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Bone Marrow Transplantation (2001) 28, 545–549
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Allogeneic transplants
Allogeneic stem cell transplantation for sickle cell disease. A study of
patients’ decisions
K van Besien1, M Koshy1, L Anderson-Shaw2, N Talishy1, L Dorn1, S Devine1, M Yassine1 and
E Kodish3
1
Section of Hematology and Oncology and 2Department of Medical Humanities, University of Illinois at Chicago and 3Department of
Pediatrics and Center for Biomedical Ethics, Rainbow Babies and Childrens Hospital and Case Western Reserve University,
Cleveland, OH, USA
Summary:
Allogeneic stem cell transplantation is increasingly considered as a curative though risky treatment option for
adults with sickle cell disease. Little is known about attitudes of adult patients and their health care providers
regarding the risks and benefits of transplantation. A
survey of 100 patients and their health care providers
was undertaken. Assessment of risk was by a reference
gamble paradigm. Comparison was made of the characteristics of those accepting substantial risk vs those not
accepting risk, as well as assessment of agreement on
risks recommended by health care providers and
accepted by patients. Sixty-three of 100 patients were
willing to accept some short-term risk of mortality in
exchange for the certainty of cure. Fifteen patients were
willing to accept more than 35% mortality risk. No differences in patient or disease-related variables were
identified between those accepting risk and those not
accepting risk. There was no agreement between the
recommendations of health care providers and the risk
accepted by patients. A substantial proportion of adults
with sickle cell disease are interested in curative treatment, at the expense of considerable risk. The decision
to accept risk is influenced by individual patient values
that cannot be easily quantified and that do not correlate with the assessment of the health care provider.
Given the substantial interest in curative therapy, education about and consultation for allogeneic stem cell
transplantation in sickle cell patients should be encouraged. Bone Marrow Transplantation (2001) 28, 545–549.
Keywords: sickle cell disease; stem cell transplantation;
risk; survey
Sickle cell disease is a common congenital disorder with
major implications for the health and longevity of affected
Correspondence: Dr K van Besien, Section of Hematology/Oncology, University of Chicago, 5841 South Maryland Avenue, Ro0m I209, MC 2115,
Chicago, Illinois, 60637, USA
Received 6 March 2001; accepted 6 July 2001
individuals.1 Several mature studies of allogeneic transplantation in children with sickle cell disease indicate a cure
rate of 80%, a transplant-related mortality of less than 10%
and a risk for serious complications (ie graft failure, grade
III–IV acute GVHD and extensive chronic GVHD) of less
than 10%.2,3 In one study, survival and cure rates were even
better in children with early stage sickle cell disease.2 In
adults, sickle cell disease causes considerably more morbidity and mortality than in children, and no satisfactory
medical treatment exists.1 Allogeneic transplantation has
until recently not been considered for adults with severe
sickle cell disease, because of their perceived inability to
tolerate intensive conditioning regimens. In order to address
this dilemma, new conditioning regimens with much
reduced toxicity, have been proposed.4,5 Such treatments
are investigational and morbidity and mortality must be
anticipated. How much risk is acceptable to adults with
sickle cell disease is unknown.
The attitude of adults with sickle cell disease toward the
illness and its treatment is influenced by a combination of
social, psychological, intellectual and medical factors.
Some patients may be willing to take considerable risks to
be ‘liberated’ from the illness, others may be ‘used’ to the
disease and the limitations on life style and life expectancy
it imposes. In recommending treatments, physicians are
influenced by equally complex but different motivations
than are the patients. Concerns over risk, and concern over
patient compliance may cause reluctance to recommend
high-risk procedures. Severity of symptoms, debilitating
complications and risk of death, may justify the recommendation of high-risk interventions. The very different viewpoint of patients and health care professionals can lead to
different attitudes toward the risks of transplantation.6–8
In a survey conducted almost 10 years ago, Kodish et
al,9 interviewed 67 parents regarding the risks they were
willing to accept in order for their child with sickle cell
disease to undergo potentially curative treatment. We conducted a similar survey of adults with sickle cell disease,
the majority of whom had been followed for a prolonged
period of time at one center. The purpose of this survey
was to determine what would constitute an acceptable death
rate of a curative treatment for adults with sickle cell disease. We also conducted an interview of the staff members
Attitudes of adults toward transplantation for sickle cell disease
K van Besien et al
546
and physicians involved in the long-term care of these
patients, to establish the rate of agreement between risks
accepted by patients and the recommendations of the
care-givers.
