Bone Marrow Transplantation (2010) 45, 558–564
& 2010 Macmillan Publishers Limited All rights reserved 0268-3369/10 $32.00
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ORIGINAL ARTICLE
Outcome of patients developing GVHD after DLI given to treat CML
relapse: a study by the chronic leukemia working party of the EBMT
Y Chalandon1, JR Passweg1, C Schmid2, E Olavarria3, F Dazzi3, MP Simula3, P Ljungman4,
A Schattenberg5, T de Witte5, S Lenhoff6, P Jacobs7, L Volin8, S Iacobelli9,10, J Finke11,
D Niederwieser12 and C Guglielmi13, on behalf of the Chronic Leukemia Working Party
of the European Group for Blood and Marrow Transplantation (EBMT)
1
Division of Hematology, Department of Internal Medicine, University Hospital, Geneva, Switzerland; 2Klinikum Augsburg II
Medizinische Klinik, Augsburg, Germany; 3Department of Haematology, Imperial College, Hammersmith Hospital, London, UK;
4
Huddinge Haematology Centre, Karolinska University Hospital, Huddinge, Sweden; 5Department of Hematology, Radboud
University—Nijmegen Medical Centre, Nijmegen, The Netherlands; 6Department of Hematology, University Hospital, Lund,
Sweden; 7Department of Haematology and BMT Unit, Constantiaberg Medi-Clinic, Searl Lab for Cellular & Molecular Biology,
Cape Town, South Africa; 8Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; 9Dipartimento Scienze
per la Salute, University of Molise, Rome, Italy; 10Chronic Leukaemia WP Registry, Department of Medical Statistics &
Bioinformatics, Leiden, The Netherlands; 11Department of Medicine—Hematology, Oncology, University of Freiburg, Freiburg,
Germany; 12Division of Haematology & Oncology, University of Leipzig, Leipzig, Germany and 13Universita´La Sapienzá, Il Facolta
di Medicina, UOC Ematologia AOS Andrea, Rome, Italy
We studied GVHD after donor lymphocyte infusion (DLI)
in 328 patients with relapsed CML between 1991 and
2004 . A total of 122 patients (38%) developed some form
of GVHD. We analyzed GVHD by clinical presentation
(acute or chronic GVHD) and onset time after the first
DLI (early (p45 days) or late (445 days)). There was a
significant overlap between onset time and clinical
presentation. Some form of GVHD occurred at a median
of 104 days, acute GVHD at 45 days and chronic GVHD
at 181 days after DLI. The clinical presentation was acute
GVHD in 71 patients, of whom 31 subsequently developed
chronic GVHD subsequently. De novo chronic GVHD
was seen in 51 patients. OS for all patients was 69%
(95% confidence interval (CI) 63–75) at 5 years, DLIrelated mortality was 11% (95% CI 8–15) and diseaserelated mortality was 20% (95% CI 16–25). Risk factors
for developing GVHD after DLI were T-cell dose at first
DLI, the time interval from transplant to DLI and donor
type. In time-dependent multivariate analysis, GVHD
after DLI was associated with a risk of death of 2.3-fold
compared with patients without GVHD. Clinical presentation as acute GVHD and early onset GVHD were
associated with increased mortality.
Bone Marrow Transplantation (2010) 45, 558–564;
doi:10.1038/bmt.2009.177; published online 27 July 2009
Keywords: DLI; relapse; CML; GVHD; allo-SCT
Correspondence: Dr Y Chalandon, Department of Internal Medicine,
Hematology Service, University Hospital of Geneva, 24 rue Michelidu-Crest, 1211 Geneva 14, Switzerland.
E-mail: [email protected]
Received 22 December 2008; revised 11 March 2009; accepted 1 June
2009; published online 27 July 2009
Introduction
The description of the GVL effect paved the way for the
development of donor lymphocyte infusions (DLI) for the
treatment of relapse in patients after allogeneic hematopoietic
SCT (HSCT).1–6 DLI is most effective in CML.4 DLI can
restore remission in many patients with CML relapsing after
HSCT.1–3 As response is less for advanced disease at the time
of relapse, molecular/cytogenetic monitoring after transplantation and prompt therapy with DLI before developing
hematological relapse may represent the optimal management of patients after transplantation.7 The applicability of
DLI in CML has been limited by morbidity and mortality
associated with GVHD.6,8–10 Over the years, the practice of
DLI has changed as the early bulk doses have been replaced
by incremental dose regimens with low starting doses
followed by escalating doses until achievement of response
or development of GVHD. This may reduce the incidence
and, more importantly, the severity of GVHD, while possibly
preserving GVL’s effects.11,12 Response to DLI has been
reported in previous analyses by the Chronic Leukemia
Working Party of the European Group for Blood and
Transplantation (EBMT).4,13
The goal of this study was to describe in detail GVHD
occurring after DLI with a focus on clinical presentation, time
of onset, organ involvement, severity, clinical course, treatment
and long-term outcome. In this retrospective study, GVHD
after DLI was defined as acute or chronic depending on the
typical clinical manifestations or the date of onset after DLI.
