Biol Blood Marrow Transplant 19 (2013) 1102e1108

Unrelated Donor Allogeneic Transplantation after Failure of

Autologous Transplantation for Acute Myelogenous ASBMT
American Society for Blood

Leukemia: A Study from the Center for International Blood and Marrow Transplantation

and Marrow Transplantation Research

James M. Foran 1, Steven Z. Pavletic 2, Brent R. Logan 3,
Manza A. Agovi-Johnson 4, Waleska S. Pérez 3, Brian J. Bolwell 5,
Martin Bornhäuser 6, Christopher N. Bredeson 7, Mitchell S. Cairo 8,
Bruce M. Camitta 9, Edward A. Copelan 5, Jason Dehn 10, Robert P. Gale 11,
Biju George 12, Vikas Gupta 13, Gregory A. Hale 14, Hillard M. Lazarus 15,
Mark R. Litzow 16, Dipnarine Maharaj 17, David I. Marks 18, Rodrigo Martino 19,
Richard T. Maziarz 20, Jacob M. Rowe 21, Philip A. Rowlings 22,
Bipin N. Savani 23, Mary Lynn Savoie 24, Jeffrey Szer 25, Edmund K. Waller 26,
Peter H. Wiernik 27, Daniel J. Weisdorf 28, *
1
Mayo Clinic Florida, Jacksonville, Florida
2
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda,
Maryland
3
Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin
4
Norman J. Arnold School of Public Health, University of South Carolina, Columbia, South Carolina
5
Cleveland Clinic Foundation, Cleveland, Ohio
6
Universitatsklinikum Carl Gustav Carus, Dresden, Germany
7
Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, Canada
8
New York Medical College, Valhalla, New York
9
Children’s Hospital of Wisconsin, Milwaukee, Wisconsin
10
National Marrow Donor Program, Minneapolis, Minnesota
11
Imperial College, London, United Kingdom
12
Christian Medical College Hospital, Tamil Nadu, India
13
Princess Margaret Hospital, Toronto, Canada
14
All Children’s Hospital, St Petersburg, Florida
15
University Hospitals Case Medical Center, Cleveland, Ohio
16
Mayo Clinic Rochester, Rochester, Minnesota
17
Bethesda Health City, Boynton Beach, Florida
18
Bristol Children’s Hospital,
19
Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
20
Oregon Health & Science University, Portland, Oregon
21
Rambam Medical Center, Haifa, Israel
22
Calvary Mater Newcastle, Waratah, New South Wales, Australia
23
Vanderbilt University Medical Center, Brentwood, Tennessee
24
Tom Baker Cancer Center, Calgary, Canada
25
Royal Melbourne Hospital, Victoria, Australia
26
Emory University Hospital, Atlanta, Georgia
27
Continuum Cancer Centers of New York at St Luke’s Roosevelt and Beth Israel Medical Centers, New York, New York
28
University of Minnesota, Minneapolis, Minnesota

Article history: a b s t r a c t
Received 29 November 2012 The survival of patients with relapsed acute myelogenous leukemia (AML) after autologous hematopoietic
Accepted 21 April 2013 stem cell transplantation (auto-HCT) is very poor. We studied the outcomes of 302 patients who underwent
secondary allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor (URD) using
Key Words: either myeloablative (n ¼ 242) or reduced-intensity conditioning (RIC; n ¼ 60) regimens reported to the
Acute myelogenous leukemia Center for International Blood and Marrow Transplantation Research. After a median follow-up of 58 months
Unrelated donor (range, 2 to 160 months), the probability of treatment-related mortality was 44% (95% confidence interval [CI],
Transplantation
38%-50%) at 1-year. The 5-year incidence of relapse was 32% (95% CI, 27%-38%), and that of overall survival
Allogeneic
was 22% (95% CI, 18%-27%). Multivariate analysis revealed a significantly better overal survival with RIC
Autologous
regimens (hazard ratio [HR], 0.51; 95% CI, 0.35-0.75; P <.001), with Karnofsky Performance Status score 90%
(HR, 0.62; 95% CI, 0.47-0.82: P ¼ .001) and in cytomegalovirus-negative recipients (HR, 0.64; 95% CI, 0.44-
0.94; P ¼ .022). A longer interval (>18 months) from auto-HCT to URD allo-HCT was associated with

Financial disclosure: See Acknowledgments on page 1107.

