Bone Marrow Transplantation (2005) 35, 601–608
& 2005 Nature Publishing Group All rights reserved 0268-3369/05 $30.00
www.nature.com/bmt
Outcome and long-term follow-up of alloreactive donor lymphocyte
infusions given for relapse after myeloablative allogeneic hematopoietic
stem cell transplantations (HSCT)
AS Michallet1, F Nicolini1, S Fürst1, QH Le1, V Dubois2, S Hayette3, JP Bourgeot4, JP Tremisi4,
X Thomas1, L Gebuhrer2 and M Michallet1
1
Service d’Hématologie Clinique, Hôpital Edouard Herriot, Lyon cedex, France; 2Laboratoire d’histocompatibilité, Etablissement
Franc¸ais du Sang, Lyon, France; 3Laboratoire d’Hématologie, Hôpital Edouard Herriot, Lyon cedex, France; and 4Banque de cellules
et de tissus, Etablissement Franc¸ais du Sang, Hôpital Edouard Herriot, Lyon cedex, France
Summary:
In order to study efficacy, toxicity and the long-term
results of donor lymphocyte infusions (DLI), we retrospectively analyzed DLI given for relapse after conventional allogeneic hematopoietic stem cell transplantation
(HSCT) in 30 patients with a median delay of 107.5
months after transplant and 58 months after DLI. After
DLI, 15 patients established full donor chimerism, three
patients developed grade III and one grade IV acute
GVHD. A total of 15 patients achieved a disease response.
Among the 14 patients with chronic myeloid leukemia
(CML), 11 are alive at the last follow-up: five are in
complete molecular response (CMR) and two in complete
cytogenetic response (CCR) with no other intervention
after DLI, three in CMR after imatinib mesylate given
after DLI and one in complete hematological response
after imatinib mesylate and reduced-intensity conditioning
allogeneic SCT performed after DLI. At the time of the
last follow-up, 19 (63%) patients died and 11 (37%)
remain alive. The 3-year probability of survival for the
entire population, CML patients and non-CML patients,
was 60, 93, 62% after transplantation, and 48, 80 and
48% after DLI, respectively. A multivariate analysis
demonstrated a significantly worse survival rate after
transplantation for female recipients, advanced disease
and acute leukemia before transplantation.
Bone Marrow Transplantation (2005) 35, 601–608.
doi:10.1038/sj.bmt.1704807
Published online 31 January 2005
Keywords: DLI; long-term outcome; CML; GVHD
Relapses of hematological malignancies continue to be one
of the main causes of failure after allogeneic hematopoietic
stem cell transplantation (HSCT). A number of approaches
to treat patients who have relapsed after HSCT could be
considered: chemotherapy whether or not followed by
donor lymphocyte infusion (DLI),1 a second allotransplantation2 and in chronic myeloid leukemia (CML) administration of interferon a,3 DLI,4 imatinib mesylate5 or both.
Alloreactive donor lymphocytes could mediate antitumor
effects called graft-versus-tumor (GVT) or graft-versusleukemia (GVL) effects.6 This antitumor effect has been
well established in CML patients relapsing after allogeneic
HSCT7 and numerous studies have subsequently confirmed
that DLI can induce complete cytogenetic and even
molecular remissions.8–9 DLI have also been used for other
malignant diseases relapsing after allogeneic HSCT but
with less success.10–12 Besides their benefit, DLI can induce
severe and sometimes life-threatening complications such
as acute and chronic graft-versus-host disease (GVHD) or
pancytopenia.13–14 These complications were seen mainly in
DLI using bulk-dose (BD) regimens most frequently and
containing a high number of CD3 þ T cells.15 Two
approaches have been introduced to reduce DLI complication incidence: one based on CD8 þ lymphocyte selective
depletion16 and the other based on initial infusion of low
numbers of T cells followed by escalating increased doses at
variable intervals (escalating dose (ED) regimen).15 Moreover, to develop DLI in the treatment of relapse after
HSCT, another important question was the DLI response
durability.17–18 The long-term efficacy and toxicity of such a
procedure have not been well documented so far. Nevertheless Dazzi et al19 showed a correlation between longterm survival and molecular remission achievement after
DLI. The principal aim of our study was to analyze the
long-term outcome after DLI given for relapse of
hematological malignancies after conventional HSCT from
sibling and unrelated donors.