Patients and methods
This study was conducted by the Chronic Leukemia
Working Party of the EBMT. Centers report minimum
Outcome of GVHD after DLI after allo-BMT for CML
Y Chalandon et al
559
essential data (MED-A) to a central database for all
transplants performed. Many centers also report a more
comprehensive dataset (MED-B). Informed consent was
obtained locally according to the regulations applicable at
the time of transplant. Since 1 January 2003, the EBMT has
required centers to confirm that written informed consent
has been obtained before data acceptance. To complete the
data set, special DLI forms (MED-C) were sent to all
EBMT centers reporting patients who had received DLI for
CML relapse. Out of 138 EBMT centers with 1045 patients
receiving DLIs to treat CML in relapse, 31 participated in
this study (see appendix). A total of 344 DLI forms were
received and 328 patients had complete data for analysis.
Each participating center completed the questionnaire for
all consecutive patients eligible for the study in their
institution, whereas non-participating centers reported
none. This was audited against the EBMT database.
Definitions
DLI. Lymphocytes were collected from the donors by
leukapheresis on one or more occasions. Infusions had to
be given on multiple days at least 7 days apart to be
counted as separate infusions. Thirty-four (10%) patients
treated with DLI had active GVHD at the time of infusion
and 27 patients (8%) were still receiving some form of
immunosuppressive therapy. GVHD newly diagnosed after
DLI or progressing to higher grades after DLI was counted
as post-DLI GVHD. Thirty-one patients received concomitant imatinib therapy with DLI, of which 12 (39%)
developed GVHD after DLI.
Relapse. Relapse was classified as molecular (that is,
BCR-ABL transcripts detected by quantitative reverse
transcriptase PCR in two consecutive tests performed over
a minimum of 4 weeks), cytogenetic (that is, reappearance of
one or more Ph chromosome-positive metaphases at BM
cytogenetics) or hematologic (that is, presence of peripheral
blood leukocytosis accompanied by a hypercellular BM with
Ph chromosome on cytogenetic analysis) in accordance with
previous reports.10,12,13 The phase of CML was classified
in accordance with criteria proposed by the Center for
International Blood and Marrow Transplant Research
(CIBMTR).14
Outcomes
Acute and chronic GVHD occurring after DLI was
reported and graded according to the standard clinical
criteria (modified Glucksberg criteria for acute GVHD and
chronic GVHD as defined by Shulman et al.).15–17 Centers
reported GVHD as being acute or chronic according to the
initial clinical presentation. However, as clinically acute
and chronic GVHD occurring after DLI had overlapping
onset times, the impact of GVHD on outcome was also
analyzed by onset date from the first DLI. We defined early
onset GVHD as GVHD occurring within 45 days after DLI
(median onset time for acute GVHD) and late-onset
GVHD as GVHD occurring after 45 days from the first
DLI. Early and late GVHD did not correlate well with
clinical presentation of GVHD: 47% of clinically acute
GVHD had late onset and 20% of chronic GVHD after
DLI was reported to be of early onset.
Myelosuppression after DLI was defined as a cytopenia
(neutrophils o0.5 109/l or plts o20 109/l) unrelated to
disease or chemotherapy. Survival was calculated from the
date of the first infusion of donor lymphocytes until death
or last follow-up. (EFS was calculated from the date of the
first infusion of donor cells until the event or last followup). An event was defined as relapse after response, or, in
patients not responding, as progression to a more advanced
disease (for example, from cytogenetic relapse to hematological relapse or from chronic phase to accelerated phase).
The DLI-related mortality was calculated from the date of
the first infusion of donor cells until non-relapse death or
last follow-up evaluation. Patients were censored at the last
follow-up.
Statistical analysis
Cox regression models of GVHD and survival were run
entering covariates associated (P ¼ 0.1) with outcome in
univariate analysis. The following covariates were evaluated for their association with GVHD and survival after
DLI: donor type, sex of donor, sex mismatch with the
donor, phase at SCT, GVHD prophylaxis with T-cell
depletion for SCT, stem cell source, interval from SCT to
DLI, occurrence of GVHD after SCT, date of DLI, stage of
relapse at time of DLI, initial cell dose (ICD) and interval
from DLI to GVHD. The impact of GVHD on mortality
was assessed by a time-dependent Cox model18 entering
GVHD as a time-dependent covariate with all patients
being in the group without GVHD and entering into the
GVHD risk sets at the time of onset.
