Influence of cigarette smoking on the presentation and course of acute myeloid leukemia

Y. Chelghoum1, C. Danaïla1, A. Belhabri1, C. Charrin2, Q.-H. Le1, M. Michallet1, D. Fiere1 and X. Thomas1,+

1 Service d’Hématologie Clinique, Hôpital Edouard Herriot, Lyon; 2 Laboratoire Central d’Hématologie et de Cytogénétique, Hôpital Edouard Herriot, Lyon, France

Received 18 December 2001; revised 28 March 2002; accepted 26 April 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

It is known that cigarette smoking is associated with an ~50% increase in leukemia risk. In order to detect a possible influence of cigarette smoking on initial characteristics at the time of presentation and on the course of the disease, we conducted a retrospective study in 643 patients with newly diagnosed acute myeloid leukemia.

Patients and methods:

The study comprised 339 males and 304 females (median age 59 years, range 18–84 years). Two hundred and ninety-six patients (46%), smoking at least one cigarette per day for 6 months, were considered as smokers, while 347 patients (54%) were non-smokers.

Results:

Cigarette smoking was significantly related to male gender (P <0.0001), professional occupancy (P = 0.002), presence of organomegaly (P = 0.01), and lower peripheral blood and bone marrow leukemic cell involvement (P = 0.007 and P = 0.0001, respectively). Leukemia of French–American–British (FAB) M1 subtype was more frequent in non-smokers (P = 0.005). Although not statistically significant, smokers tended to have lower leukocyte counts than non-smokers. No difference was noted in terms of complete remission rates between smokers and non-smokers (67% compared to 64%). However, a higher rate of severe pulmonary infection was observed in smokers during induction chemotherapy (P = 0.02). Cigarette smoking (>=20 pack-years or smoking duration >=30 years) was significantly associated with shorter disease-free survival (P = 0.03) and overall survival (OS; P = 0.02 and P = 0.004, respectively). Other characteristics associated with poor prognosis included mainly older age, unfavorable karyotype, secondary acute myeloid leukemia (AML) and elevated World Health Organization (WHO) performance status. Cigarette smoking was associated with shorter OS in younger adults, but did not significantly influence survival in patients >60 years old. Cigarette smoking worsened the poor OS in patients with unfavorable karyotype, but did not significantly influence the prognosis of other karyotypic risk groups. In a multivariate analysis, only karyotypic grouping and age remained of prognostic value for the occurrence of disease-free and overall survival.

Conclusions:

Cigarette smoking has a deleterious effect on survival in AML by shortening complete remission duration and subsequent survival. It was associated with severe infections during aplasia. Leukemogenic compounds favoring complex karyotypic abnormalities could also be involved.

Key words: acute myeloid leukemia; prognosis; smoking


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Cigarette smoking has not classically been considered an etiologic factor in leukemogenesis, although an association was reported as early as 1978 [1]. However, several epidemiologic studies reported an increased risk of leukemia among cigarette smokers [24]. Cigarette smoking is associated with an ~50% increase in leukemia risk [3, 5]. Many of the studies provided evidence for a dose–response relationship and suggested an association that is most pronounced for acute myeloid leukemia (AML) [2, 3, 68].

The mechanism by which tobacco products might influence leukemia risk is unknown. However, cigarette smoke contains many compounds, some of which have been associated with increased risk for leukemia [9]. Benzene, radioactive components, and possibly other carcinogens are present in tobacco and tobacco smoke, and may act through the production of chromosomal defects [1013]. Cigarette smoking has also been associated with immunologic perturbations [1416]. It is possible, therefore, that cigarette smoking has influenced the evolution of leukemia through potential indirect mechanisms.

