From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
TRANSPLANTATION
Brief report
Worse outcome and more chronic GVHD with peripheral blood progenitor cells
than bone marrow in HLA-matched sibling donor transplants for young patients
with severe acquired aplastic anemia
Hubert Schrezenmeier,1 Jakob R. Passweg,2 Judith C. W. Marsh,3 Andrea Bacigalupo,4 Christopher N. Bredeson,5
Eduardo Bullorsky,6 Bruce M. Camitta,5 Richard E. Champlin,7 Robert Peter Gale,8 Monika Fuhrer,9 John P. Klein,10
Anna Locasciulli,11 Rosi Oneto,4 Antonius V. M. B. Schattenberg,12 Gerard Socie,13 and Mary Eapen10
1Institute of Clinical Transfusion Medicine and Immunogenetics, University of Ulm, Germany; 2Hopitaux Universitaires, Geneva, Switzerland; 3St George’s
Hospital Medical School, London, United Kingdom, 4Ospedale S. Martino, Genova, Italy; 5Medical College of Wisconsin, Milwaukee; 6Hospital Britanico, Buenos
Aires, Argentina; 7M. D. Anderson Cancer Center, Houston, TX; 8Center for Advanced Studies in Leukemia, Los Angeles, CA; 9Universitat Munchen, Munich,
Germany; 10The Statistical Center, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee; 11Ospedale S.
Camillo-Forlanini, Rome, Italy; 12University Medical Center, Nijmegen, the Netherlands; 13St Louis Hospital-1, Paris, France
We analyzed the outcome of 692 patients with severe aplastic anemia (SAA)
receiving transplants from HLA-matched
siblings. A total of 134 grafts were peripheral blood progenitor cell (PBPC)
grafts, and 558 were bone marrow (BM)
grafts. Rates of hematopoietic recovery
and grades 2 to 4 chronic graft-versushost disease (GVHD) were similar after
PBPC and BM transplantations regardless of age at transplantation. In pa-
tients older than 20 years, chronic GVHD
and overall mortality rates were similar
after PBPC and BM transplantations. In
patients younger than 20 years, rates of
chronic GVHD (relative risk [RR] 2.82;
P ⴝ .002) and overall mortality (RR 2.04;
P ⴝ .024) were higher after transplantation of PBPCs than after transplantation
of BM. In younger patients, the 5-year
probabilities of overall survival were
73% and 85% after PBPC and BM trans-
plantations, respectively. Corresponding probabilities for older patients were
52% and 64%. These data indicate that
BM grafts are preferred to PBPC grafts
in young patients undergoing HLAmatched sibling donor transplantation
for SAA. (Blood. 2007;110:1397-1400)
© 2007 by The American Society of Hematology
Introduction
Patients, materials, and methods
Transplantation of bone marrow (BM) from an HLA-matched
sibling donor is an effective treatment for severe aplastic anemia
(SAA) with long-term survival in excess of 80% and graft
failure rates of approximately 10%.1-7 Unpublished data (January 2007) from the European Group for Blood and Marrow
Transplantation (EBMT) and the Center for International Blood
and Marrow Transplant Research (CIBMTR) suggest approximately 60% of HLA-matched sibling donor transplantations for
SAA now use peripheral blood progenitor cell (PBPC) grafts.
A similar switch to PBPC over BM grafts is reported in leukemia
transplantations.8-10 The higher rate of chronic graft-versus-host
disease (GVHD) may be offset by lower relapse rates in some
settings. In contrast, there is no perceived benefit of chronic
GVHD for SAA. Further, few data on PBPCs for SAA are
reported.11-15 In a preliminary analysis from our group, PBPC
grafts appeared to contribute to higher mortality.16 Here, we
report chronic GVHD and long-term overall survival rates in
134 PBPC recipients and 558 BM recipients of HLA-matched
sibling donor transplants for SAA.
The probabilities of hematopoietic recovery (neutrophil count ⱖ 0.5 ⫻ 109/L for
3 consecutive days and platelet count ⱖ 20 ⫻ 109/L for 7 days, unsupported) and
acute and chronic GVHD were calculated using the cumulative incidence
function method in which death without the event was the competing event.17
The probability of overall survival was calculated using the Kaplan-Meier
estimator, death from any cause was considered an event, and surviving patients
were censored at last follow-up.17 The 95% confidence interval (CI) is calculated
Submitted March 22, 2007; accepted April 30, 2007. Prepublished online as
Blood First Edition paper, May 2, 2007; DOI 10.1182/blood-2007-03-081596.