Survival was calculated using the Kaplan–Meier estimator.19 Estimates of GVHD, DLI-related mortality and
disease-related mortality were by cumulative incidence with
death from other causes defined as competing events.
Results
This study included 328 patients transplanted between 1983
and 2003 in 31 EBMT centers. They received DLI between
1991 and 2004 to treat CML relapse. None of the patients
had received imatinib before transplantation. Median
follow-up at the time of analysis of surviving patients was
50 months (range 4–167). Patient characteristics, the type of
transplant they had received, the type of relapse, acute and
chronic GVHD after transplantation, details of DLI,
timing of DLI with respect to the date of transplant,
number of DLI, T-cell dose received and the calendar year
the DLI was received are detailed in Table 1. Median time
from HSCT to first DLI was 578 days (range 67–4296).
A total of 122 patients (37%) developed GVHD at any
time after DLI. Acute grades II–IV GVHD was reported in
71 patients, of which 31 subsequently developed chronic
GVHD. De novo chronic GVHD of any severity (not
preceded by acute GVHD after DLI) was seen in 82
patients. The details of GVHD reported are specified in
Table 2. Of the 34 patients who had GVHD at the time of
DLI, 8 were still on immunosuppressive therapy and 16
developed progression of GVHD after DLI. Of the patients
who had extensive chronic GVHD at any time before DLI
Bone Marrow Transplantation
Outcome of GVHD after DLI after allo-BMT for CML
Y Chalandon et al
560
Table 1
Characteristics of patients receiving DLI for CML relapse
No.
Patient sex (m/f)
Median age in years
Year of transplant
Donor siblings/unrelated
BM/PB/missing
T-cell depletion—no/yes/unknown
Acute GVHD post-transplantation
Grade I
Grade II
Grade III
Grade IV
Chronic GVHD post-transplantation
Limited
Extensive
Unknown
328
179/149
37 (4–63)
1997 (1983–2003)
206/122
263/62/3
130/175/23
178
105
63
9
1
150
94
56
2
Interval transplant—DLI
o2 years
X2 years
202
126
Stage of disease at time of DLI
Molecular relapse
Cytogenetic relapse
Hematological relapse
Accelerated phase
Blastic phase
Unknown
75
98
102
22
21
10
No. of DLI
1
2
3
43
159
75
50
44
Year when DLI was given
1990–1997
1998–2004
109 (33%)
219 (67%)
Cell dose
41.0 107 CD3+ cells/kg
p1.0 107 CD3+ cells/kg
99 (30%)
229 (70%)
(48%)
(23%)
(15%)
(13%)
Abbreviations: DLI ¼ donor lymphocyte infusion; f ¼ female; m ¼ male.
(n ¼ 56), 37 developed GVHD after DLI, 29 of which were
chronic GVHD. We cannot differentiate between de novo
GVHD after DLI and reactivation of pre-existing GVHD.
GVHD after DLI was reported to occur at a median of 104
days (range 7–2341) after DLI (in 40 patients before day 45
and in 82 patients after day 45 from DLI). Acute GVHD
(aGVHD) was reported to occur at a median of 45 days
(range 11–599) after DLI (Table 2). In patients with aGVHD,
the median ICD was 1 107 CD3 þ cells/kg (range 0.01–32),
and 48% had received only one DLI dose (median 2, range
1–14). Acute GVHD treatment is described in Table 2;
aGVHD resolved in 53% of patients within a median of 63
days (range 7–546) after onset. Eighty-two patients (25%)
were reported to have chronic GVHD (cGVHD) (Table 2),
of which 31 (38%) followed an initial phase of aGVHD after
DLI. The median time of onset was 207 days (range 15–
2341). Similar to aGVHD, the median ICD for those with
cGVHD was 1 107 CD3 þ cells/kg (range 0.05–40), and
55% of patients received only one DLI dose. Sixty-one
patients are alive with a median follow-up of 50 months.
cGVHD resolved in 39% of patients within a median of 354
days (range 44–1588) from onset.
