Biol Blood Marrow Transplant 19 (2013) 934e939
Comparison of Outcomes after Two Standards-of-Care
Reduced-Intensity Conditioning Regimens and Two
Different Graft Sources for Allogeneic Stem Cell
Transplantation in Adults with Hematologic Diseases: A
Single-Center Analysis
ASBMT
American Society for Blood
and Marrow Transplantation
Amandine Le Bourgeois 1, Catherine Mohr 1, Thierry Guillaume 1,
Jacques Delaunay 1, Florent Malard 1, Marion Loirat 1, Pierre Peterlin 1,
Nicolas Blin 1, Viviane Dubruille 1, Beatrice Mahe 1, Thomas Gastinne 1,
Steven Le Gouill 1, Philippe Moreau 1, Mohamad Mohty 1, 2, Lucie Planche 3,
Laurence Lode 4, Marie-Christine Bene 4, Patrice Chevallier 1, 2, *
1
Department and CIC, CHU Hotel Dieu, Nantes, France
Nantes University and Inserm CRNCA UMR 892, Nantes, France
Cellule de Promotion à la Recherche Clinique, CHU Hotel-Dieu, Nantes, France
4
Hematology/Biology Department, CHU Hotel-Dieu, Nantes, France
2
3
Article history:
Received 11 January 2013
Accepted 18 March 2013
Key Words:
Cord blood
Reduced-intensity conditioning
regimen
Allogeneic stem cell
transplantation
Peripheral blood stem cell
Adult
a b s t r a c t
Recent advances in allogeneic stem cell transplantation (allo-HSCT) have included the advent of reducedintensity conditioning (RIC) regimens to decrease the toxicity of myeloablative allo-SCT and the use of
double umbilical cord blood (dUCB) units as a graft source in adults lacking a suitable donor. The FB2A2
regimen (fludarabine 30 mg/kg/day for 5-6 days þ i.v. busulfan 3.6 mg/kg/day for 2 days þ rabbit antithymocyte globulin 2.5 mg/kg/day for 2 days) supported by peripheral blood stem cells (PBSCs) and the TCF
regimen (fludarabine 200 mg/m2 for 5 days þ cyclophosphamide 50 mg/kg for 1 day þ low-dose [2 Gy] total
body irradiation) supported by dUCB units are currently the most widely used RIC regimens in many centers
and could be considered standard of care in adults eligible for an RIC allo-SCT. Here we compared, retrospectively, the outcomes of adults patients who received the FB2A2-PBSC RIC regimen (n ¼ 52; median age,
59 years; median follow-up, 19 months) and those who received the dUCB-TCF RIC regimen (n ¼ 39; median
age, 56 years; median follow-up, 20 months) for allo-SCT between January 2007 and November 2010. There
were no significant between-group differences in patient and disease characteristics. Cumulative incidences
of engraftment, acute grade II-IV and chronic graft-versus-host disease were similar in the 2 groups. The
median time to platelet recovery, incidence of early death (before day þ100), and 2-year nonrelapse mortality
were significantly higher in the dUCB-TCF group (38 days versus 0 days [P <.0001]; 20.5% versus 4% [P ¼ .05],
and 26.5% versus 6% [P ¼ .02], respectively). The groups did not differ in terms of 2-year overall survival (62%
for FB2A2-PBSC versus 61% for dUCB-TCF), disease-free survival (59% versus 50.5%), or relapse incidence
(35.5% versus 23%). In multivariate analysis, the presence of a lymphoid disorder was associated with
a significantly higher 2-year overall survival (hazard ratio, 0.42; 95% confidence interval, 0.20-0.87; P ¼ .02),
whereas patients receiving a FB2A2-PBSC allo-SCT had a significantly lower 2-year nonrelapse mortality
(hazard ratio, 0.24; 95% confidence interval, 0.1-0.7; P ¼ .01). There were no factors associated with higher
2-year disease-free survival or lower relapse incidence. This study suggests that the dUCB-TCF regimen
provides a valid alternative in adults lacking a suitable donor and eligible for RIC allo-SCT. Prospective and
randomized studies are warranted to establish the definitive role of dUCB RIC allo-SCT in adults. In addition,
strategies for decreasing nonrelapse mortality after dUCB RIC allo-SCT are urgently needed.
