Bone Marrow Transplantation (2016) 51, 186–193
© 2016 Macmillan Publishers Limited All rights reserved 0268-3369/16
www.nature.com/bmt
ORIGINAL ARTICLE
Second reduced intensity conditioning allogeneic transplant as
a rescue strategy for acute leukaemia patients who relapse after
an initial RIC allogeneic transplantation: analysis of risk
factors and treatment outcomes
R Vrhovac1, M Labopin2,3,4,5, F Ciceri6, J Finke7, E Holler8, J Tischer9, B Lioure10, J Gribben11, L Kanz12, D Blaise13, P Dreger14, G Held15,
R Arnold16, A Nagler5,17,18 and M Mohty2,3,4,5,18 on behalf of the Acute Leukemia Working Party of the European Society for Blood and
Marrow Transplantation (EBMT)
Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning
haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation
(EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2)
from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or
refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5–79) months
after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI),
leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17–28.4), 63.9% (56.7–70.1), 14.6%
(8.8–18.5) and 20.5% (14.9–26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia
(representing 89.8% of all patients), duration of remission following RIC1 4225 days, presence of CR at RIC2, patient’s Karnofsky
performance status 480 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients’
favourable outcome.
Bone Marrow Transplantation (2016) 51, 186–193; doi:10.1038/bmt.2015.221; published online 5 October 2015
INTRODUCTION
Optimal treatment for relapse of acute leukaemia following
haematopoietic stem cell transplantation (HSCT) is still poorly
defined. Limited therapeutic options are generally available for
these patients, and they usually face a very poor prognosis.1,2
Depending mostly on the timing of relapse post HSCT, only
10–32% of patients with acute myelogenous leukaemia (AML) can
achieve a new remission, whereas prognosis for ALL patients
is even worse, with a median overall survival (OS) of about
10 months.3,4 Evidence-based treatment strategies do not exist, as
most available information is derived from retrospective studies
with limited numbers of patients.
Among other risk factors, reduced-intensity conditioning (RIC)
has been shown to increase the probability of relapse following
transplantation.3,5 However, because of its relatively low toxicity, a
second RIC allogeneic stem cell transplantation (RIC2) is often the
only feasible treatment option, and might be a valuable rescue
strategy for a selected group of patients. Namely, a RIC2 HSCT has
been shown to be associated with a low and acceptable
non-relapse mortality (NRM) in patients who have undergone a
previous autologous transplantation,6,7 as well as in those who
relapse after a previous allogeneic HSCT.8
A retrospective study of the European Society for Blood and
Marrow Transplantation (EBMT) registry data was performed to
evaluate the outcome of RIC2 in terms of NRM and overall- and
leukaemia-free survival (LFS), as well as to identify prognostic
factors that determine the outcome of RIC2 in acute leukaemia
patients. Engraftment rate, GVHD and relapse incidence (RI) were
also assessed.
MATERIALS AND METHODS
Inclusion criteria and data collection
Data on patients undergoing second allogeneic transplantation using RIC
were obtained from the EBMT registry. Patients with acute leukaemia who
1
Department of Hematology, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia; 2AP-HP, Hématologie Clinique et Thérapie Cellulaire,
Hôpital Saint-Antoine, Paris, France; 3Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France; 4INSERM, UMR_S 938, CDR Saint-Antoine, Paris,
France; 5EBMT ALWP Office, Hospital Saint Antoine, Paris, France; 6Hematology and Bone Marrow Transplantation, San Raffaele Scientific Institute, Milano, Italy; 7Medicine,
Hematology and Oncology, University of Freiburg, Freiburg, Germany; 8Hematology and Oncology, University of Regensburg, Regensburg, Germany; 9Ludwig-Maximilians
University Hospital of Munich-Grosshadern, Department of Internal Medicine III, Hematopoietic cell Transplantation, Munich, Germany; 10Hematology, Oncology and Bone
Marrow Transplantation, CHU Hautepierre, Strasbourg, France; 11St Bartholomew's and The Royal London NHS Trust, London, UK; 12Department of Medicine, Tübingen University,
Tübingen, Germany; 13Transplantation and Cellular Therapy, Institut Paoli Calmettes, Marseille, France; 14Department of Medicine V, University of Heidelberg, Heidelberg,
Germany; 15Internal Medicine, BMT Unit, University of Saarland, Homburg, Germany; 16Hematology and Oncology, Charite, Universitaetsmedizin, Berlin, Germany and 17Chaim
Sheba Medical Center, Tel-Hashomer, Israel. Correspondence: Professor R Vrhovac, Department of Hematology, University Hospital Centre Zagreb, University of Zagreb School of
Medicine, Kispaticeva 12, Zagreb 10000, Croatia.
E-mail: [email protected]
18
The last two senior authors contributed equally to this work.
Received 17 March 2015; revised 18 August 2015; accepted 20 August 2015; published online 5 October 2015
Second RIC allogeneic transplantation in acute leukaemia patients
R Vrhovac et al
187
received a second allograft (RIC2) between 1 January 2000 and 31
December 2012 for relapse of leukaemia after an initial RIC HSCT were
included. Data on 250 patients from 101 EBMT transplant centres were
initially retrieved from the database, including details on patients’ and
disease characteristics, type of conditioning, donor relation and source of
stem cells that were used. Sixty-one queries were sent out to clarify
conflicting entries or inconsistencies, of which 45 were resolved. A total of
16 patients were excluded from further analyses for either entry criteria
violation or lack of response to query from center.