Bone Marrow Transplantation
The cumulative incidence of GVHD of any type at
5 years after DLI was 38% (95% confidence interval (CI)
32–43) (Figure 1a). In univariate analysis, GVHD was
more frequent in patients with a higher ICD (47% (95% CI
38–58) for 4107 CD3 þ cells/kg vs 34% (95% CI 28–41) for
o107 CD3 cells/kg, Po0.0001) (Figure 1b), if the donor
was unrelated vs related (48% (95% CI 40–58) vs 31%
(95% CI 25–38), P ¼ 0.009), if the interval between
transplant and DLI was o2 years vs longer (44% (95%
CI 38–52) vs 27% (95% CI 20–36), P ¼ 0.001) and if the
DLI was given before vs after 1998 (43% (95% CI 34–53)
vs 36% (95% CI 30–44), P ¼ 0.044). The number of DLIs
given was not analyzed as this is difficult to interpret taking
into account that GVHD occurring after the first or second
dose prevented the administration of additional doses. We
do not have information on the planned number of doses.
Hence, patients receiving 1–2 doses had a cumulative
incidence of GVHD of 42% (95% CI 36–49), whereas
patients receiving X3 doses had a cumulative incidence of
GVHD of 26% (95% CI 18–37). There was a significant
correlation between ICD and the number of doses received
as 11% of recipients of X3 doses but 38% of recipients of
1–2 doses had an ICD of 4107 CD3 þ cells/kg (Po0.0001).
The multivariate model of risk factors for GVHD after
DLI is shown in Table 3. The concomitant use of imatinib
was not associated with a significantly different risk of
GVHD after DLI. In the multivariate analysis of GVHD
risks, the relative risk (RR) was 1.18 (P ¼ 0.64). The 34
patients with pre-existing GVHD at the time of DLI did
not differ significantly from the patients without GVHD in
post-DLI GVHD risks and mortality.
In a multivariate analysis of mortality analyzing the
impact of GVHD onset in a time-dependent manner, there
was an increased risk of mortality with both early onset
(p45 days) GVHD (RR of death 2.78 (1.6–4.8)) and late
onset of GVHD (RR: 1.85 (1.04–3.3)) (Table 4). We tested
for differences between early and late GVHD by breaking
at the median onset time of all types of GVHD (that is, 104
days) and at the median onset time of aGVHD (45 days).
There was a small difference in outcome with a breakpoint
at 45 days, but there was none with a cutoff at 104 days.
When analyzing the impact of GVHD on survival by
clinical presentation, the initial presentation as acute
GVHD was associated with a higher mortality (RR: 2.25
(1.38–3.67)), but chronic GVHD without prior acute
GVHD after DLI was not (RR: 1.1 (0.62-1.94)) (Table 4).
Other covariates in the model were disease stage at the time
of DLI, and time interval from transplantation to DLI
(o vs 42 years after transplantation).
The 5-year OS after DLI was 69% (95% CI 63-75) for all
patients (Figure 2). EFS after DLI for the entire group was
63% (95% CI 57–69). DLI-related mortality was 11%
(95% CI 8–15) for all patients and disease-related mortality
was 20% (95% CI 16–25).
Discussion
This study describes the characteristics of GVHD occurring
after DLI for CML relapse in patients from the EBMT
registry. This study confirms previous analyses that showed
Outcome of GVHD after DLI after allo-BMT for CML
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561
Table 2
Characteristics of GVHD after DLI
No. with aGVHD
Median time after DLI
111 (34%)
45 days (range 11–599)
Max grade
I
II
III
IV
Grade II–IV (exact grade unknown)
Organs involved (%)
Skin
Liver
Gut
40
30
31
6
4
No. with cGVHD
Median time after DLI
Max grade
Limited
Extensive
Not specified
(36%)
(27%)
(28%)
(5%)
(3%)
92%
52%
2%
19%
1.0 107 (0.01–32) CD3+ cells/kg
Median initial cell dose
No. of DLI
1
41
Treatment
Steroids
CsA
MMF
Thalidomide
Photopheresis
PUVA
Other
Median initial cell dose
Abbreviations: aGVHD ¼ acute GVHD; ATG ¼ antithymocyte globulin; cGVHD ¼ chronic
MAB ¼ monoclonal antibody; MMF ¼ mycophenolate mofetil; PUVA ¼ photochemotherapy.