The relationship between the development and progression of various forms of leukemia in smokers and non-smokers has not been widely studied. In order to evaluate more thoroughly the association between cigarette smoking and acute myeloid leukemia, we re-contacted AML patients by telephone to obtain a lifetime smoking history. We report the result of a retrospective cohort study of 643 AML cases with regard to the influence of cigarette smoking on the initial characteristics and evolution of the disease.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Smoking information
In order to obtain a lifetime smoking history, personal interviews were conducted with subjects, or with close relatives if subjects were deceased or were too ill to be interviewed. In the event of a death, a reasonable time interval was allowed before contacting surviving family members. From the end of 1984 to the beginning of 1998, 852 patients were admitted to our hospital for diagnosis and treatment of newly diagnosed AML. Patients with AML or close relatives were interviewed from January to March 1998 (median duration from diagnosis to interview 6.4 years, range 0.1–14.6 years). The study population consisted of 643 (118 living and 525 deceased) leukemia cases. Interviews were therefore completed for 643 (75%) of the 852 cases who were eligible for study. Reasons for not including patients were loss of follow-up of patients or their close relatives. Only one patient refused to participate. Prior to interview, oral informed consent to participate in the study was obtained from each subject or their relatives.

For the telephone interviews, a structured questionnaire was used to obtain detailed information on the use of tobacco, occupational history, antecedents of toxic exposure or myelodysplasia, and medical conditions. For cigarette smoking habits, questions were asked about smoking status (never/former/current), start and stop dates, age at the start of smoking, the usual number of cigarettes smoked per day and the maximum number of cigarettes smoked for a minimum of 1 year. These data were also collected separately for smokers of filtered and non-filtered cigarettes. Smokers (ex-smokers or current smokers) were those who reported smoking at least one cigarette a day for 6 consecutive months. Former cigarette smokers were asked about the year of cessation. Questions about the use of cigars and pipe tobacco were restricted to smoking status, and the amount smoked. In addition to smoking habits, the questionnaire also enquired about cardiovascular and respiratory symptoms. Patients whose leukemia was known to be secondary to chemotherapy or radiotherapy for other conditions were analyzed separately. Cigarette smokers were categorized according to daily consumption into two groups: 1–20 and >20 cigarettes per day. Occasional smokers smoking less than one cigarette a day were included in the first group. From these data, the total number of pack-years of smoking was calculated for each subject. Pack-years were calculated as the product of the number of cigarettes smoked per day (divided by 20) times the number of years smoked.

Clinical and laboratory data
Diagnosis was based on May–Grünwald–Giemsa smears of bone marrow aspirates. Leukemic cells were classified according to the French–American–British (FAB) morphological and cytochemical criteria [17]. Cytogenetic analysis was performed on bone marrow leukemic cells or occasionally on short unstimulated peripheral blood leukemic cell cultures by using a standard technique. Metaphases were treated for RHG (reverse heat Giemsa) banding. Cytogenetic analysis was occasionally completed by a FISH (fluorescence in situ hybridization) technique using chromosome-specific paint probes. Chromosomal abnormalities were classified according to the International System for Cytogenetic Nomenclature [18]. Chromosomal analysis was performed in 596 cases. Evaluable karyotypes were obtained in 527 patients (82% of participants). Karyotypes were divided into favorable karyotypes [t(15;17), t(8;21), chromosome 16 abnormality], adverse karyotypes [complex karyotype, –7, 3q abnormality, del(5q), –5] and intermediate karyotypes [no abnormality, +8, 11q23, +21, del(7q), del(9q), +22, other numerical and other structural abnormality] according to previously published work [19]. Complex karyotypes were defined by the presence of at least three chromosomal changes.

Treatments
Leukemia patients were registered to treatment protocols on the basis of clinical and laboratory data available at time of presentation. Six hundred and twenty-six of the 643 patients entered onto different successive intensive chemotherapy trials. The remaining 17 patients were treated palliatively because of an advanced age and/or poor medical condition, or died early before any chemotherapy could be given. Induction chemotherapy consisted of an anthracycline and cytarabine ± etoposide ± 6-mercaptopurine combination. Marrow response status was determined by bone marrow aspirates at around day 30 after starting induction chemotherapy. Patients who did not achieve complete remission (CR) in one course of chemotherapy, as evaluated by the persistence of blast in bone marrow aspirate, received salvage therapy. Post-remission therapy was given according to the protocol design in which the patients were included. It comprised one or two consolidation chemotherapy courses with or without autologous stem cell transplantation. Patients with a human leukocyte antigen (HLA) sibling donor and who were <50 years of age were scheduled for allogeneic bone marrow transplantation.