Ó 2013 American Society for Blood and Marrow Transplantation.
INTRODUCTION
Currently in Europe, at least 40% of allogeneic stem cell
transplantation (allo-SCT) procedures are preceded by
a reduced-intensity conditioning (RIC) regimen [1]. This
percentage is as high as 60% in France [2] and is increasing.
RIC regimens are characterized by cytopenia of variable
duration and severity, as well as the need for stem cell
support, although cytopenia might not be irreversible [3].
Currently, the F5/6B2A2 (hereinafter, FB2A2) regimen,
Financial disclosure: See Acknowledgments on page 938.
* Correspondence and reprint requests: Patrice Chevallier, MD, Service
d’Hématologie Clinique, CHU Hotel-Dieu, Place A Ricordeau, 44093 Nantes
Cedex, France.
E-mail address: [email protected] (P. Chevallier).
adapted from the precursor F6B2A4 Slavin regimen [4] and
supported by peripheral blood stem cells (PBSCs) as the graft
source, is considered the standard RIC regimen for patients
with a suitable related or unrelated donor in many European
centers [5-9]. Another recent advance in practice of allo-SCT
is the use of double umbilical cord blood (UCB) units (dUCB)
as the graft source in adults without a suitable PBSC donor.
UCB transplantation was originally considered in children
after a myeloablative conditioning regimen using a single
UCB unit as a standard 1 donore1 recipient procedure [10].
This strategy was then extended to adults [11,12]. Later, the
concept of using 2 or more UCB units after myeloablative
conditioning to enhance engraftment was investigated with
success in both children and adults [13-16]. The first dUCB
transplantation in an adult was performed in 1999, and by
1083-8791/$ e see front matter Ó 2013 American Society for Blood and Marrow Transplantation.
http://dx.doi.org/10.1016/j.bbmt.2013.03.009
A. Le Bourgeois et al. / Biol Blood Marrow Transplant 19 (2013) 934e939
935
Table 1
Characteristics of the Study Groups at allo-SCT
FB2A2-PBSC (n ¼ 52)
Male sex, n (%)
Age at SCT, yr, median (range)
Time from diagnosis to SCT, mo median (range)
Disease, n
Acute myelogenous leukemia
Acute lymphoblastic leukemia
Biphenotypic leukemia
Myelodysplastic syndrome
Myeloproliferative syndrome
Lymphoma
Multiple myeloma
Myeloid disorders, n (%)
Previous auto-SCT, n (%)
Status at allo-SCT
First complete remission
Second/third complete remission
Active disease
Donor type
Sibling
Matched unrelated
Mismatched unrelated
Double cord blood unit matching
4/6 and 4/6
4/6 and 5/6
5/6 and 5/6
Recipient/donor CMV status negative/negative, n (%)
Nucleated cells infused, 108/kg, median (range)
32 (61.5)
59 (22-70)
9 (2.5-214)
dUCB-TCF (n ¼ 39)
P Value
19 (49)
55.5 (22-69)
10 (1.6-185)
.22
.07
.85
22
1
1
9
0
16*
3
31 (60)
18 (34.6)
16
2
1
6
1
13y
0
23 (59)
13 (33.3)
.95
.90
27 (52)
13 (25)
12 (23)
17 (44)
9 (23)
13 (33)
.55
30
20
2
23 (44)
10.9 (1.5-21.8)
39
9
8
22
21 (54)
0.40 (0.17-0.66)
.36
<.0001
* Diffuse large B cell lymphoma, n ¼ 4; follicular lymphoma. n ¼ 2; mantle cell lymphoma, n ¼ 4; peripheral T cell lymphoma, n ¼ 2; anaplastic large cell
lymphoma, n ¼ 1; Hodgkin disease, n ¼ 3.
y
Diffuse large B cell lymphoma, n ¼ 4; follicular lymphoma, n ¼ 1; peripheral T cell lymphoma, n ¼ 3; Hodgkin disease, n ¼ 2; Waldenström’s disease, n ¼ 1;
chronic lymphocytic leukemia, n ¼ 2.