Cumulative incidence
of GvHD
Cumulative incidence
of GvHD
1.0
0.6
0.4
0.2
0.0
0.0
365.0 730.0 1095.0 1460.0 1825.0
Days post-DLI
75
43
35
22
13
5
83%
52%
20%
15%
15%
10%
17%
7
1.0 10 (0.05–40) CD3+ cells/kg
No. of DLI
1
41
64 (57%)
49 (43%)
0.8
30 (37%)
50 (61%)
2 ( 2%)
Organs involved (%)
Skin
Mouth
Liver
Eyes
Lungs
Gut
88
42
30
Treatment
Steroids
CsA
ATG and MAB
Other
82(25%) 31 from aGvHD
207 days (range 25–1176)
45 (55%)
37 (45%)
GVHD;
DLI ¼ donor
1.0
P<0.0001
0.8
Initial cell dose
> 107
<= 107
0.6
lymphocyte
infusion;
0.4
0.2
0.0
0.0
365.0 730.0 1095.0 1460.0 1825.0
Days post-DLI
Figure 1 Cumulative incidence of GVHD after donor lymphocyte infusion (DLI). (a) 5-year cumulative incidence of 38% (95 confidence interval (CI)
33–43%). (b) 5-year cumulative incidence for higher initial cell dose (4107 CD3 þ cells/kg) of 47 % (95% CI 38–58 %) vs 34% (95% CI 28–41%) for lower
cell dose (o107 CD3 þ cells/kg), Po0.0001.
that GVHD presenting as acute (grade II–IV) and/or
chronic GVHD is seen in 38% of patients after DLI, that
the incidence of GVHD has decreased since 1998, that there
is more GVHD with unrelated donors and with higher
initial T-cell doses and with DLI given within 2 years after
transplantation.
GVHD after DLI is associated with a 2.3-fold increased
mortality and early onset GVHD is slightly worse than
GVHD of later onset after first DLI. Mortality is mainly
seen with presentation as acute GVHD but not with
presentation as purely cGVHD without prior aGVHD.
It is noted that the correlation between the GVHD onset
date and the clinical presentation as acute or chronic
GVHD is not very high. A significant percentage of GVHD
reported clinically as acute had a late onset date and,
similarly, an important proportion of GVHD reported as
chronic was of early onset. This reflects the confusion
between the definitions based on onset date and definitions
based on clinical presentation. GVHD after DLI may be
somewhat different from GVHD arising de novo after SCT.
For instance, the time of onset of GVHD may be later after
DLI. The median time to onset of acute GVHD after DLI
Bone Marrow Transplantation
Outcome of GVHD after DLI after allo-BMT for CML
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Table 3
Multivariate analysis of risk factors for GVHD after DLI
Parameters
HR
Lower 95% CI
Higher 95% CI
P-value
Time from BMT to DLI 42 years (better)
0.50
0.34
0.77
0.001
Initial cell dose
p106
4106 and o107
4107 CD3+ cells/kg (worse)
Type of donor (unrelated donor worse)
Date of DLI after 1998 (tendency to be better)
1
0.81
2.66
1.97
0.74
0.49
1.73
1.31
0.5
1.32
4.09
2.97
1.09
0.39
0.0001
0.001
0.12
Abbreviations: CI ¼ confidence interval; DLI ¼ donor lymphocyte infusion; HR ¼ hazards ratio.
No significant interaction terms between cell doses and year when DLI was given.
Table 4
Time-dependent covariate Cox regression model of
survival after DLI
Parameters
HR
95% CI
P-value
No. GVHD
GVHD overall effect
1
2.27
1.5–3.6
0.0001
Acute GVHD
Chronic GVHDa
2.25
1.10
1.4–3.7
0.6–1.9
0.001
0.75
GVHD within 45 daysb
GVHD after 45 days
2.78
1.85
1.6–4.8
1.0–3.3
0.001
0.013
Other covariates
Stage of disease at DLI
Molecular relapse
Cytogenetic relapse
Hematological relapse
Accelerated phase
Blast crisis
1
1.1
2.33
10.94
35.43
0.5–2.5
1.1–4.9
4.9–24.7
15.2–82.4
Time from BMT to DLI
o2 years
42 years
1
0.69
0.4–1.1
0.8
0.6
OS
69±6%
0.4
0.0001
0.2
0.0
0
1
in our study was 45 days compared with 16–20 days after
myeloablative T-replete HSCT.20,21 It is possible that both
the pace and severity of GVHD are influenced by the use of
intensive conditioning, the tissue damage, and inflammatory cytokines present after conventional SCT but not after
DLI.22 The target organs of acute GVHD after DLI seem
the same as those seen after HSCT, but the clinical
manifestations may differ. In one study, for example, a
hepatitic variant of liver GVHD characterized by marked
elevations of serum aminotransferase levels more than 10
times the upper limit of normal was observed in 15% of the
patients who received DLIs.23 Signs of both acute and
chronic GVHD may develop simultaneously after DLI.24
The risk factors for GVHD found in this study are
similar to studies reported earlier.6,8,10,25,26 Unrelated
donors and higher ICD were associated with a higher risk.