Materials and methods
After obtaining informed consent, we interviewed 100
adults with sickle cell disease. The large majority (n = 93)
of subjects were patients attending the UIC sickle cell
clinic. All consecutive patients attending the clinic during
a period of 3 weeks, were asked to participate, and those
who agreed, took the survey while waiting for their doctor’s
visit. An additional small group (n = 7) of subjects were
selected from patients belonging to a sickle cell support
group in the Chicago suburbs and were interviewed by telephone. We conducted a structured interview with each
patient. After obtaining relevant information about the
demographic characteristics of the family and the patient’s
medical history, we described the process of bone marrow
transplantation. The information we gave patients about
bone marrow transplantation was based on the survey
instrument used by Kodish et al.9
A physician who was knowledgeable about both bone
marrow transplantation and sickle cell disease, conducted
the interviews. The patients were given several opportunities to ask questions. The interview did not proceed until
the interviewer was certain that patients understood the
information they had been given. We assessed patient’s
decisions about acceptable risks of mortality and morbidity
by using questions based on the standard reference-gamble
paradigm.10 This is the same technique as was used in the
prior pediatric study. Patients were asked whether they
would consent to bone marrow transplantation in various
hypothetical situations. In the first situation, bone marrow
transplantation was described as offering 100% survival (no
risk of mortality from the transplantation) and certain cure
of sickle cell disease. In subsequent descriptions, the mortality rate associated with bone marrow transplantation was
gradually increased by 5% increments. In this way, each
patient indicated the highest risk of mortality that he or she
would accept in exchange for the prospect of cure. The first
situation in which the patient answered ‘No’ was registered
as the point of too much risk, and this section of the interview was concluded. For example, the fourth question read
as follows: ‘Suppose that for the transplant 85% lived and
15% died from the treatment. That is: 85 out of every 100
patients lived and were cured of sickle cell disease, but 15
out of 100 died in the first 30 days after the treatment. If
these were the risks would you want to have this treatment?’ To analyze our data, we compared patients who
accepted some risk associated with transplantation (at least
10%) with those who did not, by using the Fisher exacttest for dichotomous variables and the Wilcoxon rank-sum
test for ordinal variables.11 The 10% level of risk is similar
to the treatment-related death rate that has been observed
in pediatric studies of transplantation for sickle cell disease.2,3 The same level was also used as a cut-off in the
prior pediatric study. We tested for differences in the following variables between the two groups: age, gender, level
Bone Marrow Transplantation
of education, number of transfusions, WBC count, creatinine level, level of HB F, prior stroke, history of surgery,
taking pain medication, taking hydroxyurea. Some of the
variables studied were similar to the ones used in the prior
pediatric study. Others, such as WBC, creatinine level, use
of hydroxyurea have been related to survival or frequency
of painful crises.1,12 WBC, creatinine level and percentage
hemoglobin F were obtained by chart review. The data for
all other variables were obtained by self-reporting from
the subject.
In a second part of the study, six health care providers
were interviewed. They were familiar with the patients, but
did not have access to the medical record at the time of the
interview. They were asked whether they would recommend transplantation for each of their patients in the
various hypothetical situations that had been described to
the patients before.
To analyze this data set, we again compared patients who
accepted some risk for transplantation (at least 10%) with
those who did not. Then we matched the recommendations
of the health care practitioners with the patients’ decision.
The rate of agreement between the the health care providers
and the patients was calculated using a kappa statistic
(chance corrected proportional agreement).13 A value of
kappa less than 0.2 indicates poor agreement; values
between 0.2 and 0.4 indicate a fair level of agreement.
The study was approved by the institutional review board
of the University of Illinois at Chicago.
Results
We approached 103 patients with sickle cell disease
between 26 February 1999 and 18 March 1999. Three
patients we approached, declined to participate. Therefore
100 patients were interviewed. The patients ranged from
age 19 to age 60, with a median age of 36 years. All the
patients had homozygous disease. Other patient characteristics are summarized in Table 1.