2005, dUCB transplantations were more popular than single
UCB transplantations in adults [17]. The Minneapolis dUCBTCF regimen (including low-dose [2 Gy] total body irradiation [TBI] and cyclophosphamide 1 day and fludarabine 5
days) [18-20] is also considered as a reference in many
centers worldwide when considering a RIC allo-SCT in adults
lacking a PBSC donor. Series comparing outcomes after PBSCRIC allo-SCT and dUCB-RIC allo-SCT are scarce and involve,
except in 1 case [21], highly heterogeneous RIC regimens in
both approaches [20,22-24]. The aim of the present study
was to compare outcomes in 2 homogeneously treated
cohorts of patients who received either the FB2A2-PBSC
regimen or the dUCB-TCF regimen for RIC allo-SCT.
PATIENTS AND METHODS
Patient Characteristics
Between January 2007 and October 2010, a total of 91 adult patients
were identified in our department as having undergone either FB2A2 RIC
allo-SCT supported by PBSCs (n ¼ 52) or dUCB-TCF RIC allo-SCT (n ¼ 39).
Outcomes of patients in the FB2A2-PBSC subgroup have been reported
previously [25]. There were no significant between-group differences in
terms of sex, disease types, disease status at allo-SCT, number of previous
autografts, cytomegalovirus (CMV) risk status, or median time from diagnosis to transplantation. The number of patients with acute myelogenous
leukemia with high-risk cytogenetics was similar in (23% versus 30%;
P ¼ .73). All patients provided informed consent, and the study was
approved by Nantes University Hospital’s Institutional Review Board.
Patients’ characteristics are given in Table 1.
RIC Regimens and Graft-versus-Host Disease Prophylaxis
FB2A2-PBSC regimen
This regimen comprises fludarabine 30 mg/m2 i.v. from day -6 or -5 to
day -2 (120-150 mg/m2 total dose), busulfan 3.2 mg/kg i.v. on days -3 and
-2 (6.4 mg/kg total dose), and antithymocyte globulin (ATG) 2.5 mg/kg on
days -2 and -1 (5 mg/kg total dose). A reduced dose of fludarabine was
provided to patients with decreased renal function (5 days rather than
6 days; n ¼ 12). As graft-versus-host disease (GVHD) prophylaxis, recipients of a related allo-SCT (n ¼ 30) received cyclosporine alone [26], and
recipients of an unrelated allo-SCT (n ¼ 22) received cyclosporine plus
mycophenolate mofetil [27].
dUCB-TCF regimen
All patients in this group received the standard RIC regimen developed
by the Minneapolis group [19] comprising fludarabine 200 mg/m2 for 5 days
(days -6 to -2), cyclophosphamide 50 mg/kg for 1 day (day -6), and low-dose
(2 Gy) TBI on day -1. All patients in this group received cyclosporine plus
mycophenolate mofetil as GVHD prophylaxis. In addition, 4 patients (2 with
previously untreated myelodysplastic syndrome and 2 with transformed
myeloproliferative syndrome) received rabbit ATG 2.5 mg/kg/day for 2 days
(days -2 and -1), to ensure engraftment.