End points
All outcomes were calculated from the time of RIC2. NRM was defined as
death from any cause without previous relapse or progression; relapse as
any event related to recurrence of acute leukaemia; LFS as survival in
continuous CR. Relapse or death were considered events, and patients
surviving in continuous CR were censored at last follow-up. Haematopoietic recovery was defined as achieving an ANC 40.5/μL and platelets
420/μL. Cumulative incidences of grade 2–4 acute GVHD and of chronic
GVHD following RIC2 were also evaluated.
Statistical analysis
The probabilities of OS and LFS were calculated using the Kaplan–Meier
method and the log-rank test for univariate comparisons.9 Cumulative
incidence curves were used for RI and NRM in a competing risk setting.10
Acute and chronic GVHD were diagnosed and graded according to
standard criteria.11,12 Death was considered as a competing event to
GVHD. As the number of ALL patients was relatively low, prognostic factors
were studied only in AML patients pooled together with biphenotypic and
undifferentiated leukaemia. The log-rank test was used for univariate
comparisons and the Gray test for cumulative incidence curves. The
following variables were tested in univariate analyses: disease status at
RIC1, source of stem cells at RIC1, type of donor at RIC1, presence of acute
(grade II or higher) or chronic GVHD before RIC2, age at RIC2, duration of
remission following RIC1, interval from relapse to RIC2, female donor to
male recipient at RIC2, Karnofsky performance status (480 or ⩽ 80) at RIC2,
type of conditioning (RIC vs non-myeloablative) at RIC2, use of TBI for
conditioning at RIC2, source of stem cells (BM vs PBSC) at RIC2, type of
donor (matched sibling donor (MSD) vs other) at RIC2, donor change at
RIC2 compared with RIC1 (MSD at RIC1—same MSD at RIC2 vs MSD at RIC1
—other MSD at RIC2 vs MSD at RIC1—matched-unrelated donor (MUD) at
RIC2 vs MUD at RIC1—same MUD at RIC2 vs MUD at RIC1—other MUD at
RIC2), disease status at RIC2 and in vivo T-cell depletion at RIC2. The impact
of chronic GVHD after second RIC was studied using Therneau’s coxph
function in R and its extension, the Andersen-Gill model.13,14 The Simon
and Makuch curve was drawn using a macro developed in R software 3.1.2.
(R Development Core Team, Vienna, Austria) to illustrate the effect of
GVHD on OS and LFS, using a landmark at 100 days.15 Adjusted
multivariate analyses were performed using a Cox proportional hazards
regression model including time-dependent variables.16 All factors
associated with a P-value o0.10 by univariate analysis and chronic GVHD
after RIC2 as a time-dependent variable were included in the model. To
develop a prognostic classification, a stepwise backward procedure was
used on the model including all prognostic factors known at the time of
second RIC for OS, with a cutoff significance level of 0.05 for deleting
factors in the model. The three remaining significant fixed factors were
used to develop a risk score in an additive way. All tests were two-sided.
The type I error rate was fixed at 0.05 for determination of factors
associated with time to event outcomes. Statistical analyses were
performed with SPSS 19 (SPSS Inc./IBM, Armonk, NY, USA) and R 2.13.2
(R Development Core Team) software packages.
RESULTS
Patient and transplant characteristics
During a 13-year period (2000–2012), a total of 234 patients
(121 males) with acute myelogenous (205), lymphoblastic (24),
biphenotypic (4) or undifferentiated (1) leukaemia have received
RIC2 as a salvage treatment for relapse following RIC1 (Table 1).
Various regimens were used for conditioning; they were
fludarabine based in 142 and 110 patients, TBI based in 63 and
45 patients, and other chemotherapy-based conditioning in 15
and 57 cases at first and second transplant, respectively.
© 2016 Macmillan Publishers Limited
Table 1.
Patients’ characteristics at first and second transplantation
AML (N = 210)
Follow-up
21.3 (1.5–79)
Patients characteristics
Age at RIC1, median (range)
(years)
Gender
Male
Female
First RIC
Donor gender
Male
Female
Status at RIC1
CR1
CR2–3
Active disease
Donor type RIC1
MSD
UD
Haplo
Graft type RIC1
Bone marrow
PBSCs
aGVHD after RIC1
No
Grade I
Grade II
Grade III
Yes, grade unknown
Missing
Grade 0–I
Grade II+
cGVHD after RIC1
No
Yes
Grade cGVHD after RIC1
Limited
Extensive
Unknown
Conditiong at RIC1
BuFlu
BuFlu+Clofa
Bu ± other
FluMel
BuMel
Mel ± other
Treo
Treo+Flu
Treo+Mel
ALL (N = 24)
12.1 (3.3–54)
51.5 (19.8–72.0)
49.1 (27.9–73.6)
106
50.5%
104
49.5%
15
62.5%
9
37.5%
138
65.6%
72
34.4%
12
50.0%
12
50.0%
99
47.1%
27
12.9%
84
40.0%
14
58.3%
4
16.7%
6
25.0%
125
59.5%
76
36.2%
9
4.3%
13
54.2%
8
33.3%
3
12.5%
14
6.7%
196
93.3%
2
8.3%
22
91.7%
126
61.8%
45
22.1%
23
11.3%
5
2.5%
5
2.5%
6
171
85.9%
28
14.1%
19
79.2%
3
12.5%
2
8.3%
0
0.0%
0
0.0%
0.0%
22
91.7%
2
8.3%
156
74.3%
54
25.7%
17
70.8%
7
29.2%
32
21
1
4
3
0
66
1
2
41
1
1
1
19
1
0
0
0
0
0
0
0
0
0
Bone Marrow Transplantation (2016) 186 – 193
Second RIC allogeneic transplantation in acute leukaemia patients
R Vrhovac et al
188
Table 1.