* Correspondence and reprint requests: Daniel J. Weisdorf, MD, Univer-
sity of Minnesota Medical Center, 420 Delaware Street SE, MMC 480,
Minneapolis, MN 55455.
E-mail address: weisd001@umn.edu (D.J. Weisdorf).
1083-8791/$ e see front matter Ó 2013 American Society for Blood and Marrow Transplantation.
http://dx.doi.org/10.1016/j.bbmt.2013.04.022
 J.M. Foran et al. / Biol Blood Marrow Transplant 19 (2013) 1102e1108
significantly lower riak of relapse (HR, 0.19; 95% CI, 0.09-0.38; P <.001) and improved leukemia-free survival
(HR, 0.53; 95% CI, 0.34-0.84; P ¼ .006). URD allo-HCT after auto-HCT relapse resulted in 20% long-term
leukemia-free survival, with the best results seen in patients with a longer interval to secondary URD
transplantation, with a Karnofsky Performance Status score 90%, in complete remission, and using an RIC
regimen. Further efforts to reduce treatment-related mortaility and relapse are still needed.
Ó 2013 American Society for Blood and Marrow Transplantation.
INTRODUCTION
Autologous hematopoietic bone marrow (BM) or
peripheral blood (PB) stem cell transplantation (auto-HCT)
can be an effective consolidation treatment associated with
improved leukemia-free survival (LFS) in adults with acute
myelogenous leukemia (AML) in randomized trials versus
intensive consolidation chemotherapy [1-3]. The benefit of
auto-HCT appears to be especially apparent in patients with
favorable- and intermediate-risk AML [4,5] and in adults [6].
Posteauto-HCT treatment failure is related primarily to
relapse, particularly within the first 2 years [7]. Relapse is
reportedly more likely in recipients of PB grafts [8] and in
patients who do not receive pretransplantation consolida-
tion chemotherapy [9]. Unfortunately, survival in patients
who relapse after auto-HCT is very poor [1,10]. Previous auto-
HCT is associated with both a lower likelihood of achieving
subsequent complete remission (CR) [10,11] and higher
mortality, and has been identified as an independent adverse
risk feature for survival in first relapsed AML [10]. In view of
the poor outcomes with available therapies, patients who
relapse after auto-HCT are candidates for alternative strate-
gies or investigational therapy.
Some patients with relapsed AML undergo a secondary
allogeneic hematopoietic cell transplantation (allo-HCT)
after failure of auto-HCT, and long-term survival has been
noted, although often limited by high treatment-related
mortality (TRM) [12-19]. More recent reports have
described the use of RIC or nonmyeloablative conditioning
regimens (RIC/NMA) in an attempt to reduce TRM [20-26].
Patients in CR at the time of RIC/NMA appear to have
significantly lower TRM and risk of relapse, as well as supe-
rior overall survival (OS). In limited series, similar OS was
reported with RIC or myeloablative (MA) conditioning in this
clinical setting [20,24].
Using the large multicenter observational database from
the Center for International Blood and Marrow Trans-
plantation Research (CIBMTR), we examined the outcomes of
secondary unrelated donor (URD) allo-HCT in patients with
AML who underwent previous unsuccessful auto-HCT, with
the aim of identifying patients and HCT techniques most
likely to be successful.
PATIENTS AND METHODS
Data Sources
The CIBMTR is a research affiliation of the International Bone Marrow
Transplantation Registry, Autologous Blood and Marrow Transplantation
Registry, and the National Marrow Donor Program. Established in 2004, the
registry receives data from more than 450 transplantation centers world-
wide on consecutive allo-HCTs and auto-HCTs with computerized checks for
discrepancies, physicians’ review of submitted data, and onsite audits of
participating centers ensure data quality. The CIBMTR collects detailed
clinical data pre-HCT, at 100 days and 6 months post-HCT, and annually
thereafter.
Observational studies conducted by the CIBMTR are performed with
approval of the Institutional Review Boards of the National Marrow Donor
Program and the Medical College of Wisconsin.
Patient Population
A total of 302 patients were reported to the CIBMTR who underwent
secondary URD allo-HCT for either relapsed or persistent AML after previous
1103
auto-HCT between 1995 and 2005. Patients undergoing allo-HCT using cord
blood or related donors were excluded. Information on the previous auto-
HCT and lines of therapy after relapse for those achieving subsequent CR
was unavailable for the majority of the patients, and thus is not included in
this analysis.
Conditioning Regimens
Conditioning and graft-versus-host disease (GVHD) prophylaxis regi-
mens are shown in Table 1. CIBMTR definitions of MA and RIC/NMA condi-
tioning regimens (predominantly fludarabine-based; see Table 1) and HLA
matching were applied [27,28]. For HLA matching, “well matched” was
defined as no known disparity at HLA-A, -B, -C, or -DRB1; “partially
matched,” as a known or likely disparity at 1 locus; and “mismatched,” as
a disparity at 2 or more loci [29]. AML cytogenetics before auto-HCT were
categorized as “good,” “intermediate,” or “poor” risk according to the UK
Medical Research Council classification scheme [30]. Patients with
t(7;12)(q36;p13), t(16;21)(q24;q22), or del(5q)/del(7q) were included in the
poor-risk group, and those with t(9;11) were included in the intermediate-
risk group [30-32].
Endpoints
The primary outcomes studied were TRM, relapse, LFS, and OS.
Secondary outcomes were hematopoietic recovery (neutrophil and platelet
engraftment) and the incidence of grade III/IV acute GVHD (aGVHD) and
chronic GVHD (cGVHD).
An event for LFS was death or hematologic relapse after allo-HCT, and an
event for OS was death from any cause. Surviving patients were censored at
the date of last contact. TRM was defined as any death occurring before
leukemia relapse. Persistence of AML after allo-HCT was considered relapse
at day þ1 after allo-HCT.
Statistical Analysis
The analysis of outcomes after secondary URD allo-HCT considered
patient-related factors (age, sex, race, cytomegalovirus [CMV] serostatus,
Karnofsky performance status [(KPS] score, and serum bilirubin and creat-
inine levels) and disease-related factors (CR and cytogenetics), as well as
variables related to previous auto-HCT (time from auto-HCT to relapse and
to the secondary URD allo-HCT). Allo-HCTerelated variables considered
included donor age, race, sex, parity, and CMV status; PB versus BM graft and
cell dose (total nucleated cells for BM and total CD34þ cells for PB, if avail-
able); HLA matching and ABO compatibility; MA versus RIC/NMA condi-
tioning; GVHD prophylaxis (T cell depletion versus no T cell depletion); use
of growth factor post-HCT; and the incidence of aGVHD grade III/IV or
cGVHD of any severity as time-dependent variables.
Kaplan-Meier estimates were determined for OS and LFS, and the inci-
dence of TRM, relapse, and aGVHD and cGVHD were calculated using the
cumulative incidence function to accommodate competing risks. Analyses
were performed at a 5-year time point.
Multivariate analysis was conducted using the proportional hazards
model. All models were examined to confirm compliance with the propor-
tional hazards assumption, and no violations of this assumption were
detected. A stepwise approach was then used to develop Cox regression
models for OS, LFS, and time to relapse and TRM for those in CR. Interactions
between significant variables in the model were also considered for all
models.
RESULTS
Patient and Clinical Characteristics
A total of 302 patients who underwent secondary URD
allo-HCT between 1995 and 2005 for AML progression after
a previous auto-HCT were reported to the CIBMTR from 99
transplantation centers. The median patient age was 38 years
(range, 1 to 65 years), 47% were male, and 90% were Cauca-
sian (Table 1). The median time from auto-HCT to URD allo-
HCT was 14 months (range 1 to 98 months), and this interval
was >6 months in 86% of the patients. The majority (72%) of
1104 J.M. Foran et al. / Biol Blood Marrow Transplant 19 (2013) 1102e1108