Patients and methods
Correspondence: Dr A-S Michallet, Service d’Hématologie Clinique
Adultes, Hôpital Edouard Herriot, 5 Place d’Arsonval, 69347 Lyon
cedex 03, France; E-mail: [email protected]
Received 22 April 2004; accepted 25 September 2004
Published online 31 January 2005
Patient characteristics and transplant procedures
In all, 19 male and 11 female patients were studied
(total ¼ 30). The median age was 34 years (range 17–47).
The conditioning regimens were either cyclophosphamide
Long-term follow-up after DLI given for relapse after myeloablative allogeneic HSCT
AS Michallet et al
602
(60 mg/kg/day 2 days) and total body irradiation (TBI) of
12 Gy or cyclophosphamide (50 mg/kg/day 4 days) and
busulfan (4 mg/kg/day 4 days). A total of 27 patients
underwent allogeneic transplants from HLA-identical
sibling donors, two from unrelated fully HLA-identical
donors and one from a one-antigen-mismatched unrelated
donor. The diagnoses before transplantation were 14
chronic myeloid leukemias, nine acute myelogenous leukemias (AML), four acute lymphoblastic leukemias (ALL),
one non-Hodgkin lymphoma (NHL), one myelodysplasia
(MDS) and one multiple myeloma (MM). DLI were used
for hematological relapse in 26 patients (11 CML, three
ALL, nine AML, one MDS, one NHL and one MM)
(87%), central nervous system relapse in one patient (ALL)
and cytogenetic relapse in three patients (CML). The
median delay between allotransplantation and relapse was
24 months (range, 0.3–113). A total of 27 patients received
one transplant and three patients (one ALL, two CML)
two transplants. All patients received unmanipulated bone
marrow as HSC source. Initial GVHD prophylaxis
consisted of intravenous cyclosporine A (CsA) and
methotrexate (days 1, 3 and 6).
DLI regimen
Lymphocytes were harvested from 27 HLA sibling donors
and from three unrelated donors without previous growth
factor administration. In our unit, the 27 sibling donors
were harvested and lymphocytes were further fractionated
(as far as possible) in order to cryopreserve doses of 1 106,
5 106, 1 107, 5 107 CD3 þ cells/kg in 22 cases. We
discontinue immunosuppression almost 2 weeks prior to
DLI administration. The median interval between relapse
and lymphocyte infusion was 1.9 months (range, 0–52). In
all, 10 patients received a single dose that varied from 0.1 to
2.64 108 CD3/kg and among them five patients received a
BD (three 1 108 CD3/kg; one 2.53 108 CD3/kg and one
2.64 108 CD3/kg). Knowledge of the relation between
complications and BD led us to change our DLI strategy by
giving ED and the 20 patients followed received ED
varying from 0.01 to 3 108 CD3/kg. All AML patients
have received intensive chemotherapy including high dose
of cytosine arabinoside, the four ALL patients an association of mitoxantrone and cytosine arabinoside and the
NHL patient an association of etoposide, daunorubicine,
cytosine arabinoside and methyl-prednisolone. No durable
CR or PR was observed. The interval between chemotherapy and DLI was at least 2 months. MDS, MM and
CML patients received DLI without any chemotherapy
previously.
Evaluation of disease response and chimerism after DLI
After DLI, clinical, hematological, cytogenetic and molecular responses were assessed as well as chimerism.
Chimerism was initially determined using polymerase chain
reaction of a variable number of tandem repeat (VNTR)
sequences. Peripheral blood and bone marrow aspirates
were analyzed. After extraction, DNA was amplified with
specific primers located in flanking regions of VNTRs.
