होम Biology of Blood and Marrow Transplantation Frequency of Abnormal Findings Detected by Comprehensive Clinical Evaluation at 1 Year after...

Frequency of Abnormal Findings Detected by Comprehensive Clinical Evaluation at 1 Year after Allogeneic Hematopoietic Cell Transplantation

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खंड:
15
साल:
2009
भाषा:
english
पृष्ठ:
421
DOI:
10.1016/j.bbmt.2008.12.502
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आप पुस्तक समीक्षा लिख सकते हैं और अपना अनुभव साझा कर सकते हैं. पढ़ूी हुई पुस्तकों के बारे में आपकी राय जानने में अन्य पाठकों को दिलचस्पी होगी. भले ही आपको किताब पसंद हो या न हो, अगर आप इसके बारे में ईमानदारी से और विस्तार से बताएँगे, तो लोग अपने लिए नई रुचिकर पुस्तकें खोज पाएँगे.
CLINICAL RESEARCH

Frequency of Abnormal Findings Detected by
Comprehensive Clinical Evaluation at 1 Year after
Allogeneic Hematopoietic Cell Transplantation
Stephanie J. Lee,1 Travis Seaborn,1 Frances J. Mao,1 Susan C. Massey,1 Ngoc Q. Luu,1
Mary A. Schubert,3 Jason W. Chien,2 Paul A. Carpenter,1 Carina Moravec,3
Paul J. Martin,1 Mary E. D. Flowers1
Consensus guidelines recommend various screening examinations for survivors after allogeneic hematopoietic cell transplantation (HCT), but how often these examinations detect abnormal findings is unknown. We
reviewed the medical records of 118 patients who received comprehensive, standardized evaluations at 1
year after allogeneic HCTat Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance. Abnormal findings were common, including moderate to severe pulmonary dysfunction (16%), fasting hyperlipidemia (56%), osteopenia (52%), osteoporosis (6%), and active chronic graft-versus-host disease (cGVHD)
(64%). Recurrent malignancy (4%) and cGVHD (29%) were detected in previously unsuspected cases.
Only 3% of patients had no abnormal findings. We conclude that comprehensive evaluation at 1 year after
allogeneic HCT detects a high prevalence of medical problems. Longer follow-up is needed to determine
whether early detection and intervention affect later morbidity and mortality.
Biol Blood Marrow Transplant 15: 416-420 (2009) Ó 2009 American Society for Blood and Marrow Transplantation

KEY WORDS: Late effects, Allogeneic hematopoietic cell transplantation, Chronic graft-versus-host disease,
Recurrent malignancy, Hypothyroidism, Osteoporosis, Immunity

INTRODUCTION
Numerous observational studies have documented
the spectrum of late effects after allogeneic hematopoietic cell transplantation (HCT) in adults [1-8] and
children [9,10]. Several position statements have provided recommendations about appropriate patient
follow-up after allogeneic HCT [11-14]. These recommendations emphasize detection and management
of procedure-related complications and other la; te effects in HCT survivors. For example, screening for
secondary cancers and abnormalities of endocrine,
cardiovascular, pulmonary, renal, and hepatic function
is advised. Clinicians also are encouraged to discuss
psychosocial issues and general health maintenance.

From the 1Divisions of Clinical Research; 2Pulmonary and Critical
Care, Fred Hutchinson Cancer Research Center, Seattle, Washington; and 3Long-Term Follow-Up Unit, Seattle Cancer Care
Alliance, Seattle, Washington.
Financial disclosure: See Acknowledgments on page 419.
Correspondence and reprint requests: Stephanie J. Lee, MD, MPH,
Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D5-290, Seattle, WA 98109 (e-mail: sjlee@fhcrc.org).
Received November 19, 2008; accepted December 21, 2008
Ó2009 American Society for Blood and Marrow Transplantation
1083-8791/09/154-0001$36.00/0
doi:10.1016/j.bbmt.2008.12.502

416

Subspecialist evaluations by dentists, ophthalmologists, and gynecologists are recommended.
The frequency with which these late effects and
general health screening recommendations are followed, the likelihood of detecting abnormalities that
result in medical interventions, and the ultimate impact of compliance with these screening recommendations on the health of HCT survivors are unknown.
For 3 decades, the Long-Term Follow-Up (LTFU)
program at Fred Hutchinson Cancer Research Center
(FHCRC) has offered a comprehensive onsite evaluation to allogeneic HCT recipients at 1 year after transplantation (Table 1). Because the results of these
evaluations are not comprehensively collected in a research database, we reviewed medical records for 118
of the 1-year evaluations of adults who had undergone
allogeneic HCT in 2005 to identify the frequency of
abnormal findings.