Table 1 Table 2
Patient Characteristics Primary Outcomes

Characteristic Value Outcome Event Number Incidence

Number of patients 302 Evaluable (95% CI), %
Number of centers 99 Neutrophil engraftment at 301 86 (83-90)
Age at transplantation, yrs, median (range) 38 (1-65) 28 days 297 66 (61-71)
Male sex, n (%) 141 (47) Platelet engraftment
KPS score 90%, n (%) 180 (60) (20,000  109/L) at 100 days
Race, n (%) aGVHD grade III/IV at 100 days 302 25 (20-30)
Caucasian 273 (90) cGVHD at 2 yrs 295 37 (31-42)
African-American 13 (4) TRM 299
Hispanic 10 (3) 1 yr 44 (38-50)
Asian 6 (2) 5 yrs 48 (43-54)
AML cytogenetic risk, n (%) Relapse 299
Good 26 (9) 1 yr 25 (21-30)
Intermediate 184 (61) 5 yrs 32 (27-38)
Poor 13 (4) LFS 299
Unknown 79 (26) 1 yr 31 (26-36)
Conditioning regimen intensity, n (%) 5 yrs 19 (15-24)
MA 242 (80) OS 302
RIC/NMA 60 (20) 1 yr 34 (29-40)
Conditioning regimen, n (%) 5 yrs 22 (18-17)
Cyclophosphamide þ total body irradiation 118 (39)
Busulfan þ cyclophosphamide 48 (16)
Total body irradiation þ/- other 41 (14) of RIC during the study period; the use of RIC/NMA regimens
Cyclophosphamide or busulfan þ/- other 35 (12) (versus MA) increased from 3 of 94 patients in 1995-1998 to
Fludarabine þ/- melphalan þ/- other 56 (19)
Disease status before URD allo-HCT, n (%)
26 of 103 patients in 1999-2002 and to 31 of 105 patients in
CR 223 (72) 2003-2005 (P <.001). Similarly, there was a significant
Relapse 79 (26) increase in the use of RIC/NMA regimens (versus MA) with
Time from autologous HCT to URD allo-HCT increasing patient age, from 21 of 162 patients age <40 years
Median (range), mo 14 (1-98)
to 17 of 63 patients age 40-50 years and to 22 of 77 patients
6 mo, n (%) 42 (14)
>6 mo, n (%) 259 (86) age >50 years (P ¼ .005). The median duration of follow-up
HLA match, n (%) in surviving patients was 58 months (range, 2 to
Well matched 105 (35) 160 months).
Partially matched 148 (49)
Mismatched 49 (16)
Donor age, yrs, median (range) 36 (19-55) Hematopoietic Recovery and GVHD
Donor-recipient CMV serostatus, n (%) Neutrophil and platelet recovery, along with the inci-
þ/þ 75 (25) dences of grade III/IV aGVHD at 100 days and of cGVHD at
þ/ 47 (16) 2 years, are reported in Table 2. In multivariate analysis, the
/þ 95 (31)
only factors significantly associated with the development of
/ 79 (26)
Donor-recipient sex match, n (%) GVHD were CMV status (aGVHD) and use of a PB graft
Male-male 88 (29) (cGVHD). There was a significantly lower incidence of grade
Male-female 52 (17) III/IV aGVHD in CMV-negative donorerecipient pairs (HR,
Female-male 90 (30)
0.37; 95% CI, 0.18-0.78; P ¼ .009), whereas recipients of PB
Female-female 66 (22)
Graft type, n (%)
grafts (versus BM) were 70% more likely to develop cGVHD.
BM 180 (60)
PB 122 (40) Outcomes
Year of transplantation, n (%)
The probabilities of relapse, TRM, and OS at 1 year and at
1995-1998 94 (32)
1999-2002 103 (34)
5 years are presented in Table 2 and shown in Figures 1 and 2.
2003-2005 105 (35)
GVHD prophylaxis, n (%) Relapse
T cell depletion (in vivo or ex vivo) 40 (13) The greatest risk of relapse after URD allo-HCT was during
Cyclosporine or tacrolimus þ 66 (22)
mycophenolate þ/ other
the first year posttransplantation, with very few relapses
Cyclosporine or tacrolimus þ 154 (52)
methotrexate þ/ other
Cyclosporine or tacrolimus þ/ other 37 (12)
None 2 (<1)