Hematopoietic Reconstitution, Engraftment, Chimerism, and Donor
Lymphocyte Infusion
Neutrophil recovery was defined as the first of 3 consecutive days with a
measured absolute neutrophil count of >0.5 109 /L. Platelet recovery
was defined as the first of 3 consecutive days with a platelet count of
>20 109 /L without transfusion support. Primary graft failure was defined
as persistence of aplasia after day þ28 in the FB2A2-PBSC group or after
day þ42 in the dUCB-TCF group, or by documentation of autologous
reconstitution after transplantation. Secondary graft failure was defined as
reoccurrence of aplasia or autologous reconstitution after documented
successful engraftment. Allogeneic or autologous reconstitutions were
evaluated by donor CD3þ T cell chimerism studies at day þ30, day þ100, and
1 year posttransplantation in living patients on sorted peripheral blood
CD3þ T lymphocytes by quantitative PCR evaluation of differential short
tandem repeat DNA sequences, as described previously [28].
Donor lymphocyte infusion (DLI) was envisaged only in the FB2A2-PBSC
group and programmed after transplantation in cases of disease relapse
(after a salvage regimen), persistence of a mixed chimerism (<95% donor)
despite rapid withdrawal of immunosuppression, or poor hematopoietic or
immune reconstitution.
Supportive Care
Supportive care for the allo-SCT recipients has been reported previously
[25]. All patients in the dUCB-TCF group received G-CSF during
posttransplantation aplasia versus none in the FB2A2-PBSC group. In addition, prophylactic i.v. immunoglobulin (IVIG) was provided at a dose of 10 g/
week up to day þ100 for all patients in the dUCB-TCF group, to decrease the
risk of infection.
936
A. Le Bourgeois et al. / Biol Blood Marrow Transplant 19 (2013) 934e939
Table 2
Univariate Analysis
Factors
Age
<60 yr
60 yr
Sex
Male
Female
Type of disease
Myeloid
Lymphoid
Status at transplantation
Complete remission
Active disease
Donor/recipient CMV status
Negative/negative
Other
Female donor to male recipient, FB2A2-PBSC group
Yes
No
Median time diagnosis to allo-SCT
<9 mo
9 mo
Previous autologous SCT
Yes
No
RIC regimen
FB2A2-PBSC
dUCB-TCF
Chimerism at day þ100
Full: FB2A2-PBSC
dUCB-TCF
Mixed: FB2A2-PBSC
dUCB-TCF
FB2A2-PBSC: Full
Mixed
dUCB-TCF: Full
Mixed
2-year OS
2-year DFS
2-year RI
2-year NRM
67% (51.8-77.9)
55% (37.9-69.1)
P ¼ .22
59% (44.2-71.2)
50% (33-64.3)
P ¼ .25
27% (15.6-39.5)
34.5% (19.7-49.8)
P ¼ .32
14% (6-25.2)
16% (6.2-29.2)
P ¼ .88
58% (43.2-70.4)
66.5% (49.3-79.1)
P ¼ .54
51.5% (36.6-64.5)
59% (42.6-72.9)
P ¼ .57
30.5% (18-43.7)
30% (16.6-44.6)
P ¼ .83
18% (8.8-30.2)
10.5% (3.2-22.7)
P ¼ .22
49% (34.4-62.2)
78% (61.4-88.6)
P ¼ .02
48% (33.9-61.2)
65% (47.0-77.7)
P ¼ .16
32% (19.7-44.5)
27% (14.0-42.4)
P ¼ .40
20% (10.0-32.4)
8% (2.0-19.8)
P ¼ .31
63% (49.7-73.4)
59% (37.3-75.6)
P ¼ .84
59% (46-69.7)
46% (25.9-64.6)
P ¼ .74
30.5% (19.7-41.8)
29% (12.2-47.5)
P ¼ .46
10.5% (4.6-19.4)
25% (9.7-43.7)
P ¼ .16
67% (51.2-79.3)
56% (40.6-69.3)
P ¼ .28