Twenty-eight patients were unwilling to accept any risk
of short-term mortality (death within 30 days) in order to
be cured of sickle cell disease. These patients said ‘No’
to transplantation at the 100% survival-cure level: 100%
probability of cure and 0% short-term mortality. Another
nine patients were not willing to accept any significant risk
(Figure 1). These nine said ‘Yes’ to transplantation at the
100% survival-cure level, but said no at the 95% level (95%
probability of cure and 5% risk of short-term mortality).
Sixty-three of the 100 patients were willing to accept a risk
greater than 5% short-term mortality in exchange for a cure.
Forty-six were willing to accept a risk of greater than 15%,
and 20 patients were willing to accept a risk greater than
30%. Twelve patients were willing to accept a risk of shortterm mortality higher than 40%.
In contrast to the pediatric study, we could not determine
any association between patient or disease characteristics
and the risk accepted. There were no differences in patient,
disease or treatment-related parameters between those willing to accept at least a 10% risk, compared with those not
willing to accept such a risk (Table 1).
In the second part of the study, we interviewed six health
Attitudes of adults toward transplantation for sickle cell disease
K van Besien et al
Table 1
547
Patient characteristics and comparison between the two patient groups
Group I:
willing to accept risk of transplant
Group II:
not willing to accept 10% risk of
transplant
63
36 (19–58)
34/29
0.7 (0.4–8.7)
11 (5.1–44)
11 (0.7–33.6)
0 (0–8)
29/34
9/54
61/2
51/12
30/29/5
37/26
37
31 (19–59)
22/15
0.65 (0.4–9.0)
9.2 (5.7–19.5)
8.7 (1.1–23)
0 (0–6)
18/19
3/34
35/2
33/4
15/19/3
18/19
1
22
26
12
2
11
21
3
n
Median age (range)
F/M
Median serum creatinine (mg/ml) (range)
Median WBC (×109/l) (range)
HgB F%
Median number of transfusions in the past year
Employed Yes/No
Prior stroke Yes/No
Prior transfusion Yes/No
Chronic pain medication Yes/No
Hydroxyurea Yes/No/unknown
Prior surgery Yes/No
Educational level
Some high school
High school graduate
Some college
College graduate
P
0.31
0.59
0.18
0.67
0.49
0.77
0.80
0.35
0.58
0.27
0.79
0.32
0.76
80
72
70
63
60
53
No. of patients
50
46
40
34
30
27
20
20
15
10
0
0
5
10
15
20
25
30
35
12
9
9
7
7
5
40 45 50 55 60 65
Mortality accepted (%)
5
5
5
5
5
70
75
80
85
90
0
0
95
100
Figure 1 Number of patients with sickle cell disease who said they would choose bone marrow transplantation at different estimates of the mortality
rate associated with the procedure. There were 100 patients in the study. Twenty-eight said they would not consent to the procedure, even if there were
no risks associated with it. The numbers over the bars indicate how many patients said they would consent to the procedure.
care providers, two doctors and four nurses, who provided
the continuum of care in the sickle cell clinic and were
therefore familiar with the patients. The health care providers were asked what risk of transplant they would consider acceptable for each of the patients. The comparison
between recommendations of the health care providers and
patient’s decisions are tabulated in Table 2. The proportion
of patients for whom transplant would be recommended
varies considerably among the health care providers. The
first health care provider would have recommended transplantation in only nine out of 93 patients, assuming the risk
was at least 10%. By contrast, health care provider three
would have recommended it in 54 out of 90 patients and
health care provider six would have recommended it in 52
out of 88 patients. More importantly, as indicated by the
kappa statistic, there was an absolute lack of agreement
between provider’s recommendations and patient’s decisions.