Table 1.
(Continued )
Flamsa chemo
Other TBI
Fluda-TBI 4 Gy
Fluda-TBI 2 Gy
Other
Flu
Flu+ARAC
Flu+Thiotepa
Flu+Cy
Cy+Thiotepa
Missing
AML (N = 210)
ALL (N = 24)
4
15
28
0
0
2
0
0
7
6
3
12
20
0
1
1
0
0
0
2
Second RIC
Age at RIC2, median (range) 52.9 (20.1–72.4) 52.9 (28.8–74.4)
in years
Time from 1st transplant to 225.0 (34–2608) 136.5 (33–4254)
relapse, median (range) in
days
84 (10–1203) 128.5 (11–642)
Time from relapse to 2nd
transplant, median (range) in
days
366.0 (60–3165) 284.5 (67–4402)
Time from 1st to 2nd
transplant, median (range) in
days
Donor sex RIC2
Male
128
14
61.0%
58.3%
Female
82
10
39.0%
41.7%
Female D to male R RIC2
No
169
20
80.5%
83.3%
Yes
41
4
19.5%
16.7%
Graft type RIC2
Bone marrow
12
2
5.7%
8.3%
PBSCs
198
22
94.3%
91.7%
Status at RIC2
CR2
40
9
19.0%
37.5%
CR3
16
2
7.6%
8.3%
Advanced
154
13
73.3%
54.2%
CR at RIC2
No
154
13
73.3%
54.2%
Yes
56
11
26.7%
45.8%
Donor type
MSD
92
9
44%
38%
MUD
94
12
45%
50%
Haplo
24
3
11%
13%
Donor type
MSD1–same MSD2
61
2
MSD1–other MSD2
13
1
MSD1–UD2
22
3
UD1–sameUD2
17
4
UD1-otherUD2
43
3
Missing
54
11
Same donor at RIC2
No
96
9
56.5%
56.3%
Yes
74
7
43.5%
43.8%
Missing
40
8
Bone Marrow Transplantation (2016) 186 – 193
(Continued )
Conditioning at RIC2
BuFlu
BuFlu+Clofa
Bu ± other
FluMel
Mel ± other
Treo
Treo+Flu
Cyclo+Flu
Cy+Thiotepa
Cy+ARAC
Flamsa TBI
Flamsa chemo
Other TBI
Cy TBI
Fluda-TBI
Flu alone
Flu+ARAC
Flu+Thiotepa
ARAC ± other
ARAC+VP16+Ida
ARAC+Clofa
Other
Missing
RICa
NMAb
GVHD prevention
CSA
CSA+MTX
CSA+MMF
CSA+tacro
Tacro
MMF+tacro
Siro
MMF+siro
Other
Missing
ATG at RIC 2
No
Yes
Engraftment
No
Yes
Not evaluable
aGVHD after RIC2
No aGvHD present
Grade I
Grade II
Grade III
Grade IV
Present, grade missing
aGVHD grade II–IV
No
Yes
Missing
AML (N = 210)
ALL (N = 24)
23
1
3
23
13
2
20
12
3
2
6
6
6
5
20
1
9
11
11
8
3
4
18
140
72.9%
52
27.1%
2
0
0
3
0
1
2
1
0
0
0
0
0
2
6
0
1
1
0
0
0
1
4
15
75.0%
5
25.0%
34
22.5%
28
18.5%
50
33.1%
1
0.7%
3
2.0%
14
9.3%
2
1.3%
7
4.6%
12
7.9%
59
5
29.4%
3
17.6%
4
23.5%
0
0.0%
2
11.8%
1
5.9%
1
5.9%
0
0.0%
1
5.9%
7
140
66.7%
70
33.3%
16
66.7%
8
33.3%
17
8.6%
181
91.4%
12
1
4.8%
20
95.2%
3
106
27
36
11
15
3
9
5
3
1
3
0
133 (68.2)
62 (31.8)
15
14 (66.7)
7 (33.3)
3
© 2016 Macmillan Publishers Limited
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189
Table 1.