58% (41.8-71.2)
53% (37.8-66)
P ¼ .72
32% (18.8-46.3)
28% (15.8-41.2)
P ¼ .43
10% (3-21.2)
19% (9.3-31.6)
P ¼ .11
66.7% (37.5-84.6)
60.1% (41.9-74.3)
P ¼ .96
58.3% (29.3-78.9)
58.9% (41.2-72.9)
P ¼ .81
28.3% (7.87-53.5)
38.4% (22.6-54)
P ¼ .25
13.3% (1-96-35.6)
2.7% (0.2-12.3)
P ¼ .03
49% (33.6-63.4)
73% (58-84)
P ¼ .02
48.5% (33.3-62.2)
62% (46.4-74.6)
P ¼ .11
36% (22-50)
24% (12.8-37.5)
P ¼ .28
15.5% (6.7-27.7)
13.5% (5.3-25.3)
P ¼ .75
74% (55-86.2)
54% (40-66.3)
P ¼ .07
64.5% (45.1-78.5)
50% (36.2-62.2)
P ¼ .35
26% (11.9-42.1)
32% (20.4-43.9)
P ¼ .62
10% (2.4-23.2)
18% (9-29.7)
P ¼ .56
62% (47.3-74.1)
61% (43.5-74.3)
P ¼ .51
59% (43.8-70.9)
50.5% (33.7-65)
P ¼ .43
35.5% (22.4-48.8)
23% (11.2-37.3)
P ¼ .32
6% (1.5-14.5)
26.5% (13.5-41.4)
P ¼ .02
71% (51.6-83.7)
70.8% (45.8-85.8)
P ¼ .93
51.5% (24.6-73)
66.7% (33.7-86)
P ¼ .77
71% (51.6-83.7)
51.5% (24.6-73)
P ¼ .34
70.8% (45.8-85.8)
66.7% (33.7-86)
P ¼ .58
64% (44.4-78.2)
66.1% (41.3-82.3)
P ¼ .72
57.9% (33.2-76.3)
41.7% (15.2-66.5)
P ¼ .34
64% (44.4-78.2)
57.9% (33.2-76.3)
P ¼ .52
66.1% (41.3-82.4)
41.7% (15.2-66.5)
P ¼ .23
Statistical Analysis
The clinical outcomes studied were 2-year overall survival (OS), diseasefree survival (DFS), relapse incidence (RI), and nonrelapse mortality (NRM).
OS was defined as the the time from day 0 of allo-SCT to death or last followup for surviving patients. DFS was defined as the time from day 0 of allo-SCT
to the time with no evidence of relapse or disease progression, censored at
the date of death or last follow-up. Probabilities of OS and DFS were
calculated using the Kaplan-Meier method and log-rank test. Relapse was
defined as any event related to recurrence of the disease. Progression for
patients with lymphoma was defined according to the Cheson criteria [29].
NRM was defined as death from any cause without previous relapse or
progression. Cumulative incidence curves were used to calculate RI and
NRM in a competing-risk setting [30]. Acute and chronic GVHD were diagnosed and graded according to standard criteria [31,32]. Patients surviving
more than 100 days after allo-SCT with sustained donor hematopoiesis were
considered at risk for the development of chronic GVHD. Death while in
steady state was considered a competing event for GVHD.
The log-rank test was used for univariate comparisons. For all prognostic
analyses, the median value of continuous variables was used as a cutoff
point. Characteristics considered were sex (male versus female), age (cutoff
of 60 years), median time from diagnosis to allo-SCT (cutoff of 9 months),
type of disease (myeloid versus lymphoid), disease status at time of allo-SCT
(complete remission versus active disease), previous auto-SCT (yes versus
no), type of allo-SCT (FB2A2-PBSC versus dUCB-TCF), recipient/donor CMV
status (negative/negative versus other), and chimerism at day þ100 (full
versus mixed). Factors associated with a P value <.20 on univariate analysis
were included in the final Cox multivariate model. All tests were 2-sided.