patients were in CR at the time of URD allo-HCT, and 26%

were in relapse. More than one-third (37%) of the patients
had a KPS score <90%. Among the 223 patients with cyto-
genetic information available, 80% were classified as inter-
mediate risk, and only 10% were classified as poor risk; 15
patients (5%) had acute promyelocytic leukemia.
The graft source was BM in 60% of the patients in PB in
40%. The majority of patients (80%) received MA condi-
tioning, and the remaining 20% received RIC/NMA condi-
tioning. There was a significant trend toward increasing use Figure 1. Cumulative incidence of relapse and TRM.
 J.M. Foran et al. / Biol Blood Marrow Transplant 19 (2013) 1102e1108 1105

Table 3
Multivariate Analysis for Primary Outcomes

n HR 95% CI P Value
OS
KPS score
<90% 109 1.00*
90% 167 0.62 0.47-0.82 .001
Conditioning regimen
MA 217 1.00*
RIC/NMA 59 0.51 0.35-0.75 <.001
Graft source and disease status .013
at allo-HCT
BM
CR 124 1.00*
Relapse 43 1.17 0.79-1.74 .431
PB
Figure 2. Probabilities of OS and LFS.
CR 77 1.00*
Relapse 32 3.26 2.01-5.27 <.001
Donor/recipient CMV serostatus
seen after 3 years (Table 2 and Figure 1). In multivariate þ/þ 76 1.00*
analysis, the interval from auto-HCT to URD allo-HCT þ/ 38 0.49 0.30-0.79 .004
significantly influenced the subsequent risk of relapse, with /þ 89 1.13 0.80-1.59 .48
/ 73 0.64 0.44-0.94 .022
a progressively lower risk of relapse seen with longer Grade III/IV aGVHDy
posteauto-HCT intervals (>18 months) compared with short No 199 1.00*
intervals (<6 months) (Table 3). Patients with a KPS score Yes 77 1.92 1.36-2.71 <.001
90% were significantly less likely to relapse, whereas the cGVHDy
No 168 1.00*
development of cGVHD was not independently associated
Yes 108 1.20 0.81-1.79 .356
with relapse. Relapse
KPS score
TRM and Causes of Death <90% 108 1.00*
90% 171 0.45 0.29-0.71 <.001
Among the 231 deaths, the major causes were relapsed
Time from auto-HCT to URD
AML (26%), infection (20%), organ failure (14%), interstitial allo-HCT
pneumonitis (13%), GVHD (11%), and other causes (16%). TRM <6 mo 40 1.00*
was the leading cause of treatment failure after salvage URD 6-12 mo 87 0.48 0.26-0.88 .018
allo-HCT, and the risk of TRM was greatest in the first year 12-18 mo 61 0.32 0.16-0.64 .001
>18 mo 91 0.19 0.09-0.38 <.001
(Table 2 and Figure 1). In multivariate analysis, HLA-
Grade III/IV aGVHDy
mismatched URD was associated with significantly worse No 201 1.00*
TRM (hazard ratio [HR], 1.93; 95% confidence interval [CI], Yes 78 1.57 0.92-2.65 .095
1.15-3.24; P ¼ .012), but did not impact OS, whereas the use of cGVHDy
No 170 1.00*
RIC/NMA was protective for TRM (HR, 0.52; 95% CI, 0.31-0.88;
Yes 109 0.94 0.54-1.64 .821
P ¼ .015) (Table 3). Patients receiving RIC/NMA had a 20% TRM
lower absolute TRM at 1 year (Table 4), which was associated Conditioning regimen
with improved OS (see below). MA 221 1.00*
There was a significant interaction in the analysis RIC/NMA 58 0.52 0.31-0.88 .015
HLA match
between graft type (PB versus BM) and disease status (CR
Well matched 95 1.00*
versus not in CR at allo-HCT). In patients undergoing trans- Partially matched 138 1.39 0.91-2.14 .128
plantation with PB (but not BM) grafts, those not in CR had Mismatched 46 1.93 1.15-3.24 .012
3-fold higher risk of TRM (P <.001). Graft source and disease status
at allo-HCT
BM
LFS and OS CR 126 1.00*
For the entire cohort, 5-year LFS was 19% (95% CI, 15%- Relapse 43 1.08 0.68-1.72 .751
24%) (Table 2 and Figure 2). A longer interval (>18 months) PB
from auto-HCT to secondary URD allo-HCT was associated CR 78 1.00*
Relapse 32 3.05 1.6-5.83 <.001
with significantly better LFS, as was the use of RIC/NMA Grade III/IV aGVHDy
conditioning (Table 3). In contrast, those who received a PB No 201 1.00
(but not BM) graft and who were not in CR at allo-HCT had Yes 78 2.34 1.51-3.64 <.001
a more than 2-fold greater risk for death or relapse (HR, 2.30; cGVHDy
No 170 1.00*
95% CI 1.39-3.79; P ¼ .001). In our model, the development of
Yes 109 1.82 1.06-3.12 .031
grade III/IV aGVHD was associated with significantly worse LFS
LFS and OS, whereas cGVHD was not independently associ- KPS score
ated with LFS or OS. <90% 108 1.00*
In the multivariate analysis of OS, the risk for death was 90% 171 0.63 0.48-0.84 .001
Donor/recipient CMV serostatus
significantly lower in patients receiving an RIC/NMA (versus þ/þ 76 1.00*
MA) conditioning regimen (HR, 0.51; 95% CI, 0.35-0.75; þ/ 39 0.48 0.30-0.76 .002
P <.001), in patients with a KPS score 90% at the time of /þ 90 1.00 0.72-1.41 .979
URD allo-HCT (HR, 0.62; 95% CI, 0.47-0.82; P ¼ .001), and / 74 0.60 0.42-0.88 .008
(continued on next page)
among CMV-negative donorerecipient pairs (HR, 0.64; 95%
1106 J.M. Foran et al. / Biol Blood Marrow Transplant 19 (2013) 1102e1108