(Continued )
cGVHD after RIC2 (before or
after relapse)
No
Yes
Missing
Grade cGVHD
Limited
Extensive
Missing
cGVHD after RIC2 (before
relapse)
No
Yes
Missing
Grade cGVHD (before
relapse/progression)
Limited
Extensive
AML (N = 210)
ALL (N = 24)
133 (69.6)
58 (30.4)
19
18 (78.3)
5 (21.7)
1
26
28
4
133 (78.5)
41 (21.5)
19
17
24
2
2
1
18 (82.6)
4 (17.4)
1
2
2
Abbreviations: aGVHD = acute GVHD; AML = acute myelogenous leukaemia; ATG = antithymocyte globulin; cGVHD = chronic GVHD; CSA = cyclosporine A; MMF = mycophenolate mofetil; MSD = matched sibling donor;
MTX = methotrexate; MUD = matched-unrelated donor; NMA = non-myeloablative; RIC = reduced intensity conditioning; RIC1 = first RIC haematopoietic stem cell transplantation; RIC2 = second RIC transplantation;
UD = unrelated donor. aDefinition of RIC: busulfan (Bu)+fludarabine (Flu),
BuFlu+clofarabine, Bu ± other, fludarbine melphalan (Mel), Mel ± other,
treosulfan (Treo), Treo+Flu, cyclophosphamide (Cy)+Flu, Cy+thiotepa, Cy
+ARAC, Flamsa TBI, Flamsa Bu, other TBI 4 Gy, Cy TBI, Flu-TBI 4 gy, Flu
+thiotepa. bDefiniton of NMA: Flu alone, Flu+ARAC, ARAC+VP16+idarubicin, ARAC+clofarabine, clofarabine alone, idarubicin+FLAG, ARAC alone,
ARAC+Cy, ARAC+VP16+idarubicin, ARAC+clofarabine, ARAC+amsacrine,
ARAC+daunorubicin, ARAC+VP16, ARAC+gemtuzumab, ARAC+idarubicin,
TBI alone 2 Gy, Flu-TBI 2 Gy.
Data regarding conditioning at first or second transplantations
were missing for 14 and 22 patients, respectively. Cyclosporine A
(CSA) in combination with mycophenolate mofetil was used for
prevention of GVHD after RIC2 in 32.1%, CSA alone in 23.2% and
CSA in combination with methotrexate in 18.5% of the patients.
Other immunosuppressive agents and their combinations were
used in the rest of the cases (Table 1). A total of 44 patients had
received donor lymphocyte infusion (DLI) for relapse before the
second RIC allogeneic HSCT.
The median age at time of RIC2 was 53 (range 20–74) years. The
reasons for RIC were known for 110 (out of 142) patients younger
than 55 years: comorbid conditions in 27, prior autograft in 8,
protocol driven in 66 and age of recipient (between 50 and 55
years) in 9. The median time from RIC1 to relapse was 220 (range
33–4254) days, and the median time from RIC1 to RIC2 was 359
(range 60–4402) days. At the time of RIC2, 167 (71.4%) patients
had relapsed or refractory disease, 49 patients (20.9%) were in
second CR and 18 (7.7%) in third or higher CR. The decision to
perform RIC2 in all patients was based on clinical judgment of
their treating physicians, and patients transplanted in second or
higher CR achieved remission following chemotherapy and/or DLI.
Stem cells originated from HLA-identical siblings in 43.2% and
from unrelated donors in 56.8% of the cases, respectively. Out of
the 133 patients who received a second RIC from a non-sibling
donor 27 were from haploidentical and 106 from MUDs (HLA was
reported for 63 patients; 43 were 10/10; 18 were 9/10 and 2
were 8/8).
The donor at RIC2 was the same as at RIC1 in 84 cases, different
in 105 patients, whereas in 48 cases this information was missing.
The vast majority of patients (94%) received PBSC for RIC2.
© 2016 Macmillan Publishers Limited
Haematopoietic recovery
After RIC2, 201 patients (88.5%) engrafted. Median time to
neutrophil recovery was 15 (range, 1–40) days. Median time to
platelet recovery was 16 (range, 1–69) days.
Acute and chronic GVHD
Grade 2–4 acute GVHD following RIC1 was observed in 13.5% and
chronic GVHD after RIC1 (before RIC2) was present in 61 patients
(26%). Cumulative incidence of chronic GVHD 2 years after RIC2
was 39.2%.
Outcome
With a median follow-up of 21 (range 1.5–79) months after RIC2,
51 patients were still alive. At 2 years, the rates of NRM, RI, LFS and
OS were 22.4% (95% confidence interval (CI): 17–28.4), 63.9%
(56.7–70.1), 14.6% (8.8–18.5) and 20.5% (14.9–26.1), respectively.