The type I error rate was fixed at 0.05 for determination of factors associated
with time-to-event outcomes. All statistical analyses were performed using
SAS 9.3 (SAS Institute, Cary, NC).
RESULTS
Hematopoietic Reconstitution, Engraftment, Chimerism,
and Responses
Donor engraftment was achieved in respectively 96% of
the patients in the FB2A2-PBSC group and in 90% of those in
the dUCB-TCF group (P ¼ not significant). The median time to
neutrophil recovery was similar in the 2 groups: 17 days
(range, 0 to 39 days) in the FB2A2-PBSC group and 16 days
(range, 8 to 60 days) in the dUCB-TCF group. However, the
median time for platelet recovery was significantly higher in
the dUCB-TCF group (38 days [range, 13 to 150 days] versus
0 days [range, 0 to 186 days]; P <.001). Two patients
A. Le Bourgeois et al. / Biol Blood Marrow Transplant 19 (2013) 934e939
937
Table 3
Multivariate Analysis
Factors
2-year OS
Previous autologous SCT
Lymphoid disease
FB2A2-PBSC allo-SCT
Median time between diagnosis
and SCT 9 mo
2-year DFS
Lymphoid disease
PBSC transplantation
Median time between diagnosis
and SCT 9 mo
2-year NRM
Donor/recipient CMV status
negative/negative
Complete remission at allo-SCT
FB2A2-PBSC allo-SCT
Figure 1. Comparison of 2-year NRM in the FB2A2-PBSC group (6%; solid line)
and dUCB-TCF group (26%; dotted line); P ¼ .02. x-axis, months; y-axis, %
survival.
demonstrated primary graft failure in the FB2A2-PBSC group
and underwent retransplantation, at day þ49 and day þ133.
The former patient was still alive more than 3 years after his
second allo-SCT, whereas the latter died of relapse at
day þ159. One of the 4 patients with documented primary
allo-SCT failure in the dUCB-TCF group underwent retransplantation with dUCB at day þ77 after the first transplantation, but died of relapse at day þ100. Secondary graft
failure was documented in 8 patients, with a significantly
higher incidence in the dUCB-TCF group (17% versus 4%;
P ¼ .03). Only 1 of these 8 patients (in the FB2A2-PBSC group)
underwent retransplantation at day þ118, and this patient
died of relapse at day þ158.
The rate of full chimerism was similar in the 2 groups at
day þ30 (56% in the FB2A2-PBSC group versus 42% in the
dUCB-TCF group) and day þ100 (62% versus 65%)
posttransplantation. Outcomes according to full versus
mixed chimerism in each group or according to full or mixed
chimerism between groups showed no significant differences in term of 2-year OS or DFS (Table 2).
In the FB2A2-PBSC group, 18 patients (35%) received at
least 1 DLI, at a median time of 136 days (range, 74 to
930 days) after allo-SCT, for either mixed chimerism (n ¼ 9)
or relapse (n ¼ 9). In these patients, the median number of
DLIs was 1 (range, 1 to 6), and the median CD3þ cell dose
infused was 2 107/kg (range, 1 to 16 107/kg). After DLI, all
of the 9 patients with mixed chimerism achieved full
chimerism, whereas only 2 patients out of 9 in relapse achieved response (1 in association with 50 azacytidine and 1
with dasatinib). The proportion of patients with active
disease who achieved complete remission after allo-SCT was
similar in the 2 groups (58% [7 of 12] in the FB2A2-PBSC
group and 54% [7 of 13] the dUCB-TCF group). None of
these 7 patients relapsed in the dUCB-TCF group, and only 1
of 7 patients relapsed in the FB2A2-PBSC group.