After electrophoresis, PCR products were analyzed on a
Bone Marrow Transplantation
colored gel (Sybr Green, fabriquant, localisation) under
UV light. A semiquantitative study was conducted for each
donor/recipient pair and each informative VNTR. Mixed
chimerism was defined as the presence of at least 5%
recipient cells. From 1999 to 2003, chimerism analysis was
performed with the short tandem repeat method (STRs)
with promega multiplex kits (CTTV, FFFL and gamma
STR, fabriquant, localisation) based on fluorescent analysis
of repetitive sequences. After amplification with specific
primers, PCR products were analyzed on ABI 310
(Applera). Profiles obtained for each informative system
were screened through the genescan program in comparison with the memorized profile from donor and recipient
analyzed before transplantation. Peak areas gave us the
percentage of recipient cells for each sample.20 Mixed
chimerism (MC) was also defined by the presence of at least
5% recipient cells. For CML, cytogenetic responses were
evaluated by conventional karyotyping analysis (R Banding) and molecular responses by BCR-ABL transcript
detection using a quantitative RT-PCR method.
Statistical analysis
In the framework of survival analysis, Kaplan–Meier
estimates were used to estimate overall survival after
transplant and after DLI. For multivariate analysis, the
Cox proportional hazards model was used. The multivariate analysis considered before DLI: age, sex, disease
status at transplantation (CR vs PR vs refractory disease or
relapse), type of disease (all diseases vs CML), conditioning
(TBI or no TBI) and after DLI: acute GVHD and chronic
GVHD, chimerism status (full donor chimerism (FDC) vs
MC) and disease response. Outcome measure was overall
survival.
Results
The median interval between transplantation and relapse,
transplantation and DLI, and relapse and DLI were 24, 28
and 1.9 months, respectively. The median follow-up was
107.5 months (range, 69–84) after transplantation and 58
months (range, 29–36) after DLI.
GVHD
Four patients developed acute GVHD: three grade III, one
after a single dose and two after ED and one grade IV after
BD. Three of these patients had FDC and only one MC.
Two cases of grade III acute GVHD developed extensive
chronic GVHD (cGVHD). One patient developed de novo
limited cGVHD after ED. Acute and chronic GVHD
incidence and severity after DLI are shown in Table 1.
Chimerism study
A total of 27 patients (90%) presented MC before DLI and
15 (55%) (one NHL, two ALL, two AML, 10 CML)
established FDC after DLI. To establish FDC, we infused
two doses, three BD and 10 ED. The median number of
DLI patients to obtain chimerism conversion was two
Long-term follow-up after DLI given for relapse after myeloablative allogeneic HSCT
AS Michallet et al
603
Table 1
GVHD and chimerism after DLI
AML ¼ acute myeloid leukemia; ALL ¼ acute lymphoblastic leukemia; CML ¼ chronic myelogenous leukemia; CP ¼ chronic phase; NHL ¼ non-Hodgkin
lymphoma; MDS ¼ myelodysplasia; MM ¼ multiple myeloma; FDC ¼ full donor chimerism; MC ¼ mixed chimerism; No C ¼ no chimerism;
CMR ¼ complete molecular response; CCR ¼ complete cytogenetic remission; CP ¼ chronic phase; CHR ¼ complete hematological remission;
CR ¼ complete remission; PR ¼ partial remission; D ¼ disease; SCT ¼ stem cell transplantation; NE ¼ nonevaluable. Chimerism analysis was performed
on bone marrow or whole blood, in some cases on CD3+ cells denoted by*. In gray, patients who converted to FDC. Diseases responses at last follow-up
for patients number: 16, 17, 23, 24, 25 and 26 were obtained after DLI followed by no other therapy (cf table 3). AGVHD: acute GVHD, cGVHD: chronic
GVHD. Ext ¼ extensive; Lim ¼ limited.