CR was defined according to the Cancer and Leukaemia Group B (CALGB) criteria as <5% blasts in bone marrow aspirates, with evidence of maturation of cell lines and restoration of peripheral blood counts [20]. Patients failing induction therapy were categorized as failures and divided into: (i) death during induction (OF; death occurred while the patient was receiving induction therapy); and (ii) resistant (RD; the patient survived induction but resistant leukemia re-developed). Disease-free survival (DFS) was calculated from the first CR to the time of relapse or death from any cause. Overall survival (OS) was defined as time from diagnosis to death. Hematological relapse was considered when >5% blasts were seen in two bone marrow aspirates obtained at a 15-day interval [20].

Statistical analysis
Smoking was treated as both a categorical (smokers or non-smokers) and a continuous or transformed continuous variable (years of use, number of cigarettes per day, and pack-years). Initial characteristics of smokers and non-smokers were compared using the {chi}2 test and analysis of variance. Survival curves were calculated according to the product-limit estimate method of Kaplan and Meier, and compared using the log-rank test. Single parameters were investigated for their influence on CR achievement and survival duration. Multivariate analysis was made by a multiple logistic regression for CR rate and by the Cox’s proportional hazard model for DFS and OS. All probability values were two-tailed and reported as statistically significant if <0.05. Statistical analysis was performed using the BMDP PC-90 statistical program (BMDP Statistical Software, Los Angeles, CA, USA).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Characteristics of patients
A total of 643 patients with newly diagnosed AML was included in this study. Median age was 59 years (range 18–84 years). Three hundred and thirty-five patients (52%) were aged >=60 years. Two hundred and ninety-six patients (46%) were classified as smokers, and the remaining 347 were considered non-smokers. Characteristics of the patients at time of diagnosis according to their smoking status are indicated in Table 1. Cigarette smoking was significantly related to male gender (P <0.0001), professional occupancy (P = 0.002), presence of organomegaly (P = 0.01), lower mean corpuscular volume (P = 0.009) and higher creatininemia (P <0.0001). Although not statistically significant, smokers tended to have lower leukocyte counts than non-smokers. On the other hand, peripheral blood leukemic cells and bone marrow leukemic cells were lower in smokers than in non-smokers at time of diagnosis (P = 0.007 and P = 0.0001, respectively). M1 AML were less frequent in smokers than in non-smokers (14% compared with 23%, P = 0.005). Smoking was not related to any other clinical or biological characteristics measured at time of diagnosis.


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Table 1.  Comparison of initial characteristics in smokers and non-smokers at diagnosis
 
Treatment outcome
Four hundred and eighteen of the 643 patients achieved CR (65%). Three hundred and sixty-nine patients achieved CR after one course (57%) and another 49 patients (8%) achieved CR after a second induction therapy. The frequency of toxic deaths related to induction chemotherapy was 7%. Severe pulmonary infections during induction were significantly higher in the smokers’ group (26%) than in the non-smokers’ group (18%) (P = 0.02). This, however, did not influence CR rates. One hundred and ninety-eight of the 296 smokers (67%) and 220 of the 347 non-smokers (64%) achieved CR. As post-remission therapy, 21 patients received allogeneic bone marrow transplants (BMT) and 17 received autologous stem cell transplants (SCT) in the smokers’ group, while 32 and 22 patients underwent allogeneic BMT and autologous SCT in the non-smokers’ group, respectively. Median DFS and OS were 12.1 and 12.2 months, respectively, for the entire cohort. When considering smokers and non-smokers, median DFS and OS were 10.6 and 11.3 months, and 12.8 and 12.7 months, respectively. Results according to smoking status are summarized in Table 2. There was no difference in terms of outcome between the 643 patients who entered the study and those who did not.


