Transcript Risk of cancer after blood transfusion from donors with

Risk of Cancer After Blood Transfusion
From Donors with Subclinical Cancer:
A Retrospective Cohort Study
K. Pavenski, MD FRCPC
Transfusion Medicine Resident, McMaster University
TMR Journal Club
June 20, 2007
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Introduction
 Can blood transfusion transmit cancer? YES
 Postulated mechanism
• Immune modulation
• Transmission of factors causally related to cancer development (ex.
Oncogenic virus)
• Engraftment of malignant cells of donor origin
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 Cohorts and case control studies
 Blomberg 1993 (case control; based on age and sex stratified analyses,
odds ratio (OR) 1.74, 95% confidence interval (CI) 1.24 to 2.44 for
lymphoma and skin cancer)
 Brandt et al 1996 (cohort; age and sex adjusted RR for Non-Hodgkin
lymphoma (NHL) 1.74, 95% CI 1.24 to 2.44)
 Cerhan et al 2001 (cohort; age-adjusted RR for NHL 1.6, 95% CI 1.2 to
2.1)
Introduction
 Can blood transfusion transmit cancer? Yes
 Proof of principle
– Cancer can be transmitted by solid organ or tissue transplant,
hematopoietic stem cell transplant (HSCT) and from mother to
fetus (AABB News Sept/Oct 2006)
– Caveats: immunosuppression, HLA similarity, prolonged
exposure, tissue damage at exposure site, etc.
– Blood, HSCT and solid organ or tissue transplant can transmit
oncogenic viruses (ex. HHV-8)
– Needles or surgical instruments can transmit cancer cells
– Cancer cells can survive in human graft recipients
– Long-term donor microchimerism after blood transfusion has
been demonstrated (Reed 2007)
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Introduction
• Can blood transfusion transmit cancer? NO
• Case control studies (all deal with NHL)
 Adami et al 1997 (odds ratio 0.93, 95% CI, 0.71 to 1.23)
 Chow & Holly 2002 (odds ratio 1.0, 95% CI 0.84 to 1.2)
 Maguire-Boston et al 1999 (odds ratio 0.84, 95% CI 0.50 to
1.41)
 Zhang et al 2004 (odds ratio 1.0, 95% CI 0.7 to 1.3)
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Introduction
 Can blood transfusion transmit cancer? NO
 Proof of principle
 Unsuccessful attempts at transmission of cancer to human research
subjects by blood transfusion (Thiersch 1945, Lanman et al 1950) or
sternal marrow route (Thiersch 1946)
 Intentional transfusion of blood from patients with CML to patients
with AML and acute infection (Schiffer et al 1983)
 In rare cases malignant granulocytes persisted but recipients did
not develop CML
 Accidental transfusion of blood from cancerous donors does not
result in cancer in recipient (Vargas et al 1999 (case, CML),
Greenwald 1976 (cohort, leukemia and lymphoma))
 Cancer recurrence is no more likely in patients who received intra-op
salvaged autologous blood versus allogeneic blood (Stoffel 2006)
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Methods
 Design:
 Retrospective cohort study
 Goal of the study:
 To investigate the possible risk of cancer transmission
through blood transfusion
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Methods
• Databases:
– SCANDAT
• All computerized registers of blood donations and transfusions
maintained by blood banks and transfusion medicine clinics in
Sweden from 1968-2002 and Denmark from 1982-2002
• Donor and recipient variables: DOB, sex, type, number and dates
of donations/transfusions
• Each transfused blood unit can be traced to its donor
– National population and health registers of Denmark and
Sweden
• Included national registers of migration, death, cancer and in-
hospital care
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Methods
• Recipients
– All individuals with no history of cancer and who
received at least 1 unit of WB, RBC, platelets, or plasma
between 1968 and 2002
– All transfusions during the first 30 days after the first
recorded blood transfusion were considered
• Donors
– All donors that have contributed to the above
transfusions
– Precancerous blood donors - donors who have been
diagnosed with malignancy (excluding non-melanoma
skin cancer) within 5 years of a blood donation
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Methods
 Definitions:
 Exposed – recipients of blood from precancerous donors
 Unexposed (controls) – recipients of blood exclusively
from donors NOT diagnosed with cancer within 5 years
of donation
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Methods
• Follow-up
– Started 6 months after the first recorded transfusion
• Recipients who developed cancer, died or emigrated within first 6
months were excluded from analysis
• To exclude recipients with incipient cancer
– Ended on the date of first cancer diagnosis, death,
emigration, or December 31, 2002
• Censored all recipients who after the initial 30-day
exposure period received a transfusion originating
from a precancerous donor, unknown donor or a
donor with less than 5 years of follow-up