Patients receiving X3 doses had less GVHD than patients
receiving only 1–2 doses. This was also described in the
study of Raiola et al.26 in a patient population with CML
and other hematological malignancies, but in that study the
cutoff was 4 doses. This association is impossible to study
2
3
4
5
Years
0.12
Abbreviations: CI ¼ confidence interval; DLI ¼ donor lymphocyte infusion; HR ¼ hazards ratio.
a
chronic GVHD without prior acute GVHD.
b
GVHD irrespective of clinical presentation.
Bone Marrow Transplantation
1.0
Figure 2 5-year OS after donor lymphocyte infusion of 69% (95%
confidence interval 63–75%).
in an observational study as patients developing GVHD
after a first or second dose do not usually receive additional
doses. In addition, patients who do not develop GVHD
after 1–2 doses are probably less prone to develop GVHD
even if they received further DLI. In this sense, escalating
doses of DLI could select patients who are capable of
receiving (or indeed require) higher doses of T cells. GVHD
was less frequent in patients transplanted after 1998
because in more recent years the bulk dose regimens used
in the early 1990s were abandoned for incremental dose
regimens.11,12 DLIs given 42 years after transplantation
were associated with less GVHD than DLIs given within 2
years of SCT. It has been shown in animal models27,28 and
in several studies that the further away DLIs are given from
the original transplant date, the lesser GVHD is developed,3,4,29,30 although this remains controversial.13,31 This
may be due to some form of tolerance induced by the
previous transplant, the mechanisms of which remain to be
elucidated.
As post-DLI GVHD and mortality risks did not differ in
our study in patients with and without GVHD at the time
of DLI, we must assume that the GVHD present at the time
Outcome of GVHD after DLI after allo-BMT for CML
Y Chalandon et al
563
of DLI was either very mild or possibly misdiagnosed
(subsided or non-active) in those 34 patients. It is noted
that only 10 of the 34 patients had been reported with
extensive chronic GVHD before DLI. GVHD after DLI
may be de novo, but in patients who had had prior GVHD
after the transplant this may be considered as a reactivation
of pre-existing GVHD. We do not know whether this
distinction is of importance and suggest that this issue
requires further study. The concomitant use of imatinib
was not associated with an increased risk of GVHD after
DLI. However, the number of patients receiving imatinib
was low and the power to detect a difference was therefore
very limited.
This study has several limitations. It is retrospective,
multicentric and spans the period from 1991–2004. The
328 patients studied are a sample of 1045 patients in the
EBMT database treated by DLI for relapse. A comparison
of baseline characteristics and outcome with patients
not considered for this study does not show major
differences. The median follow-up was 50 months, which
is relatively short as late events in patients with cGVHD
may develop after many years. Survival is not the only issue
with GVHD as this disease greatly affects the quality of life.
Unfortunately, we lack data on the quality of life in
affected patients.
Given the above, we suggest reporting GVHD after DLI
by clinical manifestation, for example, as acute or chronic
according to clinical presentation but to factor in the onset
time ( þ / 45 days from the first DLI) as a separator
between these two entities.
In conclusion, this study shows that GVHD is a frequent
complication of DLI and is associated with adverse
outcome after DLI. Risk factors for GVHD include
donor–recipient relationship and initial DLI dose as
already shown in previous studies.11–13 Strategies to avoid
GVHD after DLI should be favored.
Conflict of interest
5
6
7
8
9
10
11
12
13
14
The author declares no conflict of interest.
15
References
1 Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G,
Brehm G et al. Donor leukocyte transfusions for treatment of
recurrent chronic myelogenous leukemia in marrow transplant
patients. Blood 1990; 76: 2462–2465.
2 Cullis JO, Jiang YZ, Schwarer AP, Hughes TP, Barrett AJ,
Goldman JM. Donor leukocyte infusions for chronic myeloid
leukemia in relapse after allogeneic bone marrow transplantation. Blood 1992; 79: 1379–1381.
3 Drobyski WR, Keever CA, Roth MS, Koethe S, Hanson G,
McFadden P et al. Salvage immunotherapy using donor
leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: efficacy and toxicity of a defined T-cell dose. Blood 1993;
82: 2310–2318.
4 Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B,
Jacobsen N, Arcese W et al. Graft-versus-leukemia effect of
donor lymphocyte transfusions in marrow grafted patients.
16
17
18
19
20
European Group for Blood and Marrow Transplantation
Working Party Chronic Leukemia. Blood 1995; 86: 2041–2050.
Bar BM, Schattenberg A, Mensink EJ, Geurts vK, Smetsers
TF, Knops GH et al. Donor leukocyte infusions for chronic
myeloid leukemia relapsed after allogeneic bone marrow
transplantation. J Clin Oncol 1993; 11: 513–519.