STUDY DESIGN
All adult patients who had undergone allogeneic
HCT at FHCRC/Seattle Cancer Care Alliance
(SCCA) in 2005 and were seen by the LTFU program
1 year later were eligible for the study. A single year
was chosen for study, because a detailed retrospective

Biol Blood Marrow Transplant 15:416-420, 2009

Table 1. Routine 1-Year Comprehensive Evaluation at
FHCRC/Seattle Cancer Care Alliance
Category

Evaluations

History and physical exam

Chronic GVHD–focused review of systems
and examination
Complete skin examination
Range of motion testing, if indicated
Weight, height, vital signs, medical
photographs
List of all medications and supplements
Complete blood cell count with differential
Reticulocyte count
Comprehensive chemistry panel
Fasting lipid panel
Virology screen (hepatitis, cytomegalovirus)
Immunization titers
Endocrine evaluations (thyroid, sex
hormones)
Iron tests
Immunosuppressive drug levels
ABO typing (if ABO-mismatched)
Chimerism testing
Bone marrow aspirate and biopsy
Skin biopsy
Pulmonary function tests
Schirmer’s test
Dual energy X-ray absorptiometry
Chest X-ray (chest computed tomography
scan if indicated)
Mammogram (if age > 35 years)
Pap smear (if age > 21 years or sexually active)
Prostate specific antigen (if age > 45 years)
Colonoscopy (if age > 50 years)
Stool for occult blood (if age > 40 years)
Ophthalmology
Oral medicine (dentist)
Gynecology

Laboratory testing

Other studies

Secondary cancer
screening

Subspecialist exams

GVHD indicates graft-versus-host disease.

chart review was required. FHCRC’s Institutional
Review Board approved the study design.
Summary letters from FHCRC and laboratory
results from the 1-year LTFU evaluation were reviewed to collect data on medical history, current
abnormal findings, treatment recommendations, vaccinations and immunity, and current medications.
Data were not collected on the patients’ pretransplantation medical status. Diagnoses of hyperlipidemia (elevated fasting cholesterol, triglycerides, or low-density
lipoprotein), thyroid abnormalities (abnormal thyroidstimulating hormone, free thyroxine, or total thyroxine), iron abnormalities (abnormal ferritin, serum
iron, total iron-binding capacity, or transferrin saturation), and immunity (preimmunization titers against
specific pathogens) were based on laboratory results.
Diagnosis of recurrent malignancy was based on radiologic studies, tissue biopsy analyses, and blood, urine,
and bone marrow tests. Chronic graft-versus-host disease (cGVHD) was diagnosed based primarily on clinical criteria [15]. Thirty charts (25%) were selected at
random for second abstraction to confirm the accuracy
of 20 key variables; the median number of abstraction
errors was 1 (5%; range, 0 to 6).

Evaluation of HCT Survivors

417

Results are reported as medians and ranges for
continuous variables and as percentages for categorical
variables. Wilcoxon’s rank-sum test was used to compare continuous variables, and the c2 or Fisher’s exact
test was used to compare categorical variables.

RESULTS
Subject Characteristics
A total of 258 adults underwent allogeneic HCT in
2005. Among these, 113 died and 11 experienced recurrent malignancy before 1 year and did not return
for LTFU evaluation. Of 134 patients who survived
at least 1 year and were alive without active malignancy, making them eligible to return for their comprehensive evaluation, 118 (88%) were included in
this study. Sixteen eligible patients (12%) did not return for 1-year evaluation. There were no statistically
significant differences in age, sex, donor type, graft
source, number of transplantations, conditioning regimen, or frequency of second transplantations between
the patients who returned for LTFU evaluation and
those who did not. Information on insurance coverage
was not available, and it is possible that lack of insurance or limitations on return visits to the transplantation center could differ between those who did and did
not return.
The study cohort included 69 men (58%), 47 patients (40%) who had received reduced-intensity conditioning (RIC), 62 (53%) who had undergone HCT
from an unrelated donor, 105 (89%) who had received
a granulocyte colony-stimulating factor (G-CSF)–
mobilized peripheral blood graft, and 18 (15%) who
had undergone a second transplantation. The median
age at HCT was 47 years (range, 19 to 69 years).
Forty-eight of the patients (41%) lived in Washington.
Most of the patients (n 5 102; 86%) spent 2 to 4 days in
Seattle for testing and consultation as part of their
LTFU evaluation; 16 (14%) provided results of diagnostic testing performed elsewhere. These outside
test results were reviewed in lieu of testing at FHCRC.
Most patients were followed by their primary oncologist and usually were not seen by the LTFU clinical
service at FHCRC/SCCA between day 100 and 1
year, even if they lived locally.
Medication Usage
At the time of the 1-year LTFU evaluation, the
patients were taking a median of 6 systemic medications (interquartile range, 4 to 9) (Table 2). Most
(94%) were still taking prophylactic antibiotics, 71%
were taking an immunosuppressive medication (56%,
a calcineurin inhibitor; 50%, a corticosteroid), 30%
were taking a bisphosphonate, 27% were receiving hormone therapy, 26% were taking an antidepressive drug,