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
The publication costs of this article were defrayed in part by page charge
© 2007 by The American Society of Hematology
BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
Patients
Data on patients undergoing their first PBPC and BM HLA-matched sibling
transplantation from 1995 to 2003 were obtained from the EBMT and the
Statistical Center of the CIBMTR at the Medical College of Wisconsin.
Only patients who received transplants at centers that provided a minimum
of 12 months of follow-up on all their surviving patients were included. The
Institutional Review Board of the Medical College of Wisconsin approved
this study. Informed consent was obtained in accordance with the Declaration of Helsinki.
Statistical methods
1397
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1398
BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
SCHREZENMEIER et al
using log transformation. Cox proportional hazards regression models were
constructed using a stepwise forward selection, with a P value of .05 or less to
indicate statistical significance.18 Variables considered in regression models are
shown in Table 1. Results are expressed as relative risk (RR); that is, the relative
occurrence of the event with transplantation of BM compared with that of
PBPCs. P values are 2-sided. SAS software version 9.1 was used for analyses
(SAS Institute, Cary, NC).
Results and discussion
Patient, disease, and transplant characteristics are shown in Table 1.
Characteristics of the treatment groups were similar except that
PBPC transplantations were more recent, and the median time
from diagnosis to transplantation was longer in PBPC recipients
older than 20 years compared with BM recipients of similar age
(6 months vs 4 months; P ⫽ .003). In patients 20 years old and
younger, the corresponding time was 2 months for both treatment
groups. More than half (59%) of PBPC transplantations in patients
20 years old and younger occurred between 2000 and 2003,
compared with 34% of BM transplantations (P ⫽ .001). Similarly,
64% of PBPC transplantations in patients older than 20 years
occurred between 2000 and 2003, compared with 31% of BM
transplantations (P ⬍ .001). Cyclophosphamide with or without
antithymocyte globulin was the predominant conditioning regimen,
and all received T-replete grafts.
Hematopoietic recovery
Though the median time to neutrophil (13 days vs 18 days) and
platelet recovery (19 days vs 25 days) were faster after transplantation of PBPCs compared with BM, the probabilities of neutrophil
Table 1. Patient, disease, and transplantation characteristics by recipient age at transplantation
Aged 20 y or younger*
Variable
Bone marrow
Older than 20 y†
Peripheral blood
Bone marrow
Peripheral blood
No.
305
44
253
90
Male sex, no. (%)
185 (61)
24 (55)
148 (59)
44 (49)
Performance score, no. (%)
90-100
180 (59)
25 (57)
110 (43)
32 (36)
Lower than 90
81 (27)
13 (30)
94 (37)
43 (48)
Unknown
44 (14)
6 (14)
49 (19)
15 (17)
248 (81)
33 (75)
167 (66)
46 (51)
57 (19)
11 (25)
86 (34)
44 (49)
1995-1999
201 (66)
18 (41)
175 (69)
33 (36)
2000-2003
104 (34)
26 (59)
78 (31)
57 (64)
TBI ⫹ other
19 (6)
2 (5)
12 (5)
7 (8)
Cy ⫹ TLI/TAI ⫾ ATG
11 (4)
2 (5)
22 (9)
6 (7)
193 (63)
21 (48)
118 (47)
44 (49)
Cy
62 (20)
13 (30)
67 (26)
11 (12)
Bu ⫹ Cy ⫾ other
16 (5)
—
22 (9)
4 (4)
2 (1)
6 (14)
9 (4)
16 (18)
—
—
2 (⬍1)
1 (1)
2 (1)
—
1 (⬍1)
1 (1)
Interval, diagnosis to HCT, no. (%)
ⱕ 6 mo
Longer than 6 mo
Years of transplantation, no. (%)
Conditioning regimen, no. (%)
Cy ⫹ ATG
Fludarabine ⫹ other
Cy ⫹ thiotepa
Unknown
GVHD prophylaxis, no. (%)
None
CSA ⫾ other
CSA ⫹ MTX ⫾ other
Tacrolimus ⫾ other
Other
1 (⬍1)
—
38 (13)
12 (27)
33 (13)
24 (27)
255 (84)
28 (64)
214 (85)
51 (57)
—
1 (⬍1)
6 (7)
2 (1)
2 (1)
—
—
2 (5)
9 (3)
2 (3)
3 (1)
9 (10)
Male to male
90 (30)
9 (20)
93 (37)
20 (22)
Male to female
66 (22)
9 (20)
63 (25)
28 (31)
Female to male
95 (31)
14 (32)
55 (22)
24 (27)
Female to female
54 (18)
12 (27)
41 (16)
18 (20)
Unknown
Donor-recipient sex match, no. (%)
Unknown
Follow-up of survivors, median (range), mo
—
—
68 (16-131)
50 (22-105)
1 (⬍1)
68 (13-134)
—
41 (15-102)
A total of 155 transplantation centers contributed data for this study. Of these, 91 transplantation centers contributed data on BM transplantations only, 27 centers
contributed data on PBPC transplantations only, and 37 centers contributed data on both BM and PBPC transplantations. Most transplantation centers (121 关78%兴 of 155)
contributed 5 or fewer patients, 22 (14%) centers contributed 6 to 10 patients, and only 12 (7%) centers contributed more than 10 patients. The median number of patients per
center is 3.
