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Leukemia Research 25 (2001) 379–384
Allogenic stem cell transplantation as salvage therapy for patientsrelapsing after autologous transplantation: experience from a single
institution
Carmen Martınez, Enric Carreras *, Montserrat Rovira, Alvaro Urbano-Ispizua,Jordi Esteve, Francesc Fernandez-Aviles, Marıa Perales, Susana Rives, Marta Gomez,
Emilio MontserratTransplantation Unit, Department of Hematology, Postgraduate School of Hematology ‘Farreras-Valentı’,
Institute of Hematology and Oncology, IDIBAPS Hospital Clınic, Uni6ersity of Barcelona, Villarroel 170, 08036 Barcelona, Spain
Received 4 July 2000; accepted 20 October 2000
Abstract
The prognosis of patients relapsing after an autologous transplant (autoSCT) is very poor. Allogenic stem cell transplantation(alloSCT) offers the possibility of curing some of these patients, at the cost, however, of a high transplant related mortality(TRM). The aim of this study was to analyze the outcome of 14 consecutive patients with hematologic malignancies, from a singleinstitution, who underwent alloSCT for progressive disease after autoSCT. Patients had relapsed at a median of 11.5 months(range 2–72) after autoSCT and they underwent alloSCT at a median of 25.5 months (range 7–73) from the first transplant. Tenpatients received HLA-identical related peripheral blood progenitor cells, three patients underwent matched-unrelated donormarrow transplants, and one patient received a mismatched related transplant. Conditioning regimens consisted of total bodyirradiation plus cyclophosphamide (n=5) or melphalan (n=1), or high-dose combination chemotherapy (n=8). Cyclosporin Aand methothrexate were administered as graft-versus-host disease (GVHD) prophylaxis. Eight patients (57%) developed gradeII–IV acute GVHD. All evaluable patients (n=6) presented extensive chronic GVHD. Overall survival at 1 year was 16%(median 3.5 months, 95% CI 0.7–10.3). Ten patients (71%) died from transplant related complications at a median of 3.5 months(range 0.7–11). Only one patient died of recurrent disease. Three patients remain alive and in complete remission at the time ofthis report (4, 20 and 20 months, respectively). In conclusion, alloSCT offers the possibility of a sustained control of the diseasein some patients who relapse after an autoSCT. However, the procedure is associated with a high transplant-related mortality.Better results might be obtained by carefully selecting patients and by reducing the intensity of the preparative regimen. © 2001Elsevier Science Ltd. All rights reserved.
Keywords: Autologous transplantation; Relapse; Allogenic transplantation
www.elsevier.com/locate/leukres
1. Introduction
Hematopoietic stem cell transplants are effective in avariety of hematologic malignancies [1–3]. Relapse ofthe underlying disease after transplantation remains themost frequent cause of treatment failure, particularlywith autologous transplants (autoSCT), and is generally
considered to have a poor prognosis. The optimaltreatment strategy for these patients is not resolved [4].Although in some patients a second complete remissioncan be obtained with conventional chemotherapy, veryfew patients, if any, are cured with this approach. Therole of second transplant in the treatment strategy ofpatients relapsing after a first transplant is controver-sial, basically because of the treatment-related toxicity.
Allogenic stem cell transplantation (alloSCT) hasbeen employed as a salvage therapy in patients whorelapse after a first alloSCT. The results from largeseries of leukemia patients reported by the both Eu-
Abbre6iations: AlloSCT, allogenic stem cell transplantation; Au-toSCT, autologous transplant; GVHD, graft-versus-host disease;TRM, transplant related mortality.
* Corresponding author. fax: +34-93-2275428.E-mail address: [email protected] (E. Carreras).
0145-2126/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.PII: S 0 1 4 5 -2126 (00 )00146 -6
C. Martınez et al. / Leukemia Research 25 (2001) 379–384380
ropean Group for Blood and Marrow Transplantationand by the International Bone Marrow Transplantationregistries have shown that a minority of the patientsachieve long-term disease-free survival. However, a sub-stantial proportion of the patients die due to the toxic-ity related to the procedure or because of the relapse ofthe disease [5,6]. Treatment results are better in youngpatients, individuals with a long time interval betweenthe first and the second transplant, and those with goodperformance status.
Experience with alloSCT in patients who relapseafter autoSCT is limited, and factors that could predicta favorable outcome in this group of patients have notbeen fully established [7–10].
