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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3702-3709
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the International Bone Marrow Transplant Registry, Health
Policy Institute, Medical College of Wisconsin, Milwaukee, WI, and the
European Group for Blood and Marrow Transplantation; the Section of
Blood and Marrow Transplantation, University of Texas-MD Anderson
Cancer Center, Houston, TX; Division d'Hématologie,
Hôpital Cantonal Universitaire, Geneva, Switzerland; Department
of Haematology, Glasgow Royal Infirmary, Glasgow, Scotland, United
Kingdom; The Dr Daniel den Hoed Cancer Center, Rotterdam, The
Netherlands; LRF Centre for Adult Leukaemia, Imperial College School of
Medicine, London, United Kingdom; Division of Haematology,
Kantonsspital, Basel, Switzerland; Zentrum Innere Medizin und
Dermatologie, Hannover, Germany; Postgraduate School of Hematology,
University of Barcelona, Barcelona, Spain; Department of
Transplantation Surgery, Huddinge Hospital, Huddinge, Sweden; and
Second Department of Internal Medicine, University of Kiel, Kiel,
Germany.
Peripheral blood cells are increasingly used in place of bone marrow
as a source of hematopoietic stem cells for allogeneic transplantation.
The relative efficacy of these 2 approaches is unknown. This
retrospective multivariate analysis compared results of 288 HLA-identical sibling blood stem cell transplantations with results of
536 HLA-identical sibling bone marrow transplantations. No transplants
were T-cell depleted. Median follow-up was 12 months, and analyses
focused on 1-year outcomes. Recipients of blood stem cell transplants
had more rapid recovery of neutrophils to at least
0.5 × 109/L (median time to recovery,
14 days, compared with 19 days for marrow transplants;
P < .001) and of platelets to at least
20 × 109/L (median time, 18 days, compared with 25 days
for marrow transplants; P < .001). There was no significant
difference in the incidence of grades II to IV acute graft versus host
disease (GVHD). The incidence of chronic GVHD was significantly higher
after blood stem cell transplantation (1-year probability [95%
confidence interval], 65% [56%-72%] compared with 53%
[47%-59%]; P = .02) Relapse incidence in the 2 transplant groups did not differ significantly. Treatment-related
mortality rates were lower and leukemia-free survival rates were higher
with blood stem cell transplants in patients with advanced leukemia
(acute leukemia in second remission or chronic myelogenous leukemia in
accelerated phase) but not in early leukemia (acute leukemia in first
remission or chronic myelogenous leukemia in chronic phase). The median
time from transplantation to hospital discharge was 23 days after blood
stem cell transplantation and 28 days after bone marrow transplantation
(P = .003). Further study with longer follow-up is
necessary to definitively establish the role of blood stem cells for
allogeneic transplantation, especially in patients with good-risk disease.
(Blood. 2000;95:3702-3709)
Bone marrow transplantation is an accepted
treatment for many patients with malignant and nonmalignant
diseases. Since the early 1990s, peripheral blood progenitor cells
collected by apheresis have largely replaced bone marrow as a source of
hematopoietic stem cells for autologous transplantation.1
Peripheral blood cells produce more rapid hematopoietic recovery,
thereby leading to reduced costs.2-5 For allogeneic
transplantation, blood stem cells collected from healthy donors
given granulocyte colony-stimulating factor are now often used
as an alternative to bone marrow.6-15 The mobilization,
collection, and safety of allogeneic blood stem cell donors has been
reviewed.16 Preliminary results of allogeneic blood stem
cell transplantation in many single centers and a small randomized
trial indicate more rapid hematopoietic recovery with this method
than with allogeneic bone marrow transplantation.6-15,17
Collections of blood stem cells contain approximately 1 log more
lymphocytes than bone marrow harvests.10,18 This could possibly affect immune reconstitution, graft versus host disease (GVHD), and graft versus leukemia effects. In most studies, the incidence of acute GVHD with blood stem cell transplants is similar to
that reported for bone marrow transplants. Some studies do not indicate
a difference in chronic GVHD,14,19 but others suggest a
substantially higher incidence of chronic GVHD with blood stem cell
transplantation.20,21 Use of allogeneic blood stem cells
reduced early morbidity and mortality in comparison with results of
bone marrow transplantation in some22 but not all17 studies. However, all these studies were small, with
fewer than 100 patients, and had relatively short follow-up periods. It
is still unclear whether blood stem cells are as good as (or better
than) bone marrow as a source of hematopoietic stem cells for
allogeneic transplantation. We report a nonrandomized comparison of 288 HLA-identical sibling blood stem cell transplantations and 536 HLA-identical sibling bone marrow transplantations for leukemia.