Table 3 Table 5
(continued) OS Based on Time from Autologous HCT to Secondary URD Allo-HCT

n HR 95% CI P Value Interval n OS (95% CI) OS (95% CI)

Time from auto-HCT to URD at 1 yr, % at 5 yrs, %
allo-HCT 6 mo 42 14 (5-27) 11 (3-24)
<6 mo 40 1.00* 6-12 mo 91 32 (23-42) 22 (14-31)
6-12 mo 87 0.72 0.47-1.10 .127 12-18 mo 71 36 (25-47) 20 (11-31)
12-18 mo 61 0.61 0.38-0.99 .045 >18 mo 97 42 (32-52) 30 (21-40)
>18 mo 91 0.53 0.34-0.84 .006 P value .003 .089
Conditioning regimen
MA 221 1.00*
RIC/NMA 58 0.55 0.37-0.8 .002
Graft source and disease status
patients achieved long-term survival. This percentage
BM
CR 126 1.00* compares favorably with historical experience, for example,
Relapse 43 1.06 0.71-1.58 .759 with the 4% 5-year survival reported by the Dutch-Belgian
PB and Swiss Collaborative Groups in a cohort of 102 patients
CR 78 1.00* with failed auto-HCT [10]. Patients with later relapse after
Relapse 32 2.30 1.39-3.79 .001
Grade III/IV aGVHDy
auto-HCT (beyond 18 months), those in CR, those with a KPS
No 201 1.00* score 90%, and those receiving an RIC/NMA regimen
Yes 78 1.84 1.31-2.59 <.001 demonstrate the best outcomes after URD allo-HCT in this
cGVHDy setting. Indeed, one-half of our patients in CR, with a KPS
No 170 1.00*
score 90%, and a long interval (>18 months) from auto-HCT
Yes 109 1.30 0.87-1.94 .193
achieved long-term survival with the use of an RIC/NMA
* Reference group. regimen, demonstrating that appropriate patient selection is
y
aGVHD and cGVHD included as time-dependent covariates.
necessary to capitalize on the benefits of this approach.
Even though our patients represent a selected cohort, the
CI, 0.44-0.94; P ¼ .02) (Table 3). An approximate 20% absolute
finding of 22% OS at 5 years in this very high-risk population
improvement in OS was seen in patients receiving an RIC/
may reflect an active graft-versus-leukemia effect. The inci-
NMA regimen (versus an MA conditioning regimen), owing
dence of cGVHD in our series was somewhat lower than
predominantly to lower TRM (Table 4).
expected, with other recent large reports of URD allo-HCT in
A longer time interval between auto-HCT to secondary
acute leukemia suggest an incidence closer to 50% [33].
URD allo-HCT was also associated with significantly better
While this might be a function of the high TRM and the
1-year OS and with a trend toward significantly better 5-year
inclusion of patients not in CR at the time of secondary URD
OS. Patients with a >18-month interval had a 42% 1 year OS,
allo-HCT, nevertheless cGVHD was not independently asso-
compared with the 14% in those with a very short
ciated with any improvement in leukemia control in our
(<6 months) interval (P ¼ .003) (Table 5).
analysis.
Multivariate Analysis to Identify a Favorable Subgroup The practice of consolidation with allo-HCT in relapsed
To identify those patients most likely to benefit from our AML is well established, and earlier reports suggested that
proposed approach, we examined OS using those clinical risk secondary allo-HCT might be an effective therapy in some
factors identified in the multivariate model that would be patients with relapsed AML after auto-HCT. In a European
apparent before URD allo-HCT (ie, not in CR, KPS score <90%, Group for Blood and Marrow Transplantation study, Ringden
MA conditioning, and CMV-positive status). We also et al. [18] reported a 37% 2-year OS in a group of 62 patients
included a <18-month interval from auto-HCT in the model, with acute leukemia who underwent allo-HCT from HLA-
given that this was significant for OS, had a significant impact matched related (n ¼ 29) and unrelated (n ¼ 33) donors.
on LFS and relapse, and is a clinically relevant factor in Blau et al. [16] described 5 of 10 patients who become long-
patient selection for salvage URD allo-HCT. term survivors (248-1140 days) after posteauto-HCT URD
Survival, categorized by the presence of these 5 risk allo-HCT. In another study, Radich et al. [17] evaluated
factors, is shown in Figure 3 (P <.001). The 35 patients (12%)
with 0 or 1 risk factors had a 5-year OS of approximately 50%.
In contrast, those with 4 or 5 risk factors (n ¼ 90, w30% of the
cohort) had a 5-year OS of <10%, and there were no 5-year
survivors with all 5 adverse risk factors. Patients with 2 or
3 risk factors had an intermediate projected 5-year OS of
20%-25% (Figure 3).