The purpose of this study was to evaluate the out-come of patients with hematologic malignancies whounderwent alloSCT for progressive disease after auto-SCT in our institution.
2. Patients and methods
2.1. Patient population
Fourteen alloSCT were performed between March1995 and December 1999 for the treatment of hemato-logic malignancies relapsing after autoSCT. Five pa-tients had non-Hodgkin’s lymphoma, four acuteleukemia, three Hodgkin’s disease, one multiplemyeloma, and one chronic myeloid leukemia. The out-come of two patients with mantle-cell lymphoma allo-grafted after relapsing from an autoSCT has beendescribed in a separate publication [11]. The clinicalcharacteristics of these patients prior to both the firstand second transplants are described in Table 1. Themedian age of patients at the time of alloSCT was 37years (range 20–57). Nine patients were male and fivewere female. The median time interval from diagnosisto autoSCT was 15 months (range 4–44). Patients hadrelapsed at a median of 11.5 months (range 2–72) afterautoSCT. All patients but one were treated with one(n=10) or ] two (n=3) chemotherapy regimens be-fore alloSCT. Only three patients were in completeremission (CR) at the time of the second transplant,and one patient with CML was maintained in thechronic phase. AlloSCT was performed at a median of25.5 months (range 7–73) following autoSCT. Themedian Karnofsky performance status score prior toalloSCT was 70% (range 40–80%).
2.2. Transplantation methods
The preparative regimen for autoSCT consisted ofcyclophosphamide (Cy) 120 mg/kg and fractionatedtotal body irradiation (TBI) 12 Gy in four patients,melphalan 200 mg/m2 in one, and high-dose combina-
tion chemotherapy in nine (Table 1). The stem cellsource for the first transplant was bone marrow (n=3),peripheral blood (n=10), or both (n=1).
The conditioning regimen for alloSCT consisted ofCy 120 mg/kg and TBI 12–13 Gy in six cases, busulfan(Bu) 16 mg/kg and Cy 120 mg/kg in four, melphalan140 mg/m2 and TBI 12 Gy in one, Cy 120 mg/kg+Bu16 mg/kg+etoposide 30 mg/kg in one, and fludarabine150 mg/m2+melphalan 140 mg/m2 in two. Ten pa-tients received HLA-identical related (sibling (n=9),father (n=1)) peripheral blood progenitor cells, threeunderwent matched-unrelated donor marrow trans-plants, and one patient received a mismatched relatedperipheral blood transplant.
All patients received cyclosporin A and short coursemethothrexate as graft-versus-host disease (GVHD)prophylaxis. The diagnosis and grading of acute andchronic GVHD was established according to the Seattlecriteria [12]. Chronic GVHD was defined as the pres-ence of GVHD after day 90.
2.3. Statistical methods
Median values and ranges for age and time intervalswere determined. Survival was measured from the dateof alloSCT to the date of death from any cause, or lastknown follow-up. The method of Kaplan and Meierwas used to plot survival and relapse curves. Theanalysis was performed with SPSS software.
3. Results
3.1. Hematopoietic engraftment
One patient died before hematopoietic engraftment.The median time to achieve an absolute neutrophilcount of \0.5×109/l and \1.0×109/l was 15 days(range 10–23), and 17 days (range 11–25), respectively.The median time to achieve a platelet count \20×109/l was 15 days (7–38) days; five patients did notachieve this platelet count after transplant. No patientrejected the graft.
3.2. GHVD
Eight patients (57%) developed acute GVHD gradeII–IV. Six patients survived more than 90 days andwere evaluable for chronic GVHD. All of them pre-sented extensive chronic GVHD; this complication wasfatal in two cases (patients c3 and c4). Two patients(cases c2 and c7) died due to infectious complica-tions associated with immunosuppressive therapy forchronic GVHD (Table 2).