(range, 1–5) after a median interval of 3.5 months (0.25–
13). At last follow-up, among the 11 long-term survivors,
10 remained in FDC and only one was in MC (patient 16,
29% recipient cells). Chimerism data are shown in Table 2
and chimerism progression after DLI in Figures 1 and 2.
Disease response after DLI
After DLI, among 30 patients, 15 (50%) achieved a disease
response. Of these 15 DLI responders, 13 showed FDC and
two persistent MC. Of 14 CML patients, two (14%) (1/3
cytogenetic relapse and 1/11 hematological relapse)
achieved a complete hematological response (CHR), nine
(64%) (2/3 cytogenetic relapse and 7/11 hematological
relapse) achieved a complete cytogenetic response (CCR)
and 5/9 achieved a complete molecular remission (CMR)
(2/3 cytogenetic relapse and 3/11 hematological relapse)
and three remained in chronic phase (CP). Among acute
leukemia patients, 3/13 (23%) achieved complete remission
(CR) and one partial remission (PR), and the NHL patient
presented CR. The median number of DLI patients to
obtain these responses was two (range, 1–5), with a median
interval between two DLI of 1.5 months. Of the 11 CML
responders with a median follow-up of 58 months (range,
29–96) after DLI, one of the two reaching CHR achieved
CCR and the other relapsed in CP and achieved a CMR
after imatinib mesylate. Of the nine who reached CCR, five
have achieved CMR and one remained in CCR after DLI
without any other intervention, three relapsed in CP (one
achieved CMR after imatinib mesylate, one CHR after
IFN þ imatinib mesylate and reduced-intensity allogeneic
stem cell transplantation and one remained in CP despite a
second myeloablative allotransplantation) (Figure 3).
Among the three patients remaining in CP after DLI, only
one patient achieved CMR after imatinib mesylate. Among
the three acute leukemia patients who responded after DLI,
one patient remained in CR and the NHL patient relapsed.
Disease responses after DLI and chimerism before and
after DLI are shown in Table 2.
Survival after DLI
Of the 30 patients, 19 (63%) died and 11 (37%) are alive,
with a median follow-up of 107.5 months (range, 69–184)
after allotransplantation and 58 months after DLI (range,
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Long-term follow-up after DLI given for relapse after myeloablative allogeneic HSCT
AS Michallet et al
604
Table 2
Chimerism and disease response after DLI
AML ¼ acute myeloid leukaemia; ALL ¼ acute lymphoblastic leukaemia; CML ¼ chronic myelogenous leukaemia; CP ¼ chronic phase; NHL ¼ nonHodgkin lymphoma; MDS ¼ myelodysplasia; MM ¼ multiple myeloma; FDC ¼ full donor chimerism; MC ¼ mixed chimerism, No C ¼ no chimerism;
CMR ¼ complete molecular response; CCR ¼ complete cytogenetic remission; CP ¼ chronic phase; CHR ¼ complete hematological remission;
CR ¼ complete remission; PR ¼ partial remission; D ¼ disease; SCT ¼ stem cell transplantation; NE ¼ nonevaluable. Chimerism analysis was performed
on bone marrow or whole blood, in some cases on CD3+ cells denoted by*. In gray, patients who converted to FDC. Diseases responses at last follow-up
for patients number: 16, 17, 23, 24, 25 and 26 were obtained after DLI followed by no other therapy (cf Table 3).