Collins Jr RH, Shpilberg O, Drobyski WR, Porter DL, Giralt
S, Champlin R et al. Donor leukocyte infusions in 140 patients
with relapsed malignancy after allogeneic bone marrow
transplantation. J Clin Oncol. 1997; 15: 433–444.
van Rhee F, Lin F, Cullis JO, Spencer A, Cross NC, Chase A
et al. Relapse of chronic myeloid leukemia after allogeneic
bone marrow transplant: the case for giving donor leukocyte
transfusions before the onset of hematologic relapse. Blood
1994; 83: 3377–3383.
Porter DL, Collins Jr RH, Shpilberg O, Drobyski WR,
Connors JM, Sproles A et al. Long-term follow-up of patients
who achieved complete remission after donor leukocyte
infusions. Biol Blood Marrow Transplant 1999; 5: 253–261.
Champlin R, Khouri I, Kornblau S, Marini F, Anderlini P,
Ueno NT et al. Allogeneic hematopoietic transplantation as
adoptive immunotherapy. Induction of graft-versus-malignancy as primary therapy. Hematol Oncol Clin North Am
1999; 13: 1041–1057.
Dazzi F, Szydlo RM, Goldman JM. Donor lymphocyte
infusions for relapse of chronic myeloid leukemia after
allogeneic stem cell transplant: where we now stand. Exp
Hematol 1999; 27: 1477–1486.
Mackinnon S, Papadopoulos EB, Carabasi MH, Reich L,
Collins NH, Boulad F et al. Adoptive immunotherapy
evaluating escalating doses of donor leukocytes for relapse of
chronic myeloid leukemia after bone marrow transplantation:
separation of graft-versus-leukemia responses from graftversus-host disease. Blood 1995; 86: 1261–1268.
Dazzi F, Szydlo RM, Craddock C, Cross NC, Kaeda J,
Chase A et al. Comparison of single-dose and escalating-dose
regimens of donor lymphocyte infusion for relapse after
allografting for chronic myeloid leukemia. Blood 2000; 95:
67–71.
Guglielmi C, Arcese W, Dazzi F, Brand R, Bunjes D,
Verdonck LF et al. Donor lymphocyte infusion for relapsed
chronic myelogenous leukemia: prognostic relevance of the
initial cell dose. Blood 2002; 100: 397–405.
Speck B, Bortin MM, Champlin R, Goldman JM, Herzig RH,
McGlave PB et al. Allogeneic bone-marrow transplantation
for chronic myelogenous leukaemia. Lancet 1984; 1: 665–668.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE,
Clift RA et al. Clinical manifestations of graft-versus-host
disease in human recipients of marrow from HLA-matched
sibling donors. Transplantation 1974; 18: 295–304.
Shulman HM, Sale GE, Lerner KG, Barker EA, Weiden PL,
Sullivan K et al. Chronic cutaneous graft-versus-host disease in
man. Am J Pathol 1978; 91: 545–570.
Shulman HM, Sullivan KM, Weiden PL, McDonald GB,
Striker GE, Sale GE et al. Chronic graft-versus-host syndrome
in man. A long-term clinicopathologic study of 20 Seattle
patients. Am J Med 1980; 69: 204–217.
Iacobelli S, Apperley J, Morris C. Assessment of the role of
timing of second transplantation in multiple myeloma by
multistate modeling. Exp Hematol 2008; 36: 1567–1571.
Kaplan EL, Meier O. Nonparametric estimation from
incomplete observations. J Am Stat Assoc 1958; 53: 457–481.
Nash RA, Pepe MS, Storb R, Longton G, Pettinger M,
Anasetti C et al. Acute graft-versus-host disease: analysis of
risk factors after allogeneic marrow transplantation and
prophylaxis with cyclosporine and methotrexate. Blood 1992;
80: 1838–1845.
Bone Marrow Transplantation
Outcome of GVHD after DLI after allo-BMT for CML
Y Chalandon et al
564
21 Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM,
Klein JL, Weisdorf D et al. Phase III study comparing
methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation.
Blood 1998; 92: 2303–2314.
22 Antin JH, Ferrara JL. Cytokine dysregulation and acute graftversus-host disease. Blood 1992; 80: 2964–2968.
23 Akpek G, Boitnott JK, Lee LA, Hallick JP, Torbenson M,
Jacobsohn DA et al. Hepatitic variant of graft-versus-host disease
after donor lymphocyte infusion. Blood 2002; 100: 3903–3907.