There was no significant difference in survival between ALL
patients and others (P = 0.78). Patients with ALL were excluded
from further analyses of prognostic factors. In the remaining
patients, there was no significant difference in survival according
to age (categorized to older or younger than the median—53
years, P = 0.51), type of donor (MSD vs other, P = 0.50), female
donor to male recipient (P = 0.63), change of donor at RIC2
(P = 0.95), source of stem cells (bone marrow vs PB, P = 0.71), use of
TBI (P = 0.09), in vivo T-cell depletion (P = 0.85) or interval from
relapse to RIC2 (shorter or longer than the median—84 days,
P = 0.14) (Table 2). Duration of remission following RIC1, disease
status at RIC2, patient's performance status at RIC2 and type of
conditioning were found to be the strongest predictors of LFS and
OS. Patients with an early relapse of their acute leukaemia
following RIC1 (defined as shorter than median, i.e. ⩽ 225 days)
had significantly higher RI (71% vs 55%; Po 0.001) and lower LFS
(7% vs 24%; P o0.001) and OS (10% vs 36%; P o 0.001) 2 years
following RIC2 allogeneic transplant (Table 2). Similarly, patients
not being in CR before RIC2 had inferior outcomes compared with
those in CR with significantly higher RI (66% vs 56%, P = 0.02) and
lower LFS (10% vs 28%, Po 0.001) and OS (16% vs 41%, P o 0.001)
2 years after RIC2 (Table 2). Patients with better performance
status (Karnofsky 480%) at RIC2 had significantly longer LFS
and OS (20% vs 8%, P = 0.004, and 29% vs 10%; P o 0.001,
respectively). Type of conditioning also had an impact on
outcomes following second transplantation—patients conditioned with a non-myeloablative regimen had inferior NRM
(12% vs 25%, P = 0.02) and better OS (33% vs 17%, P = 0.02)
compared with patients conditioned with a reduced intensity
regimen (Table 2).
In the multivariate model, time from RIC1 to relapse longer than
the median and CR at RIC2 were independent prognostic factors
associated with lower RI, longer LFS and OS (Table 3). Chronic
GVHD studied as a time-dependent variable (after RIC2) was
associated with a better LFS and OS and a trend to a lower RI.
Impact of chronic GVHD on OS of AML patients is shown in
Figure 1. An MSD at RIC2 had an independent impact on better OS
(Table 3). Similarly, in vivo T-cell depletion with antithymocyte
globulin (ATG) at RIC2 was an independent prognostic factor for
longer LFS, and age ⩾ 53 years was independently associated with
higher NRM.
Three distinct groups were identified based on the presence or
absence of three major risk factors at the time of RIC2, namely
time from RIC1 to relapse o225 days, no CR at RIC2 and reduced
intensity (vs non-myeloablative) conditioning regimen at RIC2.
Patients with none of the mentioned adverse prognostic factors
had an overall 2-year survival of 61% (95% CI: 34-88), whereas
those with 1 and 2 adverse prognostic factors had OS 46%
(95% CI: 28–64) and 12% (95%: CI 7–18), respectively (Figure 2).
Bone Marrow Transplantation (2016) 186 – 193
Second RIC allogeneic transplantation in acute leukaemia patients
R Vrhovac et al
190
Table 2.
Factors associated with outcomes of AML patients 2 years after second transplantation
RI
NRM
LFS
OS
Patient age (years)
o53
⩾ 53
P-value
65.9% (55.5–74.4)
60.1% (49.5–69.2)
0.105
15.9% (9.5–23.9)
28% (19.6–37.1)
0.026
18.2% (10.4–25.9)
11.8% (5.2–18.5)
0.766
23.8% (15.1–32.5)
21% (12.5–29.4)
0.514
Interval from RIC1 to relapse (days)
⩽ 225
4225
P-value
71.2% (61.3–79)
54.7% (43.9–64.3)
0.0002
22.3% (14.7–30.8)
21.2% (13.8–29.6)
0.940
6.5% (1.6–11.3)
24.1% (15.2–33)
o 10–5
9.8% (3.7–15.9)
35.7% (25.7–45.7)
o10–5
Interval relapse to BMT2 (days)
⩽ 84
484
P-value
63.8% (53.5–72.4)
62.2% (51.5–71.2)
0.215
21.1% (13.8–29.5)
22.7% (15.1–31.2)
0.856
15.1% (7.9–22.2)
15.1% (7.7–22.6)
0.09
22.1% (13.8–30.5)
23% (14.1–31.8)
0.14
Female D to male R RIC2
No
Yes
P-value
64.2% (56.1–71.2)
58.3% (40.7–72.3)
0.461
19.7% (13.9–26.1)
30.3% (23.5–37.3)
0.273
16.1% (10.2–22)
11.4% (1.2–21.7)
0.833
23.3% (16.4–30.2)
18.9% (6.3–31.5)
0.628
Karnofsky RIC2 (%)
⩽ 80
480
P-value
60.6% (47.2–71.6)
63.5% (50.1–74.2)
0.581
31% (20–42.6)
16.7% (8.6–27.2)
0.056
8.3% (1.4–15.3)
19.7% (9.7–29.7)
0.004
9.9% (2.4–17.4)
28.9% (17.3–40.6)
0.0003
Conditioning RIC2
RIC
NMA
P-value
61.9% (52.7–69.8)
67.9% (52.8–79.1)
0.146
25.4% (18.3–33.1)
11.7% (7–17.7)
0.017
12.6% (6.6–18.7)
20.4% (9.2–31.6)
0.283
17.4% (10.5–24.3)