DISCUSSION
In this large comprehensive study of secondary URD allo-
HCT for AML after failed auto-HCT, approximately 20% of the

Table 4
Clinical Outcome Based on Intensity of Allo-HCT Conditioning Regimen

Outcome MA RIC/NMA P Value

(n ¼ 242) (n ¼ 60)
Figure 3. Probability of OS according to 5 risk factors at the time of secondary
TRM (95% CI) at 1 yr, % 48 (41-54) 28 (17-41) .004
URD allo-HCT: <18-month interval from auto-HCT to secondary URD allo-HCT,
OS (95% CI) at 1 yr, % 30 (25-36) 50 (37-63) .007
not in CR, KPS score <90%, MA conditioning, and positive CMV serostatus. P
OS (95% CI) at 5 yrs, % 19 (14-24) 37 (25-51) .009
<.001.
 J.M. Foran et al. / Biol Blood Marrow Transplant 19 (2013) 1102e1108
59 patients age 1-57 years with leukemia and lymphoma
who relapsed after initial auto-HCT, 20 of whom underwent
secondary matched URD allo-HCT, with a 2-year disease-free
survival (DFS) of 19%. Univariate analysis of all 59 patients
showed that superior DFS was associated with age <17 years,
remission at the time of allo-HCT, use of total body
irradiationebased conditioning regimen for allo-HCT, and
a diagnosis of AML. The type of donor (related versus unre-
lated) did not appear to influence DFS.
The duration of CR is an established prognostic factor in
relapsed AML, and achievement of subsequent CR was an
important prognostic factor for survival after secondary URD
allo-HCT in our analysis. Unfortunately, detailed information
on remission status at the time of the original auto-HCT was
available for fewer than one-half of our patients (although
>90% of those were in first CR). Moreover, information on the
duration of CR after auto-HCT was not available, and thus
neither variable could be formally included in our analysis.
Nevertheless, the significant association between the
interval to secondary URD allo-HCT and subsequent clinical
outcomes (especially after 6 months) suggests that the
duration of CR after initial auto-HCT is an important prog-
nostic factor in this setting.
The present CIBMTR study highlights the importance of
patient selection for URD allo-HCT. Patients with a brief
interval from auto-HCT to salvage URD allo-HCT, those not in
CR before HCT, and particularly those with compromised
performance status have significantly worse outcomes.
Based on our analysis, patients with more than 3 identified
risk factors generally are not recommended for HCT as
a routine practice. In contrast, those with late relapse, with
a good KPS score, and in CR at second URD allo-HCT appear to
benefit the most from this approach.
Although our results describe the actual survival of our
consecutive cohort of patients, there is always potential bias
in identifying risk factors for clinical outcomes in a retro-
spective analysis. We have attempted to minimize this bias
by broadly incorporating all known and available clinical or
transplantation-related data that might influence outcome
and using appropriate statistical methods. The risk factors
identified for clinical outcome have potential clinical appli-
cation, applying to both patient and donor selection (eg, KPS
score, CMV status) as well as to disease status (eg, CR,
interval from auto-HCT) and the URD allo-HCT treatment
itself (eg, choice of conditioning regimen). Thus, this analysis
may allow for more refined patient and donor selection and
may help guide future practice in this setting.
TRM was the leading cause of treatment failure in our
cohort. Although only 20% of the patients received an RIC/
NMA regimen, this conditioning regimen was associated
with significantly lower TRM and better survival compared
with MA regimens. Unsurprisingly, the use of RIC/NMA
regimens increased over time and with patient age. This
result likely reflects HCT in a more recent era [34], and
suggests that conditioning regimens that reduce TRM will
yield better outcomes in the setting of secondary URD allo-
HCT [26]. The adverse impact of aGVHD on survival is also
not surprising [20], and further efforts are needed to
diminish the impact of aGVHD on TRM and OS, possibly
through strategies that directly target the greater GVHD risks
with increasing HLA disparities.
An interaction between disease status (CR versus relapse)
and graft source (PB versus BM) was observed, with a 2-fold
increased risk for death and treatment failure for those who
received a PB graft and were not in CR at the time of
1107
secondary URD allo-HCT. The reasons for this interaction are
not known, but might reflect selection of a PB graft for
higher-risk patients in this setting.
Cytogenetic risk was not an independent risk factor for
outcome, likely because the large majority of patients in this
analysis were at intermediate risk or had unknown cytoge-
netics. This is a potential limitation of this study, given that
only 4% of those who received salvage URD allo-HCT had
known poor-risk cytogenetics. This may reflect either an
inability to achieve adequate disease control to allow HCT in
patients with higher-risk AML or the selection of patients with
intermediate-risk cytogenetics for initial auto-HCT who may
be the most likely to benefit from that treatment. Neverthe-
less, our results with secondary URD allo-HCT may be most
applicable to patients with intermediate-risk cytogenetics.
In conclusion, our findings demonstrate that appropri-
ately selected patients may achieve long-term survival from
secondary URD allo-HCT after failure of previous auto-HCT.
Further studies to improve outcomes must focus on
improved pretransplantation salvage regimens and alterna-
tive RIC regimens with better antileukemia efficacy, along
with possible posttransplantation monitoring and mainte-
nance strategies to enhance disease control and limit
peritransplantation mortality.
ACKNOWLEDGMENTS
Financial disclosure: The Center for International Blood
and Marrow Transplant Research is supported by Public
Health Service Grant/Cooperative Agreement U24-CA76518
from the National Cancer Institute, the National Heart, Lung
and Blood Institute, and the National Institute of Allergy
and Infectious Diseases; Grant/Cooperative Agreement
5U01HL069294 from the National Cancer Institute and
the National Heart, Lung and Blood Institute; Contract
HHSH234200637015C with the Health Resources and
Services Administration; Grants N00014-06-1-0704 and
N00014-08-1-0058 from the Office of Naval Research; and
grants from Allos, Amgen, Angioblast, anonymous donation
to the Medical College of Wisconsin, Ariad, Be the Match
Foundation, Blue Cross and Blue Shield Association,
Buchanan Family Foundation, CaridianBCT, Celgene, CellGe-
nix, Children’s Leukemia Research Association, Fresenius-
Biotech North America, Gamida Cell Teva Joint Venture,
Genentech, Genzyme, GlaxoSmithKline, HistoGenetics, Kia-
dis Pharma, Leukemia and Lymphoma Society, Medical
College of Wisconsin, Merck & Co, Millennium: Takeda
Oncology, Milliman USA, Miltenyi Biotec, National Marrow
Donor Program, Optum Healthcare Solutions, Osiris Thera-
peutics, Otsuka America Pharmaceutical, RemedyMD, Sanofi,
Seattle Genetics, Sigma-Tau Pharmaceuticals, Soligenix,
StemCyte, Stemsoft Software, Swedish Orphan Biovitrum,
Tarix Pharmaceuticals, Teva Neuroscience, Therakos, and
Wellpoint. The views expressed in this article do not reflect
the official policy or position of the National Institute of
Health, the Department of the Navy, the Department of
Defense, or any other agency of the US Government.
Conflict of interest statement: There are no conflicts of
interest to report.
Authorship statement: J.M.F., S.Z.P., and D.J.W. designed the
study and wrote the manuscript. B.R.L., M.A.A., and W.S.P.
performed statistical analysis. E.K.W., E.C.A., R.P.G., C.N.B.,
B.G., P.A.R., R.T.M., G.A.H., D.I.M., V.G., P.H.W., H.M.L., J.D.,
R.M., M.B., B.M.C., M.S.C., M.R.L., M.L.S., B.N.S., D.M., B.J.B.,
J.M.R., and J.S. interpreted data and approved the final
manuscript.
1108 J.M. Foran et al. / Biol Blood Marrow Transplant 19 (2013) 1102e1108