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Results
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Table 1
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Results
• Relative risk of cancer after transfusion with blood from a
precancerous donor was assessed as incidence rate ratios
estimated from Poisson regression models
• Potential confounding factors:
– sex, age (<40, 40-59, 60-69, or >70), area of residence at the time of
first transfusion, ABO blood group, number of transfusions during
the first 30 days after first transfusion (1-2, 3-4, 5-9, or >10
transfusions), calendar period (1968-79, 1980-89, or 1990-2002)
and number of years since first transfusion (<1, 1, 2, 3-4, 5-9, 10-19,
or 20-34 years)
– Attained age, calendar period, and time since first transfusion were
treated as time-dependent covariates allowing individuals to move
between categories with time
• Subanalyses stratified by recipient age and sex, calendar period
of transfusion, number of units administered and component
type
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Results
 All recipients
 Contributed 3 200 800 person-years of follow-up
 29 651 primary cancers were diagnosed
 Exposed
 12 012 (3%) of recipients
 Contributed 90 928 person-years of follow-up
 978 cancers were recorded
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Table 2
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Results
 Overall, there was no excess of cancer among
recipients who had received one or more blood
products from a precancerous blood donor
compared with recipients who had received blood
only from non-cancerous donors
 Adjusted relative risk (RR) 1.00, 95% confidence interval
(CI) 0.94-1.07
 The relative risk was not substantially affected by
sex, age, calendar period, or number of
transfusions
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Results
 Analyses stratified by sex and follow-up revealed a
significantly increased cancer risk among exposed
male recipients in the period between 5-9 years after
the first transfusion
 Adjusted RR 1.19, 1.03-1.38
 This was not true for women or any other follow-up
period
 Spurious result?
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Results
 Sensitivity analyses
 No obvious pattern observed when definition of
precancerous blood was varied
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Number of years
Adjusted RR
4
1.00 (0.93-1.07)
3
1.00 (0.92-1.07)
2
0.93 (0.84-1.02)
1
0.93 (0.81-1.05)
Results
 Sensitivity analyses
 Little variation in adjusted rate ratios of cancer among
recipients of precancerous blood from donors at
different anatomical sites compared to recipients of noncancerous blood
 Risk of cancer transmission did not vary by type of cancer in the
donor
 Little variation in adjusted rate ratios of site-specific
cancers among recipients of precancerous blood relative
to recipients of non-cancerous blood
 There was no excess occurrences of cancers at any specific sites
in the recipients
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Table 3
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Table 4
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Results
 Sensitivity analyses:
 No excess risk when the sites deemed at highest risk of
hematogenous spread (lung, liver, skeleton and CNS)
were combined
 Adjusted RR 1.00, 95% CI 0.85-1.17
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Results
 Subanalysis (Danish data only)
 Recipients of blood from donors who presented with
metastatic cancer within 5 years of donation vs.
unexposed recipients had no excess cancer risk
 Adjusted RR 0.99 with 95% CI 0.48-1.79
 Analyses according to type of blood component,
storage time, and time to cancer death of the donor
showed no notable variation
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Critical Appraisal
 Were there clearly defined groups of patients, similar in all
important ways other than exposure to blood from
precancerous donors?
 Yes (Table 1)
 Strict definitions of exposed/unexposed to avoid
misclassification
 Analysis restricted to individuals with at least 5 years of follow-up
 Follow-up began 6 months after transfusion to exclude cancers
already present at first transfusion
 Transfusion information restricted to the first 30 days of an
individual’s recorded transfusion history
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Critical Appraisal
 Was assessment of outcomes either objective or blinded to
exposure?
 Exposure not blinded, however, assessment was
unbiased by virtue of study design
 Since impending cancer of a blood donor was unknown at the
time of transfusion, the possibilities for confounding were limited
 Subanalyses taking into account other potential confounders (ex.
blood group, area of residence, calendar period) yielded the
same results
 Outcome was objective (diagnosis of cancer)
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Critical Appraisal
 Was the follow-up of study patients long enough?