33.7% (20.4–47.1)
0.018
TBI RIC2
No
Yes
P-value
62.9% (54.9–70)
63.3% (43.5–77.8)
0.763
22.7% (16.6–29.5)
19.9% (14.2–26.5)
0.593
14.3% (8.8–19.9)
16.8% (3.4–30.1)
0.232
19.9% (13.5–26.4)
33% (16.5–49.5)
0.088
Source SC RIC2
BM
PB
P-value
75% (35.4–92.3)
62.3% (54.8–68.9)
0.363
8.3% (0.3–35)
22.7% (3–53.5)
0.200
16.7% (0–37.8)
15% (9.7–20.3)
0.719
33.3% (6.7–60)
21.6% (15.3–27.8)
0.707
Donor RIC2
All other (MUD or haplo)
MSD
P-value
60% (50–68.6)
66.5% (55.4–75.5)
0.177
24.8% (17.2–33.1)
18.2% (11.7–26)
0.115
15.2% (8.3–22.2)
15.2% (7.5–22.9)
0.964
20.7% (12.7–28.8)
24.8% (15.4–34.2)
0.504
Donor RIC2
MSD1–same MSD2
MSD1–other MSD2
MSD1–UD2
UD1–same UD2
UD1–other UD2
P-value
65% (51.2–75.8)
63.1% (22–86.9)
66.4% (40.2–83.2)
49.6% (22.3–72)
58.8% (40.8–73.1)
0.787
20.2% (2.9–48.8)
26.2% (5.1–54.7)
18.9% (2.4–47.3)
30.3% (7–58.4)
17.1% (2–45.2)
0.817
14.8% (5.6–23.9)
10.8% (0–30.4)
14.7% (0–30)
20.2% (0.1–40.2)
24.1% (10.1–38.1)
0.530
22.8% (12–33.7)
36.9% (6.1–67.7)
15.5% (0–31.6)
23.2% (1.1–45.3)
34.2% (19.1–49.3)
0.632
62.5% (51.1–72)
63% (50.6–73.1)
0.435
22% (14.1–31.1)
20.8% (13.1–29.8)
0.506
15.4% (7.5–23.4)
16.2% (7.6–24.8)
0.694
22.7% (13.5–31.9)
24.5% (14.3–34.7)
0.946
Status at RIC2
No CR at RIC2
CR at RIC2
P-value
66% (57.7–73.1)
54.8% (39.7–67.7)
0.019
23.7% (17.1–30.9)
16.9% (11.3–23.4)
0.244
10.3% (5.2–15.4)
28.3% (15.5–41)
0.00003
15.8% (9.6–22)
41.1% (26.9–55.2)
0.00003
In vivo T-cell depletion at RIC2
No
Yes
P-value
66.3% (57.5–73.7)
56.5% (43–67.9)
0.101
20% (13.7–27.2)
25.4% (18.4–33)
0.272
13.7% (7.8–19.7)
18.1% (8.3–28)
0.313
22.7% (15.3–30.2)
21.8% (11.4–32.3)
0.851
Same donor RIC1–2
No
Yes
P-value
Abbreviations: BM = bone marrow; BMT = bone marrow transplantation; LFS = leukaemia-free survival; MSD = matched sibling donor;
MUD = matched-unrelated donor; NRM, non-relapse mortality; OS = overall survival; RI = relapse incidence; RIC = reduced intensity conditioning;
RIC1 = first RIC haematopoietic stem cell transplantation; RIC2 = second RIC transplantation; UD = unrelated donor.
Bone Marrow Transplantation (2016) 186 – 193
© 2016 Macmillan Publishers Limited
Second RIC allogeneic transplantation in acute leukaemia patients
R Vrhovac et al
191
1.0
Table 3. Outcome of AML patients 2 years after second
transplantationa
0.8
LFS
cGVHD after RIC2b
Age at RIC2 ⩾ 53 years
Time from 1st transplant to relapse
4225 days
Time from relapse to 2nd transplant
484 days
MSD at RIC1
MSD at RIC2
CR at RIC2
ATG at RIC2
NMA at RIC2
RI
cGVHD after RIC2b
Age at RIC2 ⩾ 53 years
Time from 1st transplant to relapse
4225 days
Time from relapse to 2nd transplant
484 days
MSD at RIC1
MSD at RIC2
CR at RIC2
ATG at RIC2
NMA at RIC2
NRM
cGVHD after RIC2b
Age at RIC2 ⩾ 53 years
Time from 1st transplant to relapse
4225 days
Time from relapse to 2nd transplant
484 days
MSD at RIC1
MSD at RIC2
CR at RIC2
ATG at RIC2
NMA at RIC2
cGVHD
Age at RIC2 ⩾ 53 years
Time from 1st transplant to relapse
4225 days
Time from relapse to 2nd transplant
484 days
MSD at RIC1
MSD at RIC2
CR at RIC2
ATG at RIC2
NMA at RIC2
0.019 0.51
0.473 1.14
0.002 0.54
0.29
0.80
0.37
0.89
1.63
0.79
0.429 0.86
0.59
1.26
0.271
0.040
0.026
0.065
0.057
0.80
0.32
0.40
0.46
0.43
2.18
0.97
0.94
1.02
1.01
1.32
0.56
.61
0.69
0.66
53%
0.4
30%
no cGVHD
cGVHD
0.0
1
0
2
3
Time (years)
Patients at risk
0.051 0.56
0.434 1.14
0.001 0.52
0.31
0.82
0.36
1.00
1.60
0.75
0.399 0.86
0.60
1.23
0.607
0.256
0.016
0.049
0.366
1.14
0.73
0.61
0.69
0.83
0.70
0.43
0.40
0.47
0.56
1.86
1.25
0.91
1.00
1.24
0.060 0.52
0.723 0.93
0.001 0.46
0.27
0.63
0.30
1.03
1.38
0.72
0.678 0.91
0.59
1.41
0.493
0.329
0.042
0.086
0.778
1.23
0.73
0.61
0.67
1.07
0.68
0.39
0.38
0.43
0.68
2.21
1.37
0.98
1.06
1.67
0.632 0.75
0.024 2.25
0.333 0.71
0.23
1.11
0.36
2.43
4.55
1.42
0.295 0.70
0.36
1.36
0.924
0.429
0.287
0.345
0.019
0.96
0.66
0.66
0.72
0.31
0.39
0.24
0.31
0.36
0.12
2.33
1.84
1.42
1.43
0.83
0.037 0.48
0.227 1.74
0.25
0.71
0.96
4.28
0.008 2.93
1.33
6.49
0.542
0.906
0.625
0.089
0.412
0.49
0.30
0.42
0.24
0.66
3.93
2.88
1.69
1.11
2.78
1.38
0.93
0.84
0.52
1.35
Abbreviations: ATG = antithymocyte globulin; cGVHD = chronic GVHD;
CI = confidence interval; HR = hazard ratio; LFS = leukaemia-free survival;
MSD = matched sibling donor; OS = overall survival; NMA = non-myeloablative; NRM = non-relapse mortality; RI = relapse incidence; RIC2 = second
RIC transplantation. aCox model including all variables and cGVHD after
RIC2 in AML. bTime-dependent variable.