Patients
IBMTR
EBMT
Endpoints The study focused on hematopoietic recovery, acute and chronic GVHD, treatment-related mortality (TRM), leukemia-free survival (LFS), and leukemia relapse after blood stem cell transplantation compared with bone marrow transplantation.25 The primary measure of hematopoietic recovery was the time after transplantation until a neutrophil count of at least 0.5 × 109/L was observed for 3 consecutive days. Also recorded were the times until a platelet count of at least 20 × 109/L and a platelet count of at least 50 × 109/L were achieved. The incidence and time to development of grades II to IV acute GVHD and grades III to IV acute GVHD were evaluated in patients surviving 21 days with evidence of engraftment.26 Time to occurrence of any chronic GVHD was evaluated in patients surviving 90 days or longer after transplantation with engraftment.27 TRM was defined as death in continuous complete remission; patients were censored at relapse or, for patients in continuous complete remission, at last follow-up.28 LFS was defined as survival in continuous complete remission; relapse and death in remission were events, and patients surviving in continuous complete remission were censored at last contact. Treatment failure was the inverse of LFS. Relapse was defined as hematologic or clinical leukemia recurrence; patients never in remission after transplantation were considered to have had a recurrence on day 1.Statistical methods The association of graft type (blood stem cell compared with bone marrow) and other patient, disease, and transplant characteristics (Table 2) with each outcome was evaluated by using separate Cox proportional hazard regression models. Continuous variables were discretized using the cut point that minimized the 2-log likelihood of the 1-factor Cox proportional hazards
regression model.29 Variables were tested by using a
time-varying covariate method to determine whether the proportional
hazards assumption was met. Adjustments for factors found to have
nonproportional hazards used stratified proportional hazards models or
time-dependent covariates. Interactions between each variable of
interest and graft type were examined by fitting a proportional hazards
model, stratified on transplant type, and examining the interaction
term between the factor of interest and the type of transplant.
Multivariate models were built by using a stepwise forward selection
with a significance level of 0.05. Graft type was held in the model at each step. All multivariate models were examined for center effects by
using a random effects or frailty model;30 there was no
evidence of confounding of main effects by center effects. All analyses were done with PROC PHREG in SAS version 6.12 (SAS Institute Inc, Cary,
NC).
Patient characteristics Patient characteristics are summarized in Table 1. Two hundred eighty-eight patients received blood stem cell transplants and 536 received bone marrow transplants. Three hundred five patients (37%) had AML, 112 (14%) had ALL, and 407 (49%) had CML. Six hundred seventy-seven patients (82%) underwent transplantation while in first complete remission or first chronic phase, and the remaining 147 (18%) were in second complete remission or accelerated phase. Patient characteristics were relatively balanced between the blood stem cell and bone marrow transplant groups. There were significant differences in the following variables: the blood stem cell group had fewer CML patients in chronic phase; more patients with high leukocyte counts at diagnosis; a higher proportion of patients who received total-body irradiation for pretransplantation conditioning, hematopoietic growth factors after transplantation, or both; and a lower proportion of patients who received methotrexate for GVHD prophylaxis. A higher proportion of blood stem cell transplantations were performed in Europe. The distributions of leukemia subtypes and cytogenetic abnormalities were similar in the 2 groups.Hematologic recovery Patients who received blood stem cell transplants had significantly faster recovery of neutrophils and platelets (Table 3). This difference was independent of growth factor and methotrexate use. Additionally, there was less variability in recovery times with blood stem cell transplantation (ie, fewer outliers with slow hematologic recovery) (Figures 1 and 2). The median time to a neutrophil count of at least 0.5 × 109/L was 14 days (range, 10 to 40 days) with blood stem cells and 19 days (range, 11 to 35 days) with bone marrow (P < .001). The median time to a platelet count of at least 20 × 109/L was 18 days (range, 13 to 68 days) with blood stem cells and 25 days (range, 12 to 87 days) with bone marrow (P < .001). The median time to a platelet count of at least 50 × 109/L was 19 days (range, 11 to 70 days) with blood stem cells and 28 days (range, 20 to 79 days) with bone marrow (P < .001).
