Title: design, patient characters and type of

Title: Effect of
smoking on hematopoietic cell transplantation: a systemic review and future



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Smoking and BMT


Authors and Affiliations

Mohammed Abufarhaneh 1, Shawna Ehlers 2,
Shahrukh Hashmi 3, 4

Department of Internal Medicine,
KFSHRC, Riyadh, KSA 1

Department of Psychology, Mayo
Clinic, MN, USA 2

Department of Medicine, Mayo Clinic,
MN, USA 3, 4

Oncology Center, KFSHRC, Riyadh, KSA
3, 4


number included

Text pages: __  Tables: __,
Figures: _ ; Words: ______


Corresponding Author

Shahrukh Hashmi MD MPH

Dept. of Medicine, Mayo Clinic, 200 1st street,
Rochester, MN, USA 55901

[email protected]


Keywords: Smoking,
mortality, transplant


Conflicts of Interest: There are no
conflicts of interest to disclose from any authors.


Authorship Contributions

SKH and MA wrote the first draft of the manuscript. All authors
contributed substantially to the conception, acquisition, analysis, and
interpretation of the data for the work.









The purpose of the study was to conduct a systematic literature
search on the relationship between the smoking and hematopoietic cell
transplantation outcomes.



We conducted a systematic literature search in PubMed, Sage
Journals, Science Direct, Springer Link, Amedo, ProQuest, OVID-MEDLINE and
Wiley -Blackwell of studies that showed the Effect of Smoking on the outcomes
of hematopoietic cell transplantation. Data were gathered from the studies according
to our inclusion criteria.



19 Articles were included. The studies were varied in term of study
design, patient characters and type of hematopoietic cell transplantation.



Based on our review we found that smoking exposure increase the
risk of Cardiovascular diseases, Secondary Cancers, Infections and Pulmonary
complications in hematopoietic cell transplantation recipients.



Tobacco kills up to half of its users. It kills more than 7 million
people each year.1

More than 16 million Americans are living with a
disease caused by smoking. For every person who dies because of smoking, at
least 30 people live with a serious smoking-related illness. Cigarette smoking
is responsible for more than 480,000 deaths per year in the United States,
including more than 41,000 deaths resulting from secondhand smoke exposure.
This is about one in five deaths annually, or 1,300 deaths every day. If
smoking continues at the current rate among U.S. youth, 5.6 million of today’s
Americans younger than 18 years of age are expected to die prematurely from a
smoking-related illness. This represents about one in every 13 Americans aged
17 years or younger who are alive today.2Current trends show that tobacco use will cause more than 8 million
deaths annually by 20303.  On
average, smokers die 10 years earlier than nonsmokers. 4 Due
to the lack of an up-to-date systematic review for smoking and hematopoietic
cell transplantation (HCT) association we have done our comprehensive study.



Data sources:

We conducted an unrestricted systematic literature search (up to
AUG 2017) in PubMed, Sage Journals, Science Direct, Springer Link, Amedo,
ProQuest, OVID-MEDLINE and Wiley -Blackwell for studies describing the
association between cigarette smoking and HCT outcomes. The search focused on
three themes of Medical Subject Headings (MeSH) terms and related exploded
versions: smoking, tobacco or cigarette, HCT and studies with a prospective


Study selection:

The study
population included all patients who received allogenic or autologous bone
marrow transplantation. All cohort studies were included. Case reports, abstracts or
unpublished work with insufficient information were excluded. We evaluated
eligible articles first by screening titles or abstracts, followed by full-text


Data extraction:

We extracted the following information using a pre-designed
collection form: study characteristics (authors, study type, publication year,
journal, and number of participants), smoking status and patient’s
characteristics (mean age and sex), transplant type, conditioning regimen,
graft versus host disease risk (GVHD) and
transplant outcomes (Cardiovascular diseases, Secondary Cancers, Infections and
Pulmonary complications, relapse and non-relapse mortality and overall



We identified
447 records from the literature search of which 19 articles were included. Data
from 22106 individual patients were obtained and included in the systematic
review. Figure1

Patient characteristics
table 1

Outcome table 2
and 3




Smoking and
Pulmonary complications:

In Marks et al.
5 study, smokers were at higher risk of bronchiolitis obliterans (BO).
In Mo et al. 6 and Tomas et al. 7 studies the
incident of BO was 9% and 1.7% respectively. The risk of idiopathic pneumonia
syndrome (IPS) was higher among smokers in three studies.1,2,18 In
Mo et al. study the risk of IPS was 68.1%. Savani et al. 8 found
that the incidence of IPS is 4.1% among smokers. Pulmonary complications were higher
among smokers in Ehlers et al. 9 46%. In Tran et al. 10 smokers
were at higher risk of early respiratory failure. At three years
post-transplant the cumulative incidence of pulmonary complications was 26% in
non-smokers, 36% in low dose smokers and 46% in high dose smokers in Hanajiri
et al. 11. The hazard ratio was 2.9 among smokers versus
non-smokers in Chang et al. 12 In Schlemmer et al. 13 study
the risk of interstitial lung disease (ILD) was 2.4% among smokers. In Ho et
al. 14   study the incidence
of diffuse alveolar hemorrhage (DAH) was 7% and over all non-infectious
pulmonary complications was 21%. Adult respiratory distress syndrome risk was
2.7% among smokers in Savani et al. 8.


Smoking and
cardiovascular complications:

In Chow et al. 15
study the incidence of ischemic heart disease (IHD), heart failure (HF)
and cerebrovascular accidents was 3.8%, 6 % and 3.5% respectively. At 15 years
post-transplant the cumulative incidence of cardiovascular diseases (CVD) was
6% in Tichelli et al. 16 study. In Qazilbash et al. 17   the
incidence of CVD was 12.5% at 2.5 years. HF and atrial fibrillation incidence
was 7% in the same study. Chang et al. 12   found
that the hazard ratio of smoking is 1.6 in comparison to non-smokers.


Smoking and new

In Ehlers et
al. 9 study, the incidence of new cancers was 3% in smokers.
Frequency of oral cancers were higher among smokers in Mawardi et al.18
and Shah et al.19 In Inamoto et al. and Bilmon et al. the risk of
lung cancers was higher among smokers versus non-smokers.


Smoking and

In Miceli et
al. 22   study, the incidence of severe
infections was 31.6%. Bacteremia occurred in 62.9% of patients. The incidence
of pneumonia, severe colitis and septic shock was 34.4%, 21.5% and 1.7%
respectively. Risk of pneumonia was 15% in smokers as detected in Ho et al. 14
study. Invasive fusariosis occurred in 2.6% of patients in Garnica et al. 23
study. The HR of infections was 1.8 among smokers versus non-smokers in Chang
et al. 12 study. Incidence of Pneumonia in tobacco users was 2.7%
in Savani et al. 8 study. In Hanajiri et al. 11 study
the incidence of infections was higher in smokers than non-smokers, 17% non-smoker and 55% in smokers. The infectious
complications in Mo et al. 6   study occurred more in smokers. Incidence
of bacterial infections was 25% followed by viral infections (21.4%) and fungal
infections (7.1%). In Ehlers et al. 9   study, infections occurred in 13%
of tobacco users. People who smokes had a higher risk of pneumonia in Marks et
al. 5 study.



In Marks et al.
5   study the non-relapse mortality (NRM) at 5
years was 28% in non-smokers and 50% in smokers. In Ehlers et al. 9
study, the NRM was 26.7% in smokers and 19.8% in non-smokers. Tran et al. 10   study, the NRM was 37% in non-smokers, 42%
in previous smokers and 34% in current smokers. At 3 years the NRM in Hanajiri
et al. 11 study was 20% in non-smokers, 22% in low dose smokers
and 24% in high dose smokers. In Schlemmer et al. 13   study
the NRM was 33%. The mortality because of 2ry cancers was 55% in Shah et al.
study 19.   



In Marks et al.
5 study, the incident of relapse was 8% in non-smokers and 16% in
smokers at 5 years. The relapse in Chow et al. 15   study was 28.7%. In Ehlers et al. 9
study, the relapse incidence was 25.7% in non-smokers, 18.8% in previous
smokers and 8.9% in current smokers. In Tran et al. 10   study, the incidence of relapse was 20% in
non-smokers, 18% in previous smokers and 18% in current smokers. In Hanajiri et
al. 11   study, the relapse incidence was 29% in
non-smokers, 25% in low dose smokers and 35% in high dose smokers at 3 years
after HCT.  



In Marks et al.
5 study, the overall survival (OS) was 68% in non-smokers, 62% in low
dose smokers and 50% in high dose smokers at 5 years post HCT. After 100 days
of transplant the OS was 31.3% in patients with late onset severe pneumonia
(LOSP) in Mo et al. 6   study.
In Ehlers et al. 9 study, the OS was 42.9% in non-smokers, 25.7%
in previous smokers and 19.1% in current smokers at 3 years. In patients with
ejection fraction (EF) of less than 45% the OS was 25% in comparison to patients
with EF of more than 50% which was 38% in Qazilbash et al. 17   study. In Mawardi et al. 18   study,
the OS was 70% in patients with invasive oral cancer. In Schlemmer et al. 13 study, the OS was 61% in patients with interstitial lung disease
(ILD) 24 post HCT. In Savani et al. 8   study, patients who received lung shielding had OS
of 70% in comparison to the patients who did not receive lung shielding the OS
was 52%.