HCT indicates hematopoietic stem cell transplantation; TBI, total body irradiation; TLI, total lymphoid irradiation; TAI, total abdominal irradiation; Cy, cyclophosphamide;
ATG, antithymocyte globulin; Bu, busulfan; CSA, cyclosporine; and MTX, methotrexate; — indicates not applicable.
*A total of 107 centers performed transplantations on patients 20 years old and younger. A total of 91 (85%) centers performed transplantations on 5 or fewer patients, 13
(12%) centers performed transplantations on 6 to 10 patients, and 2 (3%) centers performed transplantations on more than 10 patients. The median number of patients who
received transplants per center is 2.
†A total of 109 centers performed transplantations on patients older than 20 years. A total of 94 (86%) centers performed transplantations on 5 or fewer patients, 9 (8%)
centers performed transplantations on 6 to 10 patients, and 6 (6%) centers performed transplantations on more than 10 patients. The median number of patients who received
transplants per center is 2.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
recovery at day 28 (89% vs 85%) and platelet recovery at day 100
(80% vs 85%) were similar. The proportion of patients with
primary graft failure (9% vs 9%) and secondary graft failure (6% vs
7%) were similar after transplantation of PBPCs and BM,
respectively.
GVHD
Rates of grades 2 to 4 acute GVHD were similar after PBPC and
BM transplantations (RR, 1.42; 95% CI, 0.59-3.39; P ⫽ .436; and
RR, 1.03; 95% CI, 0.60-1.79; P ⫽ .909) in patients 20 years old
and younger and older than 20 years, respectively. The day-100
probabilities of acute grades 2 to 4 GVHD in younger patients were
10% and 14%, after BM and PBPC transplantations, respectively.
Corresponding probabilities in older patients were 20% and 19%.
Chronic GVHD rates were higher after PBPC transplantations
than after BM transplantations in patients 20 years old and younger
(RR, 2.82; 95% CI, 1.46-5.44; P ⫽ .002; Figure 1A). In those older
than 20 years, rates were similar after PBPC and BM transplantations (RR, 1.14; 95% CI, 0.71-1.85; P ⫽ .589). This differs from
some reports where chronic GVHD rates were higher with PBPC
grafts regardless of age.19-21 Notably, the significant difference in
chronic GVHD rate after PBPC and BM transplantations was most
evident with follow-ups of more than 6 to 7 years. It remains to be
seen whether, with longer follow-up, chronic GVHD rates will be
higher in older patients.
Overall mortality
Overall mortality rates were higher after PBPC transplantations
than after BM transplantations in patients 20 years old and younger
(RR, 2.04; 95% CI, 1.09-3.78; P ⫽ .024; Figure 1B). In patients
older than 20 years, rates were similar after PBPC and BM
PBPC VS. BM TRANSPLANTS FOR SAA
1399
transplantations (RR, 1.27; 95% CI, 0.87-1.85; P ⫽ .119). Other
factors affecting mortality rates after PBPC and BM transplantations were poor performance score (⬍ 90) and time from diagnosis
to transplantation. For patients aged 20 years and younger, there
was a 2-fold increase in mortality in those with poor performance
scores (RR, 1.99; 95% CI, 1.16-3.44; P ⫽ .012) and a 3-fold
increase in mortality when transplantation occurred more than
6 months after diagnosis (RR, 3.22; 95% CI, 1.93-5.40; P ⬍ .001).