29–96). Among the 14 CML patients, 11 (78%) are alive at
the last follow-up: five are in CMR and two in CCR with
no other intervention after DLI, three in CMR after
imatinib mesylate and one in CHR after imatinib mesylate
and allogeneic HSCT after reduced-intensity conditioning
(RICT). The 3-year probability of survival for the entire
population after transplantation was 60% (95% CI (45–
80%)) and 48% (95% CI (30–60%) after DLI (Figure 4a
and b). When considering only CML patients, the overall
survival was better with a 3-year probability of survival of
93% (95% CI (79–100%)) after allotransplantation and
80% (95% CI (60–100%) after DLI. Among the 11 CML
survivors at last follow-up, eight were in CMR. When we
considered patients with other diseases than CML, the 3year probability of survival after transplantation was 62%
(95% CI (44.4–79.7)) and 48% (95% CI (30.1–66.5)) after
DLI. In the entire population, multivariate analysis
demonstrated a significantly worse survival rate after
transplantation for female recipients (HR ¼ 5.50 (95% CI
1.05–28.85)) (P ¼ 0.04), patients with advanced disease
(HR ¼ 6.85 (95% CI 1.99–23.50)) (Po0.01) and patients
with other diseases than CML (HR ¼ 3.84 (95% CI, 1.12–
13.3)) (Po0.01).
Bone Marrow Transplantation
Discussion
Allogeneic HSCT was the only curative approach for some
hematological malignancies but relapse remained a problem and a challenging situation that is still controversial
when considering treatment. To improve the outcome of
patients who relapsed after allogeneic HSCT, many
therapeutic options were explored such as a second
transplant,2 immunotherapy,21–22 growth factors,23–25
DLI, imatinib mesylate26 and finally monoclonal antibodies.27–28 Many authors have shown that DLI have been
used effectively to induce the GVT29–30 effect in patients
who relapsed after allogeneic HSCT. It was demonstrated
that response to DLI is closely related either to the disease
status or the kind of relapse before DLI.31 This alloreactive
strategy provided responses at the cytogenetic or molecular
level correlated with a total donor chimerism conversion.
These benefits were at the price of complications such as
GVHD and pancytopenia.13 Two types of DLI were
explored, including either single BD or ED given at
variable intervals. DLI toxicity without GVL effect
reduction15 was observed after ED and in addition,
Guglielmi et al32 demonstrated the impact of initial cell
Long-term follow-up after DLI given for relapse after myeloablative allogeneic HSCT
AS Michallet et al
605
Relapse after
SCT
Months
3
9
6
12
2
4
11
13
14
Patients
15
17
19
20
21
22
23
26
27
30
DLI
FDC
MC
Figure 1 Chimerism studies in patients who established an FDC after
DLI. The follow-up period (months) for each patient is represented by a
line and sampling patients are represented by the symbols on each line.
Patients are represented by numbers: 2, 4, 11, 13, 14, 15, 17, 19, 20, 21, 22,
23, 26, 27 and 30.
dose (ICD) on DLI toxicity, disease response and survival
after DLI. Many issues remain unsettled, including DLI
timing after transplantation, DLI doses and the durability
of response after DLI. Our principal aim was to study the
long-term outcome after DLI given for relapse after HSCT.
In comparison with Dazzi’s series,19 studying the follow-up
of relapsed CML patients after DLI, we observed a
difference in the interval between transplantation and
relapse (24 months for our series vs 12 months) and the
interval between relapse and DLI (1.9 months vs 10
months). Despite the short interval between relapse and
DLI in our series, we observed no increase in incidence of
severe GVHD in comparison to others. We observed no
influence of DLI administration type on GVHD incidence
and severity. At 3 years, we showed for CML patients a
survival probability of 93%, similar to the survival rate of
CML molecular responders after DLI observed by Dazzi
et al,19 who moreover demonstrated a correlation between
the quality of response to DLI and survival. When we
considered patients with diseases other than CML, the
3-year probability of survival after transplantation was
only 62% because of the well-known worse GVL effect
observed after DLI in other diseases than CML, particularly in ALL.10 In our series, the 11 long-term survivors
were all in complete continuous remission at the last followup, eight were in CMR but only five had only received DLI
with no other therapeutical intervention during their
DLI
Profiles of donor and
recipient before
transplantation
92
0
10
10
12
30
12
92
13
41
13
90
14
60
14
88
15
30
15
78
16
20
17
19
20
34
22
25
22
42
23
37
25
29
27
89
Rec
Relapse
8
73
0
Rec
100
90
80
70
60
50
40
30
20
10
0
36
Don
% of recipient cells
Don
Days post transplantation
CD3+
CD3-
Patient 19
(group I)
Different profiles of
recipient after transplantation
Rec 14%
Don
Rec 94%
Don
Figure 2 Chimerism analysis (STR technique) for patient 19. Peak areas give the percentage of recipient cells for each sample. Mixed chimerism was
defined by the presence of at least 5% of recipient cells.