Using this data from 19 articles which
included more than 20,000 patients, we found that smoking in patients who received
HCT associated with higher incidence of CVD, new cancers, pulmonary
complications and new infections. Incidence of relapse was higher among tobacco
users. Moreover, smoking decreased the overall survival in transplant
recipients. A recent New England Journal of Medicine article showed that
smokers were three times more likely to die of all cancers than nonsmokers.1
That same study, however, also showed the protective nature of quitting;
individuals who quit between the ages of 55 and 64 gained 4 more years of life,
and the reduction in premature death was even more favorable for those who quit
at younger ages.1 ###


Tobacco use was associated with higher rate
of non-relapse mortality (NRM), relapse and decrease in overall survival (OS). 5,9,10,11

Smoking increases the risk of CVD in transplant
recipients as observed in some studies.

The incidence of oral and lung cancers was higher
in smoker.

As observed in some studies, the pulmonary complications
were higher among smokers. . 5,6,7,8,9,10,11,12,13,14

Infectious complications were associated with
tobacco use in some of included studies. 5,6,8,9,11,12,14,22,23



Grading system
is used to assess the quality of evidence and strength of recommendations of published
guidelines. For the quality of evidence, it has been categorized into 3 levels.
Level A is the high level of evidence in which consistence from well performed
high quality studies. Level B is moderate to low evidence in which studies from
systematic rjlevise with few important limitations. Level C is the very low
evidence studies serious flaws, expert opinion and standards of care. Grade of
recommendation are four grades. Grade I strong recommendation. IIa moderate.
IIb weak recommendation. III not to do. According to benefit and risk.



The national comprehensive cancer network (NCCN) published an
updated guideline for smoking cessation in patients with cancers. Combining
pharmacological and behavior therapy is the most effective approach and leads
to the best result for smoking cessation. The best medical therapy was a
combination of nicotine replacement therapy (NRT) and varenicline. Multiple
counseling sessions is very effective as well. Also, they recommended to
document an updated smoking status in each visit, quit attempts made, and
interventions utilized. Because of smoking relapse is common they recommended
to provide guidance and support to encourage smoking cessation attempts.
Cessation of smoking should be offered and continued throughout the treatment
plan. All recommendations were grade 2A unless otherwise indicated 24.



society of clinical oncology (ASCO) has published guidelines for smoking
cessation. Firstly, they encouraged the oncology providers to talk to their
patients about the poor treatment outcomes regardless of whether the cancer was
tobacco related. and they recommended to assess the tobacco use in every visit.
Secondly, patients should be motivated to stop smoking. Patient should now that
smoking will decrease their treatment effectiveness. They also recommended to
monitor patient attempts to quit, any success in quitting and any relapse.
Thirdly, addition of tobacco should be considered an addiction to nicotine.
Cessation strategies that recommended by the physicians more likely to be
followed and adhered by the patients. Because of electronic cigarettes and
smokeless tobacco are not evidenced based methods for smoking cessations they
are not recommended by ASCO. Lastly, every staff member should be educated
about smoking dangers and they should be encouraged to stop using it. Medical
records should be updated about smoking status every visit. 25


In September
2015, the united states preventive services task force (USPSTF) published a
recommendation for smoking cessation. In adults who are not pregnant they
recommended that all physicians should ask the patients about tobacco use,
advise them to stop using it and provide behavioral as well as U.S. Food and
Drug Administration (FDA)-approved pharmacotherapy for cessation to adults who
smokes (Grade A). In pregnant women, the USPSTF recommended that all physicians
should ask the patients about tobacco use, advise them to stop using it and
provide behavioral interventions for cessation (Grade A). 26  

To the best of our knowledge this is the first systemic
review of the association between smoking and bone marrow transplant. Patient
with a history of smoking were at higher risk of pulmonary complications, CVD,
new cancers and infections. Overall survival was lower in smoker group. The
risk of relapse and non-relapse mortality was higher among smokers.


Limitations of this study include absence of individual level
of data. So, metanalsysis cant be done.

Strengths  the largest
study, association of smoking and iutcomes and we looked for oncological /