REFERENCES 19. Meshinchi S, Leisenring WM, Carpenter PA, et al. Survival after second
hematopoietic stem cell transplantation for recurrent pediatric acute
1. Nathan PC, Sung L, Crump M, Beyene J. Consolidation therapy with
myeloid leukemia. Biol Blood Marrow Transplant. 2003;9:706-713.
autologous bone marrow transplantation in adults with acute myeloid
20. Baron F, Storb R, Storer BE, et al. Factors associated with outcomes in
leukemia: a meta-analysis. J Natl Cancer Inst. 2004;96:38-45.
allogeneic hematopoietic cell transplantation with nonmyeloablative
2. Levi I, Grotto I, Yerushalmi R, et al. Meta-analysis of autologous bone
conditioning after failed myeloablative hematopoietic cell trans-
marrow transplantation versus chemotherapy in adult patients with
plantation. J Clin Oncol. 2006;24:4150-4157.
acute myeloid leukemia in first remission. Leuk Res. 2004;28:605-612.
21. Fung HC, Cohen S, Rodriguez R, et al. Reduced-intensity allogeneic
3. Breems DA, Lowenberg B. Autologous stem cell transplantation in the
stem cell transplantation for patients whose prior autologous stem cell
treatment of adults with acute myeloid leukaemia. Br J Haematol. 2005;
transplantation for hematologic malignancy failed. Biol Blood Marrow
130:825-833.
Transplant. 2003;9:649-656.
4. Fernandez HF, Sun Z, Litzow MR, et al. Autologous transplantation gives
22. Corradini P, Zallio F, Mariotti J, et al. Effect of age and previous
encouraging results for young adults with favorable-risk acute myeloid
autologous transplantation on nonrelapse mortality and survival in
leukemia, but is not improved with gemtuzumab ozogamicin. Blood.
patients treated with reduced-intensity conditioning and allografting
2011;117:5306-5313.
for advanced hematologic malignancies. J Clin Oncol. 2005;23:
5. Pfirrmann M, Ehninger G, Thiede C, et al. Prediction of post-remission
6690-6698.
survival in acute myeloid leukaemia: a post-hoc analysis of the AML96
23. Feinstein LC, Sandmaier BM, Maloney DG, et al. Allografting after
trial. Lancet Oncol. 2012;13:207-214.
nonmyeloablative conditioning as a treatment after a failed conven-
6. Woods WG, Neudorf S, Gold S, et al. A comparison of allogeneic bone
tional hematopoietic cell transplant. Biol Blood Marrow Transplant.
marrow transplantation, autologous bone marrow transplantation, and
2003;9:266-272.
aggressive chemotherapy in children with acute myeloid leukemia in
24. Grullich C, Bertz H, Spyridonidis A, et al. A fludarabine, thiotepa
remission. Blood. 2001;97:56-62.
reduced-toxicity conditioning regimen designed specifically for allo-
7. Majhail NS, Bajorunaite R, Lazarus HM, et al. High probability of long-
geneic second haematopoietic cell transplantation after failure of
term survival in 2-year survivors of autologous hematopoietic cell
previous autologous or allogeneic transplantation. Bone Marrow
transplantation for AML in first or second CR. Bone Marrow Transplant.
Transplant. 2008;41:845-850.
2011;46:385-392.
25. Al-Qurashi F, Ayas M, Al Sharif F, et al. Second allogeneic bone marrow
8. Gorin NC, Labopin M, Blaise D, et al. Higher incidence of relapse with
transplantation after myeloablative conditioning: analysis of 43 cases
peripheral blood rather than marrow as a source of stem cells in adults
from a single institution. Hematology. 2004;9:123-129.
with acute myelocytic leukemia autografted during the first remission.
26. Bashey A, Owzar K, Johnson JL, et al. Reduced-intensity conditioning
J Clin Oncol. 2009;27:3987-3993.
allogeneic hematopoietic cell transplantation for patients with hema-
9. Tallman MS, Perez WS, Lazarus HM, et al. Pretransplantation consoli-
tologic malignancies who relapse following autologous trans-
dation chemotherapy decreases leukemia relapse after autologous
plantation: a multi-institutional prospective study from the Cancer and
blood and bone marrow transplants for acute myelogenous leukemia
Leukemia Group B (CALGB trial 100002). Biol Blood Marrow Transplant.