Toxicity, GVHD and Posttransplantation Infections
NRM was higher in the dUCB-TCF group at day þ100 (13%
versus 0%; P <.01) and at 2 years (26% versus 6%; P ¼ .02) after
allo-SCT (Figure 1). On multivariate analysis, the only
HR
95% CI
P Value
0.82
0.42
0.81
1.82
(0.4-1.9)
(0.2-0.9)
(0.4-1.6)
(0.9-3.6)
.63
.02
.5
.08
0.70
0.75
1.66
(0.4-1.3)
(0.4-1.3)
(0.9-3.0)
.28
.34
.09
0.34
(0.1-1.0)
.06
0.62
0.24
(0.2-1.9)
(0.1-0.7)
.42
.01
independent factor associated with a lower NRM was FB2A2PBSC allo-SCT (hazard ratio [HR], 0.24; 95% confidence
interval [CI], 0.08-0.73; P ¼ .01) (Table 3). Cumulative incidences of GVHD were statistically similar in the FB2A2-PBSC
and dUCB-TCF groups (acute grade II-IV GVHD: 31% versus
26%; acute grade III-IV GVHD: 15% versus 8%; 2-year chronic
GVHD: 35% versus 26%). Finally, there were no significant
between-group differences in CMV reactivation (27% in the
FB2A2-PBSC group versus 23% in the dUCB-TCF group) or
Epstein-Barr virus (EBV) reactivation (15% versus 10%) after
allo-SCT. Of note, EBV-associated lymphoma was observed in
2 patients in the dUCB-TCF group after EBV reactivation.
Survival
Median follow-up was similar in the 2 groups: 19 months
(range, 9 to 37 months) in the FB2A2-PBSC group and
20 months (range, 7 to 39 months) in the dUCB-TCF group.
Two-year OS (62% versus 61%; Figure 2), DFS (58% versus
50.5%; Figure 3), and RI (35.5% versus 23%) were also similar
in the 2 groups. At last follow-up, 20 patients (38%) in the
FB2A2-PBSC group had died, from relapse in 16 patients
(80%), acute GVHD in 3, and secondary bladder tumor in 1. In
comparison, 18 patients (46%) from the dUCB-TCF group had
died, from relapse in 8 patients (44%), infection in 3, acute
GVHD in 2, multiple organ failure in 2, EBV-associated
Figure 2. Comparison of 2-year OS in the FB2A2-PBSC group (62%; solid line)
and dUCB-TCF group (61%; dotted line); P ¼ .51. x-axis, months; y-axis, %
survival.
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A. Le Bourgeois et al. / Biol Blood Marrow Transplant 19 (2013) 934e939
Figure 3. Comparison of 2-year DFS in the FB2A2-PBSC group (59%; solid line)
and dUCB-TCF group (50.5%; dotted line); P ¼ .43. x-axis, months; y-axis, %
survival.
lymphoma in 1, hemorrhage in 1, and encephalopathy in 1.
The incidence of early deaths (ie, before day þ100) was
significantly higher in the dUCB-TCF group (20%; n ¼ 8,
including only 1 due to relapse) compared with the FB2A2PBSC group (4%; n ¼ 2, both due to relapse) (P ¼ .05).
On univariate analysis (Table 2), the 2 factors associated
with a better 2-year OS were a lymphoid disease (78% versus
49%; P ¼ .02) and a median time from diagnosis to allo-SCT of
9 months (73% versus 49%; P ¼ .02). No prognostic factor
was associated with 2-year DFS or RI. Patients in the dUCBTCF group had a higher 2-year NRM (26.5% versus 6%;
P ¼ .02).
On multivariate analysis (Table 3), the only independent
factor associated with a significantly higher 2-year OS was
a lymphoid disorder (HR, 0.42; 95% CI, 0.20-0.86; P ¼ .02),
whereas FB2A2-PBSC allo-SCT was associated with a significantly lower 2-year NRM (HR, 0.24; 95% CI, 0.1-0.7; P ¼ .01).
No prognostic factor was associated with 2-year DFS or RI.