Acute GVHD Risks of grades II to IV acute GVHD were similar with blood stem cell and bone marrow transplants (Table 3). Adjusted 100-day (after transplantation) probabilities of grades II to IV acute GVHD were 40% (95% CI, 33%-46%) with blood stem cells and 35% (95% CI, 31%-39%) with bone marrow (Figure 3). Results were similar for grades III to IV acute GVHD. Adjusted probabilities of grades III to IV acute GVHD after transplantation were 13% (95% CI, 8%-19%) with blood stem cells and 19% (95% CI, 15%-26%) with bone marrow.
Chronic GVHD The risk of chronic GVHD in the first year after transplantation was higher in recipients of blood stem cell transplants than in recipients of bone marrow transplants. The probability of chronic GVHD at 1 year after transplantation was 65% (95% CI, 56%-72%) with blood stem cells and 53% (95% CI, 47%-59%) with bone marrow. Adjusted probabilities are shown in Figure 4. The relative risk of having chronic GVHD after a blood stem cell transplantation compared with a bone marrow transplantation was 1.30 (95% CI, 1.00-1.70; Table 3). Similar results were obtained when only extensive chronic GVHD was considered. Data on the incidence, severity, and organ involvement of chronic GVHD are summarized in Table 4.
TRM The relative risk of TRM with blood stem cell compared with bone marrow transplants differed according to the type and stage of leukemia. Among patients with acute leukemia in first remission, the risk of TRM in those who received blood stem cells was not different from the risk in those given bone marrow (Table 5). The 1-year cumulative incidence of TRM was 18% (95% CI, 11%-26%) with blood stem cells and 28% (95% CI, 21%-35%) with bone marrow (Figure 5A). Among patients with acute leukemia in second remission, the risk of TRM was significantly lower after blood stem cell transplantation than after bone marrow transplantation (Table 6). The 1-year cumulative incidence of TRM was 13% (95% CI, 5%-26%) with blood stem cells and 30% (95% CI, 16%-44%) with bone marrow (Figure 5A). Among patients with CML in first chronic phase, the risk of TRM was similar with blood stem cells and bone marrow (Table 5B). The 1-year cumulative incidences of TRM were 37% (95% CI, 25%-49%) and 27% (95% CI, 19%-32%), respectively, with blood stem cells and bone marrow (Figure 5B). Among patients who underwent transplantation while in accelerated or second chronic phase, TRM risk was significantly lower with blood stem cells (Table 6). The 1-year cumulative incidences of TRM were 26% (95% CI, 10%-46%) with blood stem cells and 67% (95% CI, 37%-85%) with bone marrow (Figure 6). Thus, use of blood stem cells rather than bone marrow decreased TRM in patients with advanced disease.
Relapse There was no apparent difference in the risk of relapse after blood stem cell and bone marrow transplantation, though the follow-up was relatively short to evaluate this outcome (Table 5). The 1-year cumulative incidences of relapse among patients with acute leukemia in first remission were 14% (95% CI, 7%-23%) with blood stems cells and 11% (95% CI, 7%-17%) with bone marrow (Figure 6A). Among patients who had transplantation while in second remission, the 1-year cumulative incidences of relapse were 8% (95% CI, 2%-20%) with blood stem cells and 13% (95% CI, 4%-26%) with bone marrow (Figure 6A).LFS Similar to the results for TRM, the relation between graft type and LFS after transplantation varied according to the type and stage of leukemia. Among patients with acute leukemia in first remission, the risk of treatment failure (relapse or death; inverse of LFS) was similar with blood stem cell and bone marrow transplants (Table 5). Their adjusted 1-year probabilities of LFS were 70% (95% CI, 56%-80%) with blood stem cells and 61% (95% CI, 52%-68%) with bone marrow (Figure 7A). Among patients with acute leukemia in second remission, the risk of treatment failure was significantly lower after blood stem cell transplantation than after bone marrow transplantation (Table 5). Adjusted 1-year probabilities of LFS in these patients were 77% (95% CI, 57%-88%) with blood stem cells and 57% (95% CI, 40%-71%) with bone marrow (Figure 7A). Among patients with CML in first chronic phase, the risk of treatment failure was similar with blood stem cells and bone marrow (Table 5): their adjusted 1-year probabilities of LFS were 63% (95% CI, 49%-74%) and 74% (95% CI, 66%-80%), respectively, with blood stem cells and bone marrow (Figure 7B). Among patients who had transplantation while in accelerated or second chronic phase, treatment failure was significantly lower with blood stem cells (Table 5). Their adjusted 1-year probabilities of LFS were 68% (95% CI, 45%-84%) with blood stem cells and 23% (95% CI, 9%-40%) with bone marrow (Figure 7B). Causes of death after blood stem cell and bone marrow transplantation were similar (Table 6).