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Table 2. Treatment outcome according to smoking status
 
Prognostic value of cigarette smoking
Patients who had smoked for >=30 years had more frequently persisting bone marrow blasts at time of induction evaluation than patients who had smoked for <30 years (P = 0.03). Quantity and duration of smoking were significantly associated with shorter DFS and OS (Table 3; Figures 1 and 2). This was also observed when considering only smokers with cut-off at 20 pack-years smoked and at 30 years of smoking (Table 3). There were no significant differences in the number of pack-years smoked and smoking duration when considering karyotype grouping, except for with the unfavorable risk group. In this group, the median OS was 8.7 and 4.5 months in patients with <20 and >=20 pack-years smoked, respectively (P = 0.05). Similarly, median OS was 8 months in patients who had smoked for <30 years compared with 4.3 months in those who had smoked for >=30 years (P = 0.03). Although not significant, total or partial deletion of chromosome 5 and complex karyotypes were more frequent in smokers than in non-smokers. Among smokers, these karyotypic abnormalities were more frequent in patients with >=20 pack-years smoked (Table 4). When considering age, quantity and duration of smoking were only of significant prognostic value in patients aged <60 years. Median OS was 31.7 months in young adults with <20 pack-years smoked compared with 12.6 months in those with >=20 pack-years smoked (P = 0.01). Median OS was 29.1 months in patients who had smoked for <30 years compared with 10.7 months in those who had smoked for >=30 years (P = 0.05).


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Table 3. Prognostic value of cigarette smoking
 


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Figure 1. Overall survival according to pack-years smoked.

 


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Figure 2. Overall survival according to duration smoked.

 

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Table 4. Chromosomal abnormalities in unfavorable karyotype risk-group according to smoking status
 
Other prognostic factors
Other initial characteristics of patients were also submitted to univariate analysis with regard to CR achievement, DFS and OS. Other characteristics associated with poor prognosis included mainly older age, unfavorable karyotype, secondary AML and elevated WHO performance status. Parameters that were significantly associated with cigarette smoking or that tended to have prognostic value were simultaneously included in a multivariate analysis performed in patients in whom all these parameters were available. Only karyotypic grouping and age remained of prognostic value for the occurrence of DFS [P <0.0001, relative risk (RR) = 1.01, 95% confidence interval (95% CI) 1.00–1.02; and P <0.0001, RR = 1.75, 95% CI 1.38–2.21, respectively] and OS (P <0.0001, RR = 1.79, 95% CI 1.50–2.15; and P <0.0001, RR = 1.02, 95% CI 1.01–1.03, respectively) in the multivariate model.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The impact of tobacco smoking on lung cancer risk has been investigated thoroughly since the 1950s, but other types of cancer have also been associated with smoking [3, 5, 6, 21, 22]. This study examines the case of AML, for which a meta-analysis has indicated an elevated risk among people who have ever smoked compared with non-smokers [8]. Although some studies have observed no significant associations with smoking [23, 24], the overall attributable risk for acute leukemia from smoking has been estimated at between 7% and 14% [7, 8]. In contrast with another study [21], no association was found with respect to gender by our group. Smoking may be responsible for a larger proportion of leukemia cases in the elderly. Among people aged >=60 years, smoking was associated with a two-fold increase in risk for AML [7]. In our study, we demonstrated a relationship between the duration of toxic exposure and the outcome of leukemia. However, when separating leukemic patients according to age, cigarette smoking appeared to be only of prognostic value in young adult patients. An increased risk among older patients would have seemed more evident, reflecting differences in DNA repair, a long latency for any smoking effect, or differences in the numbers of cigarettes smoked. Such findings could probably have been masked by other prognostic factors in the elderly.

Our AML patient population had clinical and biological characteristics similar to those observed in most other series described in the literature. At time of presentation, we did not find any significant differences in the degree of leukemic proliferation between smokers and non-smokers. Cigarette smoking has long been known to induce a rise in peripheral leukocyte count in normal individuals, especially in heavy smokers and in those who inhale the smoke [25]. However, the precise mechanism of this phenomenon, which persists several years after quitting smoking, is unknown [26]. Although cigarette smoking is known to increase peripheral leukocyte count in normal individuals, no such increase could be demonstrated in our smoking patients by comparison with the non-smokers. Smokers even tended to have lower leukocyte counts than non-smokers, confirming a previous report on cigarette smoking in chronic myeloid leukemia [27].