© 2016 Macmillan Publishers Limited
0.6
0.2
no cGVHD
cGVHD
102
28
12
9
5
25
18
11
Figure 1. Impact of chronic GVHD on overall survival of AML
patients.
1.0
No adverse prognostic factor
1 adverse prognostic factor
2 or 3 adverse prognostic factors
0.8
Overall survival
OS
cGVHD after RIC2b
Age at RIC2 ⩾ 53 years
Time from 1st transplant to relapse
4225 days
Time from relapse to 2nd transplant
484 days
MSD at RIC1
MSD at RIC2
CR at RIC2
ATG at RIC2
NMA at RIC2
95% CI
Overall survival
P-value HR
60.6% (n = 13)
0.6
46.1% (n = 38)
0.4
0.2
12.3% (n = 141)
0.0
0
1
2
3
Years
*Adverse prognostic factors include:
– time from RIC1 to relapse <225 days
– no CR at RIC2
– reduced intensity (vs. non-myeloablative) conditioning regimen at RIC2
Figure 2. Impact of adverse prognostic factors on overall survival
following RIC2 in patients with AML and a relapse after RIC1.
DISCUSSION
RIC allogeneic HSCT with its markedly reduced toxicity in
comparison with myeloablative conditioning HSCT, opened new
possibilities in the treatment of patients with acute leukaemia,
especially older ones and those with comorbidities. However,
because of lower conditioning-related direct antileukaemic effect,
as well as unfavourable biological features of acute leukaemia in
the elderly, an increased relapse rate ranging between 20 and
61% has been seen after RIC.17–19 As a consequence, the total
number of patients with relapsed acute leukaemia following a first
RIC allogeneic HSCT is rising, and their optimal treatment remains
challenging.
This is the largest study to date on patients with acute
leukaemia receiving a second RIC allogeneic transplant after
relapse following an initial RIC allograft. Previously reported
studies addressed the issue of second transplantation for treating
relapsed disease after the first transplant, but the vast majority of
Bone Marrow Transplantation (2016) 186 – 193
Second RIC allogeneic transplantation in acute leukaemia patients
R Vrhovac et al
192
patients received myeloablative conditioning, but not RIC at first
transplant.8,20–24 Furthermore, only more recent studies included
also transplants from unrelated donors at RIC2.8,25,26
Historically, retransplantation with a second myeloablative
conditioning was complicated by high rates of NRM, reported to
be up to 46%.19,23,27 The largest study investigating the outcome
of a RIC2 following an initial myeloablative transplant included 71
patients (the majority of them having leukaemia or myelodysplasia) and demonstrated acceptable TRM (24% at 1 year), comparable to the one expected after the initial myeloablative transplant
procedure.8 Eapen et al.28 reported a 1-year TRM of 26% in a
group of 279 patients treated with second allogeneic HSCT, 45 of
which of the RIC type. Christopoulos et al.25 retrospectively
analysed 58 patients receiving a second allograft for AML relapse
after the first (mostly myeloablative conditioning) transplantation,
reporting a TRM of 31.4% at 3 years, most of it occurring in the first
6 months following RIC2. Christopeit et al.26 performed a
retrospective registry study on 179 patients with relapsed acute
leukaemia treated with a second allogeneic HSCT, 33% of them
receiving RIC at second transplantation. NRM after second
transplantation was 31.8% for the whole group. Selecting a new
donor for second transplantation, which was done in 54.2% of
these patients, did not result in a relevant improvement in overall
survival.26 Two other studies on small number of patients also
reported low TRM after RIC transplant for the treatment of relapse
following a myeloablative transplant.29,30 Our study suggests that
a RIC regimen for the first allogeneic HSCT further reduces overall
transplant-related toxicity, making a second RIC transplant feasible
for a significant number of patients.