Previous studies of allogeneic blood stem cell transplantation indicated more rapid hematologic recovery than with allogeneic bone marrow transplantation and similar risks of acute GVHD. There are conflicting data on the risk of chronic GVHD. Most studies used historical bone marrow transplantation controls, 6-15,22 although 1 small randomized trial has been reported.16 It is unclear from these data whether allogeneic blood stem cells have an advantage over bone marrow in TRM or overall survival.17 The current study compared early results of concurrent allogeneic blood stem cell and bone marrow transplantations by 105 teams that reported data to the IBMTR or EBMT. The source of allografts was chosen by the treatment center. All patients older than 20 years with acute leukemia in first or second remission or with CML in chronic or accelerated phase who underwent transplantation during the period studied were included. All patients had HLA-identical sibling donors and none received T-cell-depleted grafts. Although some differences existed, patient characteristics in the 2 groups were relatively well balanced. Multivariate analyses were used to adjust for potentially confounding effects of other variables. We found a more rapid hematologic recovery, with a shorter interval to recovery of neutrophils and platelets, with blood stem cell transplants than with bone marrow transplants. The risk of acute GVHD was comparable in the 2 groups, similar to results of previous studies.
Submitted October 4, 1999; accepted February 15, 2000.
Supported by Public Health Service grants P01-CA-40053 and 1 U24 CA76518-01 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute, of the US Department of Health and Human Services; and grants from Amgen, Inc; Anonymous; Baxter Fenwal; Berlex Laboratories; BioWhitakker, Inc; Blue Cross and Blue Shield Association; Lynde and Harry Bradley Foundation; Bristol-Myers Squibb Company; Cell Therapeutics, Inc; Center for Advanced Studies in Leukemia; Chimeric Therapies; Chiron Therapeutics; COBE BCT Inc; Charles E. Culpeper Foundation; Eleanor Naylor Dana Charitable Trust; Eppley Foundation for Research; Genentech, Inc; Human Genome Sciences; Immunex Corporation; Kettering Family Foundation; Kirin Brewery Company; Robert J. Kleberg Jr and Helen C. Kleberg Foundation; Herbert H. Kohl Charities, Inc; Nada and Herbert P. Mahler Charities; Milstein Family Foundation; Milwaukee Foundation/Elsa Schoeneich Research Fund; NeXstar Pharmaceuticals, Inc; Samuel Roberts Noble Foundation; Novartis Pharmaceuticals; Orphan Medical; Ortho Biotech, Inc; John Oster Family Foundation; Jane and Lloyd Pettit Foundation; Alirio Pfiffer Bone Marrow Transplant Support Association; Pfizer, Inc; RGK Foundation; Roche Laboratories; SangStat Medical Corporation; Schering AG; Schering-Plough Oncology; Searle; SmithKline Beecham Pharmaceutical; Stackner Family Foundation; Starr Foundation; Joan and Jack Stein Foundation; Swiss National Research Foundation; SyStemix; United Resource Networks; and Wyeth-Ayerst Laboratories.
Reprints: Mary M. Horowitz, International Bone Marrow Transplant Registry, Medical College of Wisconsin, 8701 Watertown Plank Road, PO Box 26509, Milwaukee, WI 53226; e-mail: marymh{at}mcw.edu.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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Abstract
Introduction
a randomized, controlled trial.
Ann Intern Med.
1997;126:600