As with all retrospective studies, biased or inaccurate reporting of exposures must be considered. The next of kin would be less likely than the cases themselves to recall details of smoking, particularly in the distant past, but this would suggest again that the risk estimated in this study is an underestimate of the actual risk. The use of next-of-kin respondents for deceased cases may have introduced some bias. However, this probably cannot account for our findings since spouses are usually aware of their partners’ smoking habits. The next of kin would be less likely than the cases themselves to recall details of smoking, but this would suggest again that the risk estimated in this study is an underestimate of the actual risk. Some subjects may have changed their smoking habits during the course of the study. However, subjects with leukemia were not more likely than other subjects to have stopped before their illness occurred. The positive association between tobacco smoking and AML may be due, at least in part, to confounding factors such as occupational exposure to benzene or radioactive materials. Smokers were more likely to report exposure to chemicals and solvents, but not to radiation, than non-smokers [28].

Overall, our study supports other studies that suggest a positive association between cigarette smoking and some forms of leukemia. Risk increased significantly with the number of pack-years smoked and decreased with the number of years stopped smoking [6]. We showed that outcome of treatment in AML patients was also related to the intensity and duration of cigarette smoking. Cigarette smoking may lead to leukemias of specific morphological and chromosomal types. The M1 AML subtype appears, however, more frequently in the life-long non-smoker group. Smoking was associated with increased risk for AML classified as FAB type M2 at all ages [7]. M2 is more common in chemically induced leukemia and is observed following exposure to alkylating agents and radiation. Associations between smoking and M6 and possibly M5 subtypes have also been reported [29]. A negative association with the M3 subtype was suggested [7, 29]. In a 16-year follow-up survey of US military-service veterans, a relationship has been found between cigarette smoking and monocytic types of AML [2]. Rising trends for all AML types have been observed when the number of cigarettes smoked increase [3]. Secondary AMLs had an equally poor outcome in smokers and in non-smokers.

No clear associations between smoking and cytogenetic subtypes of AML have been observed [29]. However, although not significant, long duration smoking and high cumulative smoking doses (pack-years) tended to be associated with unfavorable cytogenetics. Complex karyotypes were more frequent in patients with >20 pack-years smoked. Smoke exposure may lead to non-random molecular genetic changes that affect the development or proliferation of stem cells. Cells at a specific stage of differentiation may be more vulnerable to genetic damage induced by smoking or other agents. In some other studies, cigarette smoking has been associated with specific cytogenetic abnormalities such as loss of chromosome 7 and Y, and trisomy 13 [7]. It can be postulated that cigarette smoke might favor relapse by further increasing the genetic instability of leukemic cells. Related effects may include alteration of apoptosis and alteration of clonal expansion of blood progenitor cells [30]. On the other hand, cigarette smoking has been associated with immunologic perturbations [15, 16]. However, smokers generally survive for a shorter time than non-smokers, and we cannot exclude the possibility that the effect of smoking, observed in our study, may not be specific for leukemia at all.

Our conclusion is that cigarette smoking has a deleterious effect on survival in AML by shortening the time of CR and subsequent survival. First, it affects the pulmonary tract, favoring severe infections during aplasia. Secondly, although cigarette smoke does not come into direct contact with the hematopoietic tissues, it is still possible that some carcinogenic agent derived from cigarette smoke might reach these tissues. The mechanism as to how this occurs remains to be determined. Cigarette smoke contains urethane and nitrosamines, which cause leukemia in animals, as well as benzene and radioactive compounds, which are known to be leukemogenic in man.


    Footnotes
 
+ Correspondence to: Dr X. Thomas, Service d’Hématologie Clinique, Hôpital Edouard Herriot, Place d’Arsonval, 69437 Lyon cedex 03, Lyon, France. Tel: +33-472-11-73-95; Fax: +33-472-11-74-04; E-mail: xavier.thomas{at}chu-lyon.fr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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