Bone Marrow Transplantation
Attitudes of adults toward transplantation for sickle cell disease
K van Besien et al
548
Discussion
Ten years ago, Kodish et al,9 showed that there is considerable interest in allogeneic transplantation among parents of
children with sickle cell disease. Nevertheless, accrual to
studies of allogeneic transplantation has been slow in the
United States.3 Numerous factors play a role in the decision
to offer transplantation to a patient. The most important one
is that only a small percentage of patients have HLAidentical siblings.14 Another factor is the wide disparity in
the concept of who is, or is not qualified for transplant. In
a survey of 22 centers, the proportion of patients that qualified for transplant protocols ranged from 0.9% to 36% in
different centers, indicating radically different attitudes
among physicians regarding indications for transplantation
in children. Some would recommend transplantation to all
children with hemoglobinopathies,2,15 others recommend
conservative treatment in the large majority.16,17
Sickle cell disease constitutes an even greater problem
in adults, but transplantation is only starting to be explored,
and little is known about patients’ and doctors’ attitudes
toward the risks of transplantation. In our survey, we
attempted to quantify the acceptable risk by presenting
adults with sickle cell disease with a set of hypothetical
scenarios. Forty-six percent of the patients we interviewed
would be willing to consent to stem cell transplantation
with a 15% or greater risk of short-term mortality. These
data are strikingly similar to those obtained by Kodish et
al,9 in their survey of parents of children with sickle cell
disease. Kodish et al found that the risk considered acceptable by parents was related to the level of education, and
the number of children with sickle cell disease in the family. In adults, we did not identify patient- or disease-related
variables that could predict the risk a patient would be willing to take for bone marrow transplantation. In addition
to interviewing the patients, we surveyed their health care
providers. Among health care providers, perceptions about
acceptability of risk varied considerably. There was no
agreement between the recommendations of the health care
providers and the risks acceptable to the patients themselves.
The data of this survey should be interpreted with caution. By necessity, the hypothetical scenarios presented to
the subjects provide limited information about the procedure and implications of transplant. Information on conditioning therapy, acute and chronic GVHD and late sideeffects on fertility was not provided and might have further
influenced the patient’s thoughts.18 The survey also does
not provide us with any insights into the motivations behind
patient’s decisions or recommendations of the health care
providers.
Despite these limitations, two credible conclusions
emerge. First, there is a considerable interest among adults
with sickle cell disease in a potentially curative treatment,
despite a risk of treatment-related death. Second, there is a
lack of agreement between physicians’ recommendations
and patients’ attitudes. The conclusion from the earlier
report by Kodish et al continues to be applicable: ‘Patients
may not think about risks and benefits the way doctors do’.9
If such is the case, should physicians discuss transplantation with their patients, even though they may not feel
Bone Marrow Transplantation
Table 2
Rates of agreement between risks acceptable to patients and
risk that their health-care providers consider acceptable
Patient Y
N
total
kappa = 0
Patient Y
N
total
kappa = 0
Patient Y
N
total
kappa = 0
Patient Y
N
total
kappa = 0
Patient Y
N
total
kappa = 0
Patient Y
N
total
kappa = 0.26
Y
6
3
9
Health care provider 1
N
53
31
84
total
59
34
93
Y
25
14
39
Health care provider 2
N
32
17
49
total
57
31
88a
Y
30
24
54
Health care provider 3
N
23
13
36
total
53
37
90a
Y
15
9
24
Health care provider 4
N
36
15
51
total
51
24
75a
Y
9
8
17
Health care provider 5
N
40
19
59
total
49
27
76a
Y
35
17
52
Health care provider 6
N
14
22
36
total
49
39
88a
Y = risk of treatment-related death ⭓10% is acceptable; N = risk of treatment-related death ⭓10% is not acceptable; kappa = measure of agreement
(see statistical section).
a
There were some subjects with whom individual health care providers
were not familiar, and for whom they declined to provide a recommendation.
that it is an appropriate procedure for a specific patient?
In our opinion, the answer is Yes. Providing appropriate
information and education about all treatment alternatives
in a way that promotes patient autonomy and rational
decision-making, is one of the fundamental duties of the
physician.19,20 The core of patients rights is the right to
receive care from an accountable physician who shares all
relevant information with the patient, and who guarantees
the patient the right to make the final decision about treatment.21 The right to information includes the right to be
informed about reasonable alternative treatments, including
research protocols that are relevant to the patient’s condition.21 Although the treatment choice of the patient may
not be in accordance with the physician’s recommendations, competent autonomous decisions should be honored.19 In other words, the patient’s autonomy and dignity
should be respected, and medical paternalism is to be
Attitudes of adults toward transplantation for sickle cell disease
K van Besien et al
avoided.22 Given the interest of a substantial proportion of
patients in curative approaches, and despite their risks, it
is imperative that adults with sickle cell disease be provided
information about and access to allogeneic transplant trials.
Careful attention to informed consent, including a thorough
discussion of the risks, benefits and alternatives to marrow
transplantation for sickle cell disease, will empower
patients to make their own decisions about this promising
but risky therapy.
10
11
12
13
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