The results of our study also clearly demonstrate that AML
patients with delayed relapses after RIC1, those with chemosensitive disease and good performance status at RIC2 are those who
benefit the most from a second RIC transplantation. Furthermore,
our study shows that in this patient population nonmyeloablative
conditioning at second transplantation reduces NRM by more
than a half, which translates into longer LFS and OS.
Regarding timing of relapse, in our study the difference in
overall survival was noted after 225 days (7.5 months), which was
also the median time of relapse occurrence following RIC1.
Duration of remission following first transplant was the factor that
greatly impacted outcome of patients after the second allograft in
other reported series, as well.8,20,23,28,31 Timing of relapse
following transplantation is a very robust and consistent
prognostic factor for overall outcome. It is interesting to note
that Levine et al.32 found also that AML patients who relapsed
6 months or later following allogeneic HSCT were almost four
times more likely to achieve remission compared with those who
relapsed in the first 6 months following allogeneic HSCT.32 In
addition, a large retrospective study on 399 patients with relapsed
AML following allogeneic HSCT by Schmid et al.33 demonstrated
that patients who received DLI and chemotherapy did better than
those treated with chemotherapy alone. The use of DLI retained
significance on multivariate analysis in this study but was not as
important as younger age or time of relapse 45 months post
allogeneic HSCT. Notably, the benefit of DLI in this study was
greatest for those patients who attained a second CR before DLI.
Importance of chemosensitivity of the disease in our study is
also in line with results published by other groups that have
investigated second (or subsequent) allogeneic transplantations
and the influence of disease burden on the outcome. Long-term
survival was very poor in patients who did not achieve remission
of their disease before RIC2. This finding is consistent with data
from other reports on relapse after RIC.33,34 Kishi et al.31 and Mrsic
et al.35 demonstrated that acute leukaemia in remission before the
second transplant is a factor clearly correlated with better
outcome. Kedmi et al.36 retrospectively analysed the outcome
after second or subsequent allogeneic transplantation for different
indications, and found that factors indicating higher likelihood for
Bone Marrow Transplantation (2016) 186 – 193
survival were a non-malignant disease, full HLA-matching, the use
of RIC and a non-relapse indication. Furthermore, patients with
resistant malignancies who did not respond to chemotherapy had
a lower chance to respond to a second transplant procedure.
Hosing et al.37 also found that patients with AML/MDS have better
outcome after a second transplant if they start the procedure with
lower disease burden, defined as the absence or o5% blasts in
the peripheral blood.
Chemotherapy used for the treatment of patients who had
relapsed after RIC1 has not been investigated in our study.
Successful salvage with FLAG-Ida (fludarabine, cytarabine and
idarubicin), MEC (mitoxantrone, etoposide and cytarabine) or
similar combination chemotherapy followed by RIC allograft has
been reported in small series of patients.2,29,38 The intensity of
chemotherapy should be adjusted depending on the timing of
relapse and medical condition of the patient, as tolerance to
chemotherapy in the early post-transplant setting is generally
poor and can lead to severe complications. Because of the
retrospective nature of our study, patients who remained in
remission long enough to get a RIC2 represent a selected group.
Presence of chronic GVHD was reported by some groups as a
favourable prognostic factor for survival,20,23 which has been
confirmed by our study as well. Time dependent analysis on the
impact of chronic GVHD on outcome of our patients clearly
demonstrated its association with a trend to a lower RI and a
better LFS, and had a clear, statistically significant association with
a better OS. Although univariate analyses did not reveal positive
prognostic influence of an MSD at RIC2 on outcome, in a
multivariate model, an MSD at RIC2 was found to be a favourable
prognostic factor for OS.
Other factors were not found to influence outcome in our series
of patients. Change of donor at second transplantation, and
female to male donor vs others also did not have a significant
prognostic value in multivariate analyses.
Based on our results, future prospective clinical trials could
address the role or RIC2 allogeneic HSCT in acute leukaemia
patients relapsing after RIC1 by investigating: second RIC
allogeneic HSCT vs more 'conservative' treatment, that is,
chemotherapy+DLI approach; intensity of conditioning (reduced
toxicity vs reduced intensity vs non-myeloablative) in fit patients,
or RIC2 only in patients achieving CR after chemo and/or DLI vs
straight sequential FLAMSA (or similar) allogeneic HSCT approach.
CONCLUSIONS
Overall, our findings suggest that a second RIC transplant is a
feasible rescue strategy for acute leukaemia patients who relapse
after an initial RIC allogeneic transplantation, especially if
compared with historical data from standard myeloablativeconditioning second allogeneic HSCT. Of note, fit AML patients
who relapse beyond 7.5 months after a first RIC allogeneic HSCT
and those with chemosensitive disease are potential candidates
for a second RIC allogeneic HSCT with an acceptable rate of NRM.
Non-myeloablative conditioning regimens seem to provide a
good balance of efficacy and toxicity in this setting. Conversely,
there is no solid evidence that other groups of patients with
relapsed acute leukaemia following RIC1 could benefit from an
RIC2, and these should therefore be considered for investigational
therapies in the context of well-designed clinical trials.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
MM would like to thank Pr JV de Melo (University of Adelaide, Australia) for critical
reading of the manuscript.
© 2016 Macmillan Publishers Limited
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R Vrhovac et al
193
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