C. Martınez et al. / Leukemia Research 25 (2001) 379–384 381
Tab
le1
Pat
ient
char
acte
rist
icsa
Dia
gnos
isT
ime
toA
utoS
CT
Tim
eto
Allo
SCT
Tim
ebe
twee
nSe
xP
atie
ntA
geat
allo
SCT
auto
SCT
–re
laps
ebau
toSC
Tb
Stem
cell
Con
diti
onin
gC
ondi
tion
ing
Stem
cell
sour
ceal
loSC
Tb
Kar
nofs
kyP
Sso
urce
regi
men
regi
men
01C
yTB
IM
7273
HL
A-m
atch
edU
NR
BM
BuC
Y80
26A
ML
11B
MB
uCy
1239
HL
A-m
atch
edU
NR
BM
CyT
BI
BM
80C
ML
3102
M48
BM
+P
BF
BuC
y9
12H
LA
-mis
mat
ched
sibl
ing
PB
CyT
BI
6027
AM
L10
03P
BF
BE
AC
1026
HL
A-m
atch
edsi
blin
gP
BC
yTB
I80
38N
HL
4404
ML
F9
19H
LA
-mat
ched
sibl
ing
PB
ML
FT
BI
PB
2005
4M
M48
M23
PB
BE
AC
1129
HL
A-m
atch
edsi
blin
gP
BB
uCyV
P50
0636
MH
DB
EA
C24
33H
LA
-mat
ched
sibl
ing
PB
CyT
BI
PB
60F
0735
NH
L45
PB
FB
EA
C24
30H
LA
-mat
ched
sibl
ing
PB
CyT
BI
8053
MC
L15
08P
BM
BE
AC
1319
HL
A-m
atch
edsi
blin
gP
BC
yTB
I80
57M
CL
1509
CyT
BI
711
HL
A-m
atch
edfa
ther
PB
BuC
yP
B60
1010
AC
L28
MC
yTB
I11
5M
7H
LA
-mat
ched
sibl
ing
PB
BuC
y60
42N
ML
7P
BC
yTB
I42
47H
LA
-mat
ched
UN
RB
MB
uCyA
TG
BM
60A
LL
512
M24
PB
FB
EA
C15
25H
LA
-mat
ched
sibl
ing
PB
Flu
dara
ML
F90
20H
D23
1327
PB
BE
AC
217
HL
A-m
atch
edsi
blin
gP
BF
luda
raM
LF
80M
1432
HD
aK
arno
fsky
PS,
Kar
nofs
kype
rfor
man
cest
atus
;A
ML
,ac
ute
mie
lobl
asti
cle
ukem
ia;
CM
L,
chro
nic
mie
loid
.le
ukem
ia;
NH
L,
non-
Hod
gkin
lym
phom
a;M
M,
mul
tipl
em
yelo
ma;
HD
,H
odgk
indi
seas
e;M
CL
,man
tle
cell
lym
phom
a;A
LL
,acu
tely
mph
obla
stic
leuk
emia
;Cy,
cycl
opho
spha
mid
e;T
BI,
tota
lbod
yir
radi
atio
n;B
u,bu
sulf
an;B
EA
C,B
CN
U,e
topo
side
,ara
-C,c
yclo
phos
pham
ide;
ML
F,
mel
phal
an;
VP
,et
opos
ide,
Flu
dara
,flu
dara
bine
;U
NR
,un
rela
ted;
BM
,bo
nem
arro
w;
PB
,pe
riph
eral
bloo
d.b
Mon
ths.
C. Martınez et al. / Leukemia Research 25 (2001) 379–384382
Table 2Allogenic transplantation outcome
Chronic GVHD Cause of deathPatient StatusAcute GVHD
01 Grade III NEa Idiopathic pneumonitis+acute GVHD Dead, day +45Extensive Bacterial sepsis+chronic GVHDGrade II Dead, 11 months02
Grade III03 Extensive Chronic GVHD Dead, 11 monthsNE04 Idiopathic pneumonitisGrade I Dead, 2 monthsNE Multiorgan failure+fungal infection0 Dead, day +2105Extensive Chronic GVHD06 Dead, 7 monthsGrade IIExtensive Bacterial sepsis+chronic GVHDGrade II Dead, 9 months07
Grade II08 Extensive Alive, 20 monthsExtensive0 Alive, 20 months09
Grade II10 NV Viral infection Dead, day +107NE Relapse Dead, 3 months11 0NE Viral infection+acute GVHD Dead, 2 monthsGrade II12
Grade III NE13 Alive, 4 months14 NE NE Idiopathic pneumonitis Dead, day +22
a NE, not evaluable.