Similarly, in patients older than 20 years, rates were higher in those
with poor performance scores (RR, 2.32; 95% CI, 1.57-3.44;
P ⬍ .001) and when transplantation occurred more than 6 months
after diagnosis (RR, 1.44; 95% CI, 1.01-2.05; P ⫽ .041).
Higher chronic GVHD after PBPC transplantations in younger
patients likely contributed to the excess mortality. This has been
reported in younger patients with acute leukemia and older patients
with good-risk chronic myeloid leukemia.20,21 Others have reported
the significant negative impact of chronic GVHD on survival after
HLA-matched sibling transplantations.5 Though we did not observe a statistically significant survival advantage for 1 graft type
over the other in patients older than 20 years of age, the 5-year
probability of overall survival after PBPC transplantations was
52% compared with 64% after BM transplantations. The recent
report by Locasciulli and colleagues7 demonstrate improvement in
overall survival with BM grafts over time, suggesting the recent
use of PBPC grafts from HLA-matched sibling donors for SAA
have for the first time in more than a decade resulted in lower
survival rates.
Ours is not a randomized study, and is subject to selection bias
as well as other known and unknown or unmeasured factors that
may have influenced the choice of 1 graft over another. However,
known patient-, disease-, and transplant-related characteristics
were comparable between PBPC and BM groups. Further, 59% of
centers used BM grafts and 17% used PBPC grafts exclusively, and
24% used both BM and PBPC grafts. At centers that used both
grafts, PBPCs were used more frequently after 2000 and accounted
for 50% of transplantations compared with 20% of BM transplantations, independent of age. These data indicate PBPC grafts from
HLA-matched siblings were associated with higher chronic GVHD
and lower survival in younger patients. The lower—though not
statistically significant—overall survival rates after PBPC transplantations in older patients is discouraging. New transplantation
technologies have brought about constant improvement in outcome
for the last 20 years, and for the first time, such a change has
resulted in lower survival.
Acknowledgments
This work was supported by Public Health Service Grant
U24-CA76518-08 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the
National Heart, Lung, and Blood Institute.
Authorship
Figure 1. Patients 20 years old and younger and older than 20 years with SAA
after PBPC (PB) and BM transplantation. (A) Probability of chronic graft-versushost disease. (B) Probability of overall survival.
Contribution: H.S., J.R.P., J.C.W.M., and M.E. had primary
responsibility for the project and contributed equally to study
design, interpretation of data, manuscript preparation, and approval
of final manuscript. R.O. prepared the data file. J.P.K. and M.E.
performed the statistical analysis. A.B., B.M.C., R.E.C., R.P.G.,
J.P.K., A.V.M.B.S., and G.S. participated in data interpretation,
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1400
BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
SCHREZENMEIER et al
manuscript preparation, and approval of final manuscript. C.N.B.,
E.B., M.F., A.L., and R.O. approved the final manuscript.
Conflict of interest disclosure: The authors declare no competing financial interests.
Correspondence: Mary Eapen, Statistical Center, Center for
International Blood and Marrow Transplant Research, Medical
College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI
53226; e-mail: [email protected].
References
1. Storb R, Etzioni R, Anasetti C, et al. Cyclophosphamide combined with antithymocyte globulin in
preparation for allogeneic marrow transplants in
patients with aplastic anemia. Blood. 1994;84:
941-949.
2. Storb R, Leisenring W, Anasetti C, et al. Longterm follow-up of allogeneic marrow transplants in
patients with aplastic anemia conditioned by cyclophosphamide combined with antithymocyte
globulin. Blood. 1997;89:3890-3891.
3. Deeg HJ, Leisenring W, Storb R, et al. Long-term
outcome after marrow transplantation for severe
aplastic anemia. Blood. 1998;91:3637-3645.
4. Horowitz MM. Current status of allogeneic bone
marrow transplantation in acquired aplastic anemia. Semin Hematol. 2000;37:30-42.
5. Bacigalupo A, Brand R, Oneto R, et al. Treatment
of acquired severe aplastic anemia: bone marrow
transplantation compared with immunosuppressive therapy—The European Group for Blood and
Marrow Transplantation experience. Semin Hematol. 2000;37:69-80.
6. McCann S, Passweg J, Bacigalupo A, et al. The
influence of cyclosporin alone, or cyclosporin and
methotrexate, on the incidence of mixed haematopoietic chimaerism following allogeneic sibling
bone marrow transplantation for severe aplastic
anaemia. Bone Marrow Transplant. 2007;39:109114.