in first remission. Biol Blood Marrow Transplant. 2006;12:204-216.
2011;17:558-565.
10. Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for
27. Giralt S, Ballen K, Rizzo D, et al. Reduced-intensity conditioning
adult patients with acute myeloid leukemia in first relapse. J Clin Oncol.
regimen workshop: defining the dose spectrum. Report of a workshop
2005;23:1969-1978.
convened by the Center for International Blood and Marrow Transplant
11. Burnett AK, Goldstone AH, Stevens RM, et al., UK Medical Research
Research. Biol Blood Marrow Transplant. 2009;15:367-369.
Council Adult and Children’s Leukaemia Working Parties. Randomised
28. Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of condi-
comparison of addition of autologous bone-marrow transplantation to
tioning regimens: working definitions. Biol Blood Marrow Transplant.
intensive chemotherapy for acute myeloid leukaemia in first remis-
2009;15:1628-1633.
sion: results of MRC AML 10 trial. Lancet. 1998;351:700-708.
29. Weisdorf D, Spellman S, Haagenson M, et al. Classification of HLA
12. de Lima M, van Besien KW, Giralt SA, et al. Bone marrow trans-
matching for retrospective analysis of unrelated donor transplantation:
plantation after failure of autologous transplant for non-Hodgkin’s
revised definitions to predict survival. Biol Blood Marrow Transplant.
lymphoma. Bone Marrow Transplant. 1997;19:121-127.
2008;14:748-758.
13. Tsai T, Goodman S, Saez R, et al. Allogeneic bone marrow trans-
30. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic
plantation in patients who relapse after autologous transplantation.
classification in acute myeloid leukemia: determination of prognostic
Bone Marrow Transplant. 1997;20:859-863.
significance of rare recurring chromosomal abnormalities among 5876
14. Chiang KY, Weisdorf DJ, Davies SM, et al. Outcome of second bone
younger adult patients treated in the United Kingdom Medical
marrow transplantation following a uniform conditioning regimen as
Research Council trials. Blood. 2010;116:354-365.
therapy for malignant relapse. Bone Marrow Transplant. 1996;17:39-42.
31. Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnor-
15. Martinez C, Carreras E, Rovira M, et al. Allogenic stem cell trans-
malities are predictive of induction success, cumulative incidence of
plantation as salvage therapy for patients relapsing after autologous
relapse, and overall survival in adult patients with de novo acute
transplantation: experience from a single institution. Leuk Res. 2001;
myeloid leukemia: results from Cancer and Leukemia Group B (CALGB
25:379-384.
8461). Blood. 2002;100:4325-4336.
16. Blau IW, Basara N, Bischoff, et al. Second allogeneic hematopoietic stem
32. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of
cell transplantation as treatment for leukemia relapsing following
acute myeloid leukemia in adults: recommendations from an inter-
a first transplant. Bone Marrow Transplant. 2000;25:41-45.
national expert panel, on behalf of the European LeukemiaNet. Blood.
17. Radich JP, Gooley T, Sanders JE, et al. Second allogeneic transplantation
2010;115:453-474.
after failure of first autologous transplantation. Biol Blood Marrow
33. Ringden O, Pavletic SZ, Anasetti C, et al. The graft-versus-leukemia
Transplant. 2000;6:272-279.
effect using matched unrelated donors is not superior to HLA-
18. Ringden O, Labopin M, Gorin NC, et al., Acute Leukaemia Working
identical siblings for hematopoietic stem cell transplantation. Blood.
Party of the European Group for Blood and Marrow Transplantation
2009;113:3110-3118.
(EBMT). The dismal outcome in patients with acute leukaemia who
34. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allo-
relapse after an autograft is improved if a second autograft or
geneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:
a matched allograft is performed. Bone Marrow Transplant. 2000;25:
2091-2101.
1053-1058.