 Follow-up probably sufficiently long
 Time between exposure and clinical cancer outcome was assumed
to be less than 5 years
unrealistically short induction period for early stage carcinogens
 circulating tumour cells can be detected at an early stage (ex. 16-45%
of men with localized prostate cancer have detectable disease in
peripheral circulation or bone marrow)

 Long-term excess risk is probably very low
 Point estimate of relative risk is slightly below 1 with an upper
95% CI 1.38 for the follow-up period 20-34 years after first
transfusion
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Critical Appraisal
 Was the follow-up of study patients complete?
 Yes
 SCANDAT database of high quality (internally and
externally consistent)
 Cancer registers of Sweden and Denmark are known to
have a high degree of completeness
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Results
 Do the results satisfy “diagnostic tests for
causation”?
 Did exposure precede the onset of outcome?
 Yes
 Is there a dose-response gradient?
 Not observed
 Is association consistent from study to study?
 No, some studies support and others refute the association
 Does association make biological sense?
 Yes (see introduction)
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Critical Appraisal
 Are these valid results of this harm study important?
Adverse Outcome
Present
Exposed
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Absent
Yes
978
11034
No
28 673
313 409
Critical Appraisal
 Are these valid results of this harm study important?
 Relative risk (RR)
RR = [ a / (a+b) ] / [ c / (c+d) ] =
[978/12012]/[28673/342082] = 0.97
 Number needed to harm (NNH)
NNH = 1 / [( a / (a+b) ) - ( c / (c+d))]
unable to calculate
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Critical Appraisal
 Should these valid, potentially important results
change the treatment of our donors/recipients?
 Practice of transfusion medicine (donor suitability
criteria, universal leukoreduction) in Sweden and
Denmark is similar to ours
 LR efficiently removes spiked cancer cells from blood (Evans
1997)
 Study addressed risk of transfusing blood from donors
with subclinical cancer
 Suggests that blood from donors with cancer may be safe
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In lieu of discussion
 Cancer is common
 American Cancer Society 2005
 1.3 million new cancer diagnoses/year
 9.8 million cancer survivors in US
 10 000-100 000 donors each year have cancer cells in peripheral
circulation at time of donation
 Post-donation information (PDI)
 5% of PDIs in US
 >1000 donors per year report a history of cancer after donation
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In lieu of discussion
 Is this a risk to a donor?
 Unlikely
 Is this a risk to a recipient?
 Unlikely
 No current federal regulations (FDA) or industry
standards (AABB)
 In U.S., donors evaluated and deemed suitable by a
blood centre medical director
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In lieu of discussion
 How do other blood agencies treat donors with
cancer?
 ABC survey 2005:
 65% of blood centres had a 5 year deferral for breast cancer,
adenocarcinoma, and sarcoma; donor had to be cancer and
treatment free before eligible to donate again
 50% of blood centres permanently deferred patients with
melanoma
 Majority of centres deferred donors with history of hematological
malignancy indefinitely
 Majority of centres accepted donors with basal cell or squamous
cell carcinoma as long as the cancers were excised and healed
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In lieu of discussion
 How do other blood agencies treat donors with
cancer?
 ABC survey 2005:
 For donors deferred with a cancer diagnosis, most centres
retrieved all active products but did not perform lookback; others
retrieved in-date components and performed lookback or did
none of the above
 American Red Cross
 Defer donors with solid cancers for 5 years after curative
treatment
 Donors with hematological cancers are permanently deferred)
 CBER workshop 1999
 Cured donors should be allowed to donate
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In lieu of discussion
 How does CBS treat donors with a history of cancer?
 Donors with fully treated basal cell or squamous cell
carcinoma as well as treated in situ cervical carcinoma are
eligible to donate
 Permanent deferral for all other types of cancer
 Retrieval of in-date components, lookback and notification of
recipients at the discretion of the medical director
 Some CBS stats (courtesy of Heather Hume)
 For 2004-2006, 1750 cancer-related PDIs were reported to
CBS
 Transfused minimum 2625 labile blood components from
donors who were subsequently diagnosed with cancer
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Conclusion
 Blood transfusions from precancerous blood donors
are not associated with increased risk of cancer
among recipients
 Should we consider accepting blood from donors with
a history of cancer?
 Yes
 What type of cancer?
 How long after cure?
 Increase donor base at a price of a small (real?) risk of
transmitting a cancer
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