418

S. J. Lee et al.

Biol Blood Marrow Transplant 15:416-420, 2009

Table 2. Medication Use at 1 Year after Allogeneic HCT in
118 Patients
n (%)
Anti-infective agent
Calcineurin inhibitor
Corticosteroid
Antihypertensive agent
Bisphosphonate
Hormone replacement therapy
Antidepressive agent
Diabetes medication
Thyroid replacement therapy
Lipid-lowering agent

111 (94)
66 (56)
59 (50)
38 (32)
35 (30)
32 (27)
31 (26)
18 (15)
15 (13)
11 (9)

15% were taking antidiabetes medication, 13% were
on thyroid hormone replacement, 38% were taking
an antihypertensive agent (7% with an angiotensionconverting enzyme inhibitor or an angiotensin II receptor blocker), and 9% were taking a lipid-lowering
agent (7% with a 3-hydroxy-3-methyl-glutaryl–CoA
reductase inhibitor). We did not collect information
about medication usage before HCT.
Prevalence of Problems and Frequency of
Recommendations
Table 3 shows the prevalence of selected problems
after HCT. Among the 106 patients who had no previous evidence of disease relapse after HCT (90%), 4
(4%) were diagnosed with recurrent malignancy during the LTFU visit. Before the LTFU visit, 56% of patients had active cGVHD, 18% had inactive or
resolved cGVHD, and 31% did not have cGVHD.
Of the patients without previous cGVHD, 9 (29%)
were diagnosed with cGVHD during the LTFU visit;
thus, the overall prevalence of active cGVHD was
64%. Pulmonary function tests were available for
116 subjects. Only 26 (22%) had a normal modified
lung function score (mLFS) according to forced expiratory volume for 1 second (FEV1) and diffusing capacity of carbon monoxide (DLCO) adjusted for
hemoglobin [16]. Seventy-two (62%) had mild pulmonary dysfunction (mLFS 3 to 5), 16 (14%) had moderate dysfunction (mLFS 6 to 9), and 2 (2%) had severe
pulmonary dysfunction (mLFS 10 to 12). Compared
with pulmonary function tests conducted before
HCT (n 5 115), 56 patients (49%) did not change categories and 6 (5%) improved by at least 1 category. In
contrast, 46% worsened by either 1 category (n 5 50;
43%) or 2 categories (n 5 3; 3%).
Gynecologic exam results were available for 45
of 49 women (92%). Pap smears were abnormal
(n 5 10) or insufficient (n 5 1) in 24%, and led to recommendations for retesting before 1 year for 6 women
(13%) and interventions for 2 women (4%). Twentyfive underwent mammography, all of which were
normal. Vulvovaginal cGVHD was diagnosed in 20
women (47%), judged to be mild in 12 (29%), moderate in 5 (11%), and severe in 3 (7%). Overall, 26 of 45

women (58%) had 1 or more abnormal gynecologic
findings, leading to recommendations for altered
screening schedules, therapeutic interventions, or
medication changes in 20 of these 26 women (77%).
Only 4 patients (3%) had no abnormal findings.
Most of the patients had either 2 (n 5 29; 25%) or 3
(n 5 40; 34%) abnormal findings. The median number
of treatment recommendations provided by FHCRC
was 2 (n 5 50 [42%]; interquartile range, 2 to 3);
only 1 patient (1%) did not receive a new recommendation after the LTFU evaluation. Active cGVHD
and abnormal bone mineral density were the major
problems that led to a dosage change or new medication for affected patients, whereas moderate to severe
pulmonary dysfunction usually led to recommendations for more frequent pulmonary function testing.
Abnormal laboratory studies (serum iron, fasting
lipids, and thyroid function tests) were least likely to
result in changes to treatment or monitoring. There
was no statistical difference in the frequency of abnormal findings and treatment recommendations between
patients who had received RIC and those who had
received myeloablative conditioning.
Vaccination and Immunity
Almost all patients received routine immunizations
at the 1-year LTFU visit. Some physicians did not give
immunizations to patients who were currently ill or
known to have very low B cell numbers, although this
practice was not standardized. Lack of protective antibodies was documented for pneumococcus in 45% of
patients, haemophilus influenza B in 79%, tetanus in
64%, and hepatitis B in 74%; additional doses of at least
1 vaccine were recommended for 95% of patients.

