The first successful transplants of
hematopoietic stem cells were
performed in 1968 in three children with congenital immune deficiency
diseases.[1-4] In each instance, stem cells were collected from the bone marrow
of sibling donors who were genotypically identical or closely matched to the
recipient for human leukocyte antigens (HLA). Since then, thousands of patients
have received hematopoietic stem cell transplants as treatment for malignant and
Approximately 50,000 transplants are performed worldwide each
year (Figure 1). Reasons for the increased use of stem cell transplantation over
the past 3 decades include its proven and potential efficacy in many diseases,
better understanding of the appropriate timing of transplantation and patient
selection, greater availability of donors, better techniques for determining HLA
match, greater ease of stem cell collection, and improved supportive care
resulting in less transplant-related morbidity and mortality.
About two-thirds of hematopoietic stem cell transplants use
autologous cells, generally extracted from peripheral blood by leukapheresis.
The remainder are allogeneic transplants, most commonly using cells collected
directly from the bone marrow of
HLA-identical sibling donors (Figure 1 and Figure
The growth of hematopoietic stem cell transplantation has been
accompanied by a coordinated, international effort to collect and analyze data
on transplant outcomes through the International Bone Marrow Transplant Registry
(IBMTR), established in 1972, and the Autologous Blood and Marrow Transplant
Registry (ABMTR), established in 1990. Over 350 institutions in 47 countries
contribute data to the IBMTR, and over 250 institutions in North and South
America contribute data to the ABMTR. Participating centers submit data on their
consecutive transplants to the IBMTR/ABMTR Statistical Center. The Center
receives data on more than 12,000 new transplants each year and maintains a
database that now includes information on more than 120,000 transplant
The activities of the IBMTR and ABMTR are supervised by
Advisory, Executive, and Working Committees and a joint IBMTR/ABMTR Steering
Committee (Figure 3). The Advisory and Executive Committees review policies for
the use of IBMTR/ABMTR data and advise the scientific and statistical directors
on administrative and scientific matters. The Working Committees design and
conduct studies that are relevant to their subject area, consider proposals to
use IBMTR/ABMTR data for specific studies, periodically assess and revise
relevant sections of IBMTR/ABMTR data collection forms, and plan and conduct
workshops at IBMTR/ABMTR meetings. The Steering Committee establishes priorities
for scientific activities.
Since 1972, the IBMTR/ABMTR Statistical Center has been central
to Registry activities, coordinating data collection and management, and
providing statistical and administrative support for studies using Registry
data. The Statistical Center is an academic division of the Health Policy
Institute of the Medical College of Wisconsin in Milwaukee.
The IBMTR/ABMTR collects data on two levels: registration and
research. Registration data include disease type, age, sex, pretransplant
disease stage and response to chemotherapy, date of diagnosis, donor type, graft
type (bone marrow- and/or blood-derived stem cells), transplant regimen,
posttransplant disease progression and survival, engraftment, graft-vs-host
disease (GVHD), development of a new malignancy, and cause of death. All
IBMTR/ABMTR centers contribute registration data.
Research data are submitted on comprehensive report forms
completed for a subset of registered patients in IBMTR/ABMTR research centers.
Research data include detailed pre- and posttransplant clinical information such
as disease subtype, tumor size and pathology, sites of disease, nontransplant
treatment of the primary disease, performance status, organ function, details of
the transplant regimen including dose and schedule of high-dose therapy, graft
manipulation, supportive care, posttransplant toxicities, and functional status.
Both databases are longitudinal; patients are followed through
their transplant centers with yearly updates.
The Use of Multicenter Observational Databases
Transplant outcomes are influenced by many patient- and
disease-related factors (such as age, disease stage and prior treatment), as
well as transplant-related factors such as stem cell source, conditioning
regimen, and prophylaxis for GVHD. Ideally, most transplant strategies would be
evaluated by large randomized clinical trials. However, various factors limit
the application of randomized trials in hematopoietic stem cell transplantation.
Many diseases treated with transplants are uncommon; thus, single centers may
treat only a few patients with a given disorder. This makes randomized trials
difficult and also limits the ability to perform nonrandomized (phase II) trials
with sufficient power to detect meaningful effects. Small trials, even when
randomized, may provide misleading results.
New transplant technologies are rapidly being introduced, so the
results of prospective clinical trials may be obsolete before they are
published. Some important transplant issues are not amenable to randomization,
eg, differences in outcome associated with differences in donor type. In a
systematic review of 255 transplant-related studies published between 1990 and
1992, only 16 (6%) were randomized trials; most of these studies had fewer than
Even when randomized trials are performed, enrolled patients may
represent only a small proportion of the target population and may not be
representative of the larger group.[7-10] The results of treatments administered
in these trials may differ from those obtained when the technology is more
widely applied. Most clinical trials focus on short- and intermediate-term
outcomes (1 to 5 years). However, there is a need for long-term follow-up of
transplant recipients because high-dose therapy may be associated with important
effects, such as therapy-related cancers, that may not develop until years after
the transplant was performed.
Observational databases may facilitate our understanding of
transplant outcomes by addressing questions that are difficult to address in
randomized trials. These include descriptions of transplant results in various
disease states and patient groups; analysis of prognostic factors; evaluation of
new transplant regimens; comparison of transplant with nontransplant therapy;
defining intercenter variability in diagnosis, practice, and outcome; and
developing analytic approaches to evaluating transplantation outcomes and costs.
The value of observational studies in assessing treatment
effects was highlighted by two recent articles published in the New England
Journal of Medicine.[11,12] Clinical databases may also be useful in developing
optimal designs for randomized studies and in interpreting the results of such
Databases that include a large number of centers involved in
allogeneic and autologous transplantation are uniquely suited for descriptive
studies. This is particularly important in the case of rare diseases or more
common conditions for which transplantation is infrequently performed. In these
situations, single centers often have only one or a few cases, precluding
meaningful assessment of outcome. The publication of outcomes may be biased to
results that are particularly good or bad. By combining data from many
centers and obtaining data systematically on all transplants, regardless of
outcome, registries can provide a more precise and unbiased estimate of results.
Examples of descriptive studies using IBMTR/ABMTR data are analyses of
transplants for Ph+ acute lymphoblastic leukemia, Diamond-Blackfan
anemia, chronic lymphocytic leukemia, and paroxysmal nocturnal
Identification of Prognostic Factors
The heterogeneity and large numbers of patients reported to the
IBMTR/ABMTR allow use of multivariate regression techniques to evaluate
associations between patient- and disease-related variables and outcome. Because
transplant centers must report all consecutive transplant recipients, the full
range of characteristics found in transplant patients is available for study.
This is an important use of large observational databases, since many prognostic
factor studies are limited by small numbers, nonrepresentative populations,
and/or insufficient detail on patient and disease characteristics.[18-21]
Examples of large prognostic factor studies using IBMTR/ABMTR
data include assessment of (1) risk factors for acute and chronic GVHD,[22,23]
interstitial pneumonia,[24,25] and veno-occlusive disease of the liver; (2)
prognostic factors for relapse and leukemia-free survival after transplants for
acute myelogenous leukemia, acute lymphoblastic leukemia, and chronic
myelogenous leukemia[27-30]; (3) risk factors for graft failure after
transplants for severe aplastic anemia; and (4) factors associated with
the outcome of autotransplants for metastatic breast cancer.
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