24 Alyea EP, Soiffer RJ, Canning C, Neuberg D, Schlossman R,
Pickett C et al. Toxicity and efficacy of defined doses
of CD4(+) donor lymphocytes for treatment of relapse
after allogeneic bone marrow transplant 55. Blood 1998; 91:
3671–3680.
25 Gale RP, Bortin MM, van Bekkum DW, Biggs JC, Dicke KA,
Gluckman E et al. Risk factors for acute graft-versus-host
disease. Br J Haematol 1987; 67: 397–406.
26 Raiola AM, Van Lint MT, Valbonesi M, Lamparelli T,
Gualandi F, Occhini D et al. Factors predicting response and
graft-versus-host disease after donor lymphocyte infusions: a
study on 593 infusions. Bone Marrow Transplant 2003; 31:
687–693.
27 Johnson BD, Truitt RL. Delayed infusion of immunocompetent donor cells after bone marrow transplantation breaks
graft-host tolerance allows for persistent antileukemic reactivity without severe graft-versus-host disease. Blood 1995; 85:
3302–3312.
28 Kolb HJ, Gunther W, Schumm M, Holler E, Wilmanns W,
Thierfelder S. Adoptive immunotherapy in canine chimeras.
Transplantation 1997; 63: 430–436.
29 Sullivan KM, Storb R, Buckner CD, Fefer A, Fisher L,
Weiden PL et al. Graft-versus-host disease as adoptive
immunotherapy in patients with advanced hematologic neoplasms. N Engl J Med 1989; 320: 828–834.
30 Mackinnon S, Papadopoulos EB, Carabasi MH, Reich L,
Collins NH, O’Reilly RJ. Adoptive immunotherapy using
donor leukocytes following bone marrow transplantation for
chronic myeloid leukemia: is T cell dose important in
determining biological response? Bone Marrow Transplant
1995; 15: 591–594.
Bone Marrow Transplantation
31 Huff CA, Fuchs EJ, Smith BD, Blackford A, Garrett-Mayer
E, Brodsky RA et al. Graft-versus-host reactions and the
effectiveness of donor lymphocyte infusions. Biol Blood
Marrow Transplant 2006; 12: 414–421.
Appendix 1
EBMT centers (center number)
E Olavarria, Hammersmith Hospital, London, UK (205)
A Schattenberg, University Medical Centre St Radboud, Nijmegen,
The Netherlands (237)
P Jacobs, Constantiaberg Med-Clin, Cape Town, South Africa (772)
P Ljungman, Huddinge University Hospital, Huddinge, Sweden (212)
J Finke, University Hospital Freiburg, Freiburg, Germany (810)
S Lenhoff, University Hospital, Lund, Sweden (283)
L Volin, Helsinki University Central Hospital, Helsinki, Finland (515)
N Jacobsen, Rigshospitalet, Copenhagen, Denmark (206)
J Passweg, Hopital Cantonal Universitaire, Geneva, Switzerland (261)
JP Jouet, Hopital Claude Huriez, Lille, France (277)
CA de Souza, Univ. Est. de Campinas/TMO/UNICAMP, Campinas
SP, Brazil (374)
M. Michallet, Hopital E Herriot, Lyon, France (671)
A Ferrant, Cliniques Universitaires St Luc, Brussels, Belgium (234)
JL Harousseau, Hotel Dieu, Nantes, France (253)
D Milligan, Birmingham Heartlands Hospital, Birmingham, UK (284)
E Liakopoulou, Christie NHS Trust Hospital, Manchester, United
Kingdom (780)
D Bron, Institut Jules Bordet, Brussels, Belgium (215)
R Hamladji, Centre Pierre et Marie Curie, Alger, Algeria (703)
V Koza, Charles University Hospital, Pilsen, Czech Republic (718)
B Bandini, Hospital San Orsola, Bologna, Italy (240)
V Leblond, Pitie-Salpetriere, Paris, France (262)
R Haas, Heinrich Heine Universität, Düsseldorf,Germany (390)
Y Beguin, University of Liege, Liege, Belgium (726)
G Mufti, GKT School of Medicine London, United Kingdom (763)
M Bornhäuser, Universitätsklinikum Dresden, Dresden, Germany (808)
M Boogaerts, University Hospital of Leuven, Leuven, Belgium (209)
JM Davies, Western General Hospital, Edinburgh, Scotland, UK (228)
J Sierra, Hospital Santa Creu I Sant Pau, Barcelona, Spain (260)
U Pihkala, University of Helsinki, Hospital for Children & Adolescents, Helsinki, Finland (219)
A Zander, University Hospital Eppendorf, Hamburg, Germany (614)
J Pretnar, University Medical Center, Ljubljana, Slovenia (640)