DISCUSSION
Although our patients were all evaluated at approximately 1 year after HCT, our findings are consistent
with the literature regarding the overall incidence of
late effects. Specifically, our rates of osteoporosis,
osteopenia, hyperlipidemia, diabetes, gynecologic
abnormalities, and pulmonary function deficits are
similar to those reported in survivors at later times
after HCT [2-4,6,7,9,17,18]. Recurrent malignancy
(4%) and cGVHD (29%) were detected in previously
unsuspected cases. Detection of new cases of cGVHD
did not result from implementation of the new NIH
Consensus Criteria, because the new standards are
more restrictive than previous definitions [15].
Several problems, such as hyperlipidemia, iron abnormalities, and thyroid function abnormalities, were
less likely to be noted in the medical records or to generate a treatment recommendation. We hypothesize
that physicians may have believed that these laboratory
abnormalities would resolve with time, or they may

Biol Blood Marrow Transplant 15:416-420, 2009

Evaluation of HCT Survivors

419

Table 3. Prevalence of Abnormal Findings and Frequency of Recommendations at 1 Year after Allogeneic HCT
Recommendations for Affected Patients

Problem

Prevalence

Continuation of Current
Management

Abnormal iron tests
Active chronic GVHD
Abnormal gynecologic findings
Elevated fasting lipid levels
Osteopenia + osteoporosis
Abnormal thyroid tests
Moderate to severe pulmonary dysfunction
Recurrent malignancy

71%
64%
58%
56%
52% + 6%
22%
16%
4%*

24%
19%
28%
38%
42%
52%
22%
0%

Dosage Change,
New Medication, or Change
in Monitoring Schedule

No Recommendation
or No Discussion
in Medical Records

17%
79%
77%
18%
44%
16%
78%
100%

59%
2%
0%
44%
14%
32%
0%
0%

HCT, hematopoietic cell transplantation; GVHD, graft-versus-host disease.
*In patients with no previous evidence of disease.

have been reluctant to recommend a new medication
or intervention given the number of medications
already taken by the patients. Reports of late cardiovascular and other complications after allogeneic
HCT suggest that more aggressive management of
laboratory abnormalities may be warranted [8,17].
The high rate of abnormal findings in our study
suggests that it is reasonable to use the 1-year anniversary of the graft infusion as a simple, easily remembered
reminder to conduct a comprehensive evaluation. In
fact, earlier screening may be warranted for some
conditions for which interventions can be applied
within the first posttransplantation year. Our experience is that using the transplantation anniversary date
helps physicians track scheduled screening examinations and ensures that recommended testing is
completed. Testing can be done by the transplantation center or by the patient’s oncologist or primary
physician.
The present study identified some routine tests
that do not appear to be justified based on clinical
use of the information. For example, results from routine chest X-rays, Schirmer’s tests, and skin biopsy
analyses appeared to have little effect on treatment
and monitoring recommendations unless supported
by clinical symptoms [14]; thus, these tests would be
better reserved for symptomatic patients or situations
in which there is a defined clinical or research question.
Limitations of this study include the retrospective
study design and the assessment of practices only in
a single year at a single institution, which might not
be representative of other time periods or other institutions. We reviewed chart notes and electronic medical records including laboratory data, but these
sources may not have fully captured medical problems,
medical decision-making processes, and physician recommendations. Sixteen patients (12%) did not return
for LTFU evaluation. Although we did not identify
any differing characteristics, these patients may have
had their LTFU evaluations done locally or may differ
in important ways from the returning cohort. For example, a patient with no apparent transplantation-related

medical problems at 1 year might have felt that there
was no need to return for a comprehensive evaluation.
We conclude that routine comprehensive LTFU
evaluation at 1 year after allogeneic HCT detects
a high prevalence of medical problems necessitating
intervention or adjustment of therapy. Although the
ultimate effect on health outcomes is unknown, our
findings suggest that systematic evaluation as early as
1 year after HCT is an important aspect of early
detection and monitoring for late effects. Continued
longitudinal study of this group of patients is needed
to determine whether serious late effects and late
treatment-related mortality (TRM) can be prevented
through continued screening and appropriate early
interventions [19,20].

ACKNOWLEDGMENTS
Financial disclosure: This work was supported by
National Cancer Institute Grant CA018029. We
thank our colleagues, the nurses, and the clinical staff
of the LTFU program at FHCRC/Seattle Cancer
Care Alliance, as well as our patients, for their valuable
contributions to the clinical and research program.

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