomy (monosomy or trisomy) is the most common event. Abnormalities of chromosomes 5 (monosomy or del(5q31)), 7 (monosomy), 8 (trisomy), and 21(trisomy) are the most prevalent abnormalities seen in cases presumed to be related to benzene metabolites [99, 105]. Monosomy and trisomy are presumably the result of injury to centrioles with subsequent unbalanced distribution of chromosomes to daughter cells (nondisjunction) and not necessarily direct DNA damage. Effects on chromosome 22 have not been reported in cell culture studies. In a small group of benzene-exposed individuals, a higher frequency of monosomy and trisomy was observed than in age- and sex-matched controls [106]. The effect observed on chromosome 9 was the formation of trisomy [99, 106]. Thus, there has been no evidence that benzene metabolites can induce breaks in chromosome 9 or 22, or, more specifically, breaks at the specific sites, 9q34;22q11, required to permit fusion and the resultant BCR-ABL oncogene.

The risk for BCR-ABL–positive CML has not been shown to be increased in studies of late effects of chemotherapy for a variety of malignancies (see Chemotherapy and Acute and Chronic Myelogenous Leukemia above); neither have chemotherapeutic agents nor benzene metabolites that invoke DNA damage in human lymphocytes, CD34 marrow cells, or other cell targets in vitro induced breaks in chromosome 9 or 22, nor resulted in the 9;22 chromosome translocation, the proximate cause of CML. Studies of chromosomes in humans who have had occupational exposure to benzene and developed CML are problematic because one cannot distinguish de novo leukemia from a purported secondary case of CML in an individual. For example, there are no individual distinctions between de novo and suspected radiation-induced cases of CML. Moreover, such observations require the support of prospective epidemiologic studies consistent with causation, which are lacking and may be less likely to be conducted because of the diminishing risk of leukemogenic occupational benzene exposure because of regulatory oversight and the fact that AML causation is sufficient to justify the limitation of benzene exposure. If benzene metabolites act on chromosomes in a manner analogous to alkylating agents and, perhaps, topoisomerase II inhibitors, which most studies conclude, one would not expect to see t(9;22) resulting from benzene exposure.

The four principal types of leukemia are biologically distinctive and should be separated when studying causation. The continuing reference to the term "leukemia" as the dependent variable in epidemiological studies is disconcerting, especially because collapsing all leukemias together can result in a spurious causal relationship of all subtypes to benzene exposure by the weight of the effect of AML itself, the leukemia with the highest incidence rate, magnified further if high dose-time exposures to benzene are under study. The consistency of findings linking high dose-time exposures of benzene in industrial populations to AML and MDS makes that association quite strong and universally accepted, although regulation of benzene exposure in the workplace has made this type of secondary myelogenous leukemia less common in the First World today [93, 95, 98, 107, 108, 109].

The need to avoid generalizations when it comes to potential environmental chemical leukemogens has been summarized thoughtfully by the president of the American Council on Science and Health in her short essay, "Science on Trial" [110].


   SUMMARY
Top
 Learning Objectives
 Abstract
 Introduction
 Causes of AML and...
 Chromosome and Genic Damage...
 Radiation and Acute and...
 Chemotherapy and Acute and...
 Benzene and Acute and...
 Summary
References
 
There are no epidemiological studies that have found a statistically significant association of CML with an exposure to chemicals, such as benzene, alkylating agents, topoisomerase II inhibitors, and other chemotherapeutic agents. There is no body of evidence that satisfies Bradford Hill's requirements for causation (of CML by a chemical exposure) [14].

There is a dissociation of CLL from radiation-induced secondary leukemias (AML, CML, and ALL) and a dissociation of CML (and probably CLL) from chemically induced secondary cancers (AML/MDS and, perhaps, ALL). It would be sophistic to suggest that CML can be caused by the chemicals cited but at a frequency below that which is detectable. The suggestion that a (rare) genetic predisposition or severe immune deficiency in individual persons could be involved in CML onset after chemical exposure has been made [78]. There is, however, no evidence at this time to support such a conjecture. A germline predisposition gene might be involved in a small proportion of cases as a predisposing factor to postchemotherapy AML [111]. Because estimates of secondary AML range as high as 10% of all cases of AML occurring annually, it seems unlikely that a (rare) germline predisposition gene is a major factor. Predisposition genes (syndromic and nonsyndromic) [112] are not precursors of CML. Case reports of familial CML are extraordinarily rare and analytical epidemiological evidence for a familial predisposition is absent, unlike AML [112, 113]. It is possible that cases recorded as AML may have the t(9;22) translocation, but studies, such as those listed in Table 1 and all but one in Table 2, do not suggest that to be the case. Moreover, one would then have to conclude that the phenotype induced is that of AML, not CML. It is very unlikely that the duration of follow-up of populations treated with chemotherapy is too short to identify cases of secondary CML. Based on studies of the appearance of radiation-induced CML and of secondary AML, one would expect to see a significant fraction of CML cases appear within the duration of most published studies. Chromosome translocations found in presumptive post-therapy secondary AML have included t(11q23), t(8;21), t(15;17), t(1;7), and others. The preferential sites of chromosome injury by alkylating agents, topoisomerase II inhibitors, and benzene apparently do not include 9q34 and 22q11.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Causes of AML and...
 Chromosome and Genic Damage...
 Radiation and Acute and...
 Chemotherapy and Acute and...
 Benzene and Acute and...
 Summary
 References
 

  1. Preston DL, Kusumi S, Tomonaga M et al. Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950–1987. Radiat Res 1994;137(suppl 2):S68–S97; (corrected to Matsuo T et al.)[Medline]
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