7. Locasciulli A, Oneto R, Bacigalupo A, et al. Outcome of patients with acquired aplastic anemia
given first line bone marrow transplantation or
immunosuppressive treatment in the last decade:
a report from the European Group for Blood and
Marrow Transplantation (EBMT). Haematologica.
2007;92:11-18.
8. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in
patients with hematologic cancers. N Engl J Med.
2001;344:175-181.
9. Powles R, Mehta J, Kulkarni S, et al. Allogeneic
blood and bone-marrow stem-cell transplantation
in haematological malignant diseases: a randomised trial. Lancet. 2000;355:1231-1237.
10. Schmitz N, Beksac M, Hasenclever D, et al.
Transplantation of mobilized peripheral blood
cells to HLA-identical siblings with standard-risk
leukemia. Blood. 2002;100:761-767.
11. Herrera-Garza J, Jaime-Perez J, Montemayor J,
Ibarra-Peart R, Gomez-Almaguer D. High-dose
peripheral blood stem cell transplant for multitransfused severe aplastic anaemia patients without antithymocyte globulin in the conditioning
regimen. Bone Marrow Transplant. 1999;24:845848.
12. Hsu HC, Tsai WH, Lin JS, Tzeng CH, Wang SY,
Ho CH. Primary transplantation of allogeneic peripheral blood stem cell for severe aplastic anemia. Ann Hematol. 1997;74:191-192.
13. Gurman G, Celebi H, Ustun C, et al. Allogeneic
peripheral blood stem cell transplantation for severe aplastic anemia. Ther Apher. 2001;5:54-57.
14. de la Rubia J, Cantero S, Sanz GF, et al. Transplantation of CD34⫹ selected peripheral blood to
HLA-identical sibling patients with aplastic anaemia: results from a single institution. Bone Marrow Transplant. 2005;36:325-329.
15. Kumar R, Prem S, Mahapatra M, et al. Fludarabine, cyclophosphamide and horse antithymocyte
globulin conditioning regimen for allogeneic pe-
ripheral blood stem cell transplantation performed
in non-HEPA filter rooms for multiply transfused
patients with severe aplastic anemia. Bone Marrow Transplant. 2006;37:745-749.
16. Schrezenmeier H, Bredeson C, Bruno B, et al.
Comparison of allogeneic bone marrow and peripheral blood stem cell transplantation for aplastic anemia: collaborative study of European Blood
and Marrow Transplant Group (EBMT) and International Bone Marrow Transplant Registry
(IBMTR) [abstract]. Blood. 2003;102:79a.
17. Klein J, Moeschberger M. Survival Analysis:
Techniques of Censored and Truncated Data.
2nd ed. New York: Springer-Verlag; 2003.
18. Cox DR. Regression models and life tables. J R
Stat Soc. 1972;34:187.
19. Flowers ME, Parker PM, Johnston LJ, et al. Comparison of chronic graft-versus-host disease after
transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: longterm follow-up of a randomized trial. Blood. 2002;
100:415-419.
20. Eapen M, Horowitz MM, Klein JP, et al. Higher
mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and
Alternate Stem Cell Source Working Committee
of the International Bone Marrow Transplant Registry. J Clin Oncol. 2004;22:4872-4880.
21. Schmitz N, Eapen M, Horowitz MM, et al. Longterm outcome of patients given transplants of mobilized blood or bone marrow: a report from the
International Bone Marrow Transplant Registry
and the European Group for Blood and Marrow
Transplantation. Blood. 2006;108:4288-4290.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
2007 110: 1397-1400
doi:10.1182/blood-2007-03-081596 originally published
online May 2, 2007
Worse outcome and more chronic GVHD with peripheral blood
progenitor cells than bone marrow in HLA-matched sibling donor
transplants for young patients with severe acquired aplastic anemia
Hubert Schrezenmeier, Jakob R. Passweg, Judith C. W. Marsh, Andrea Bacigalupo, Christopher N.
Bredeson, Eduardo Bullorsky, Bruce M. Camitta, Richard E. Champlin, Robert Peter Gale, Monika
Fuhrer, John P. Klein, Anna Locasciulli, Rosi Oneto, Antonius V. M. B. Schattenberg, Gerard Socie
and Mary Eapen
Updated information and services can be found at:
http://www.bloodjournal.org/content/110/4/1397.full.html
Articles on similar topics can be found in the following Blood collections
Brief Reports (1936 articles)
Clinical Trials and Observations (4553 articles)
Hematopoiesis and Stem Cells (3432 articles)
Transplantation (2228 articles)
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society
of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.