DISCUSSION
In this study, we compared 2 cohorts of patients treated
homogeneously with allo-SCT using a standard RIC regimen
with either PBSCs or dUCB as the stem cell source. Despite
the selection biases inherent to all retrospective studies, we
found similar 2-year OS and DFS in the FB2A2-PBSC and
dUCB-TCF groups (62% versus 61% and 59% versus 50.5%,
respectively). NRM was significantly higher in the dUCB-TCF
group, as shown by the higher incidence of early death in this
group (20% versus 4%). Conversely, the percentage of deaths
due to relapse was higher in the FB2A2-PBSC group (80%
versus 44%). The RI was lower in the dUCB-TCF group (23%
versus 35.5%), but the difference was not statistically
significant.
The data reported here confirm the results of previous
retrospective studies comparing PBSCs and dUCB as the stem
cell source in the setting of adult RIC allo-SCT [20-24].
However, those earlier series were very heterogeneous and
included adult patients treated either during different time
periods (before or after 2005), with heterogeneous RIC
regimens, or even in some cases with bone marrow or single
UCB as the stem cell source, and showed relatively lower OS
compared with our series.
Various factors may explain our good results. Clearly,
much progress has been made in the supportive care and
management of patients since the advent of RIC dUCB allo-
SCT, and all of our patients underwent transplantation after
2006. Second, the FB2A2 regimen has been used extensively
in recent years, with very good results [5,7-9]. Likewise, UCBTCF regimens have been retrospectively associated with
better OS and DFS and lower NRM compared with UCB-other
RIC regimens in allo-SCT with both single UCB units [33] and
dUCB [20]. The preliminary results of a French prospective
phase II trial of dUCB-TCF allo-SCT in patients with acute
myelogenous leukemia in first or second complete remission
are in accordance with these retrospective data [34]. These
good results are explained mainly by the fact that UCB-TCF
regimens do not incorporate ATG as part of GVHD prophylaxis, given that ATG may be associated with an increased
incidence of deleterious infections, especially EBV-related
complications [35-37]. Only 4 patients (10%) in our in the
dUCB-TCF group received ATG, compared with 34%-99% of
patients in previous studies [20,23,24]. Finally, the use of
dUCB rather than a single UCB unit may be associated with
a lower rate of relapse, associated not only with a greater
degree of HLA mismatch (“ménage à trois”) or maternal
microchimerism, but also with a particular profile of immune
reconstitution after transplantation and the rejection of 1 of
the UCB units, leading to a more potent graft-versusmalignancy effect [20,38-42]. This might help explain the
similar outcomes in our 2 groups, despite the systematically
higher NRM and lower incidence of chronic GVHD in our
dUCB-TCF group. Nevertheless, even though a recent study
has demonstrated, unexpectedly, the benefit of dUCB over
single UCB from an economic standpoint [43], the preference
for dUCB over an adequately dosed single UCB has not yet
been fully established in either adults or children, and
prospective trials are needed to clarify this question [44].
Thus, careful selection of both patient and UCB grafts, as
well an appropriate conditioning regimen, clearly are
important factors in predicting outcome and reducing NRM
after dUCB allo-SCT [20,45,46]. In addition, strategies to
improve engraftment [46] and immune recovery [41] are
urgently needed to decrease the risk of infections, which
represent a major cause of morbidity after dUCB allo-SCT.
In conclusion, this study suggests that the dUCB-TCF
regimen is a valid alternative to the FB2A2-PBSC regimen
in adults lacking an HLA-matched related or unrelated donor
and requiring urgent RIC allo-SCT because of rapidly
progressive disease. Further prospective and randomized
studies are warranted to establish the definitive role of single
UCB versus dUCB as a stem cell source. In addition, strategies
for decreasing nonrelapse mortality after dUCB RIC allo-SCT
are urgently needed.
ACKNOWLEDGMENTS
Financial disclosure: The authors have nothing to disclose.
Conflict of Interest: There are no conflicts of interest to
report.
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