Bone Marrow Transplantation
Long-term follow-up after DLI given for relapse after myeloablative allogeneic HSCT
AS Michallet et al
606
1 CCR
(patient 19)
1 CMR
(patient 17)
2 HR
Glivec ®
14 CML
1 CMR (patient 25)
1 CP (patient 18)
Glivec ®
3 CP
1 CP (patient 24)
1 CCR (patient 30)
1 CMR (patient 15)
1 CMR (patient 14)
9 CCR
3 CCR
3 CMR (patients 20, 21, 22)
Glivec ®
3 CP
1 CMR (patient 16)
RICT after failure IFN+Glivec ®
2eme myeloablative HSCT
1 CHR (patient 23)
1 CP (patient 26)
Figure 3
Probability of survival
a
Follow-up of the 14 CML patients.
1.0
0.8
0.6
0.4
0.2
0.0
0
Probability of survival
b
100
50
150
200
1.0
0.8
follow-up. Among these five CMR patients, three were in
hematological relapse (3/11) and two in cytogenetic relapse
(2/3) before DLI, which again demonstrated a better
response when DLI was performed earlier.31 As previously
described4,7–10,14,19,33 CCRs were observed in our series in
CML patients, which confirmed once again the real
sensitivity of CML patients to adoptive cell immunotherapy. The maximal follow-up after DLI of 96 months (our
series) and 72 months (Dazzi’s series19) is an important
argument for the curative power of DLI for CML relapse
after allogeneic transplantation. Strangely, we demonstrated in the multivariate analysis a significantly worse
survival after transplantation for female recipients but,
when we considered the age of the population, female
subjects (median age: 36.5 years) were older than male
0.6
0.4
Figure 4 Overall survival after transplantation and after DLI. (a) The
0.2
0.0
0
20
Bone Marrow Transplantation
40
60
80
Months
100
120
3-year probability of overall survival after transplantation for the whole
population was 60% (95% CI (45–80%)). When considering only CML
(line — in the figure) patients, the 3-year probability of survival was 93%
(95% CI (79.36–100%)); (b) After DLI, the 3-year probability of overall
survival of the whole population was 48% (95% CI (30–60%)) and 80%
(95% CI (60–100%)) when considering only CML patients.
Long-term follow-up after DLI given for relapse after myeloablative allogeneic HSCT
AS Michallet et al
607
subjects (median age: 28.5 years), which could explain this
observation.
Until now, because of these observed results, DLI
remains the only curative therapy in this situation and
has to be compared to other promising treatments such as
imatinib mesylate, which permits molecular remission and
chimerism conversion when given for CML relapse after
HSCT.34 Vela-Ojeda et al35 have observed that interferon a
potentiate the GVL effect of DLI in some CML patients.
This study showed that DLI could clearly induce a longterm GVT effect in CML patients. Consequently, CML
relapse after HSCT remains an indication of choice for this
adoptive immunotherapy, but early relapse detection by
molecular monitoring and chimerism kinetics may improve
DLI management, decreasing their potential toxicity and
increasing their efficacy. In addition, imatinib mesylate
efficacy has to be confirmed in long-term follow-up studies
and needs prospective trials. Moreover, a new therapeutic
strategy combining imatinib mesylate, allogeneic transplantation and DLI could induce interesting and durable
responses in advanced CML or Philadelphia-positive acute
lymphoblastic leukemia.36
10
11
12
13
14
15
Acknowledgements
This work was supported by grants from the Unité de Recherche
Clinique (URC) (pavillon E, Hôpital Edouard-Herriot, Lyon).
16
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