3.3. Sur6i6al and cause of death
The Kaplan–Meier estimated overall survival at 1year was 16% (median 3.5 months, 95% CI: 0.7–10.3)(Fig. 1). One patient died 3 months after transplant dueto leukemic relapse. Ten patients (71%) died fromtransplant related complications at a median of 3.5months (range 0.7–11) after the procedure. As shownin Table 2, causes of death included GVHD in sixcases; bacterial, fungal or viral infections in five; idio-pathic pneumonitis in three; and multiorgan failure inone. At the time of this report, three patients remainalive (Table 2). Two of them (patients c8 and c9)had mantle cell lymphoma and underwent alloSCT inCR and partial remission, respectively. Both developedextensive chronic GVHD remaining in CR 20 monthsafter transplantation with a Karnofsky performancestatus score of 90%. Patient c13 had a resistantHodgkin disease with lung involvement. She developedan acute grade III GVHD responding to immunosup-pressive therapy. At the time of writing, the patient is inCR, 8 months after the alloSCT and she has developedextensive chronic GVHD. In these patients, the dura-tion of the remission after the second transplant waslonger than after the autoSCT.
4. Discussion
Patients with hematological malignancies who relapseafter autoSCT have a very poor prognosis with amedian survival of less than 1 year [4]. In most cases, asecond autoSCT is not feasible due to the resistance ofthe disease to the therapy, or to the impossibility ofcollecting enough stem cells. For all these reasons,alloSCT is a potentially interesting salvage therapyoffering the advantages of both the lack of tumor
contamination of the graft and the antitumoral activitymediated by the so-called graft-versus-tumor effect[13–16].
The outcome of patients receiving an alloSCT afterfailing an autoSCT has been analyzed in several studies,the majority coming from registries or multiple institu-tions [7–10]. The largest series analyzed treatment re-sults in patients with acute leukemia and has recentlybeen reported by the European Blood and MarrowTransplantation Registry [7]. In this study, patientsrelapsing after an autoSCT underwent a second au-tologous (n=74) or allogenic (n=94) transplant assalvage therapy. Transplanted-related mortality (TRM)at 2 years was 51% in recipients of matched alloSCTand 26% following a second autoSCT (PB0.05).Leukemia-free survival (LFS) was not statistically dif-ferent between the two groups since higher diseaseprogression was observed after autoSCT. In the multi-variate analysis, parameters associated with shorterLFS were: age \25 years, interval from first autoSCT
Fig. 1. Overall survival after alloSCT.
C. Martınez et al. / Leukemia Research 25 (2001) 379–384 383
to relapse of 8 months or less, and TBI used as partof the preparative regimen in the first autoSCT.
The role of second transplants in the managementof patients with lymphoid malignancies has not beenwidely investigated [9,10,17–19]. Tsai et al. [9] ana-lyzed 20 patients, 14 of them with lymphoma, whounderwent alloSCT after failing autoSCT. In thisstudy, the median survival was only 2 months; all thedeaths were due to transplant-related complicationsthat included bacterial or fungal infection, veno-occlu-sive disease of the liver, idiopathic interstitial pneu-monitis and chronic GVHD. Only three patients werealive at the time of this report. Similar results havebeen shown in patients with multiple myeloma havingrelapsed after autoSCT [10,20]. Thus, Mehta et al.[10] performed a case-matched study comparing pa-tients who underwent an alloSCT or a second au-toSCT for relapsed or refractory multiple myeloma.The conclusions of this study were that while au-toSCT might be superior to alloSCT when consider-ing overall survival (54 vs. 29%, respectively,P=0.01), the event-free survival was comparablegiven the significantly lower disease progression afteralloSCT (72 vs. 31%, respectively, P=0.03).
In our single institution study, which included allpatients that had received an alloSCT after havingrelapsed from an autoSCT, alloSCT resulted inprompt engraftment. However, TRM due to toxicity,and the incidence of GVHD and infections were ex-tremely high. Although the series is small, the propor-tion of long-term survivors does not appear to bedifferent from that found in other series. It should benoted that, although most patients had relapsed after8 months from autoSCT and only four received TBIas part of the preparation regimen for the first trans-plant, a great proportion of them were over 25 andhad been heavily pretreated, factors which have beenassociated with poor outcome [7–10]. The last twopatients of the series received low-intensity condition-ing regimens in order to reduce the toxicity associatedto the procedure. One of them is alive and in CR atthe time of this report
In summary, in patients who relapse after an au-toSCT, salvage therapy with alloSCT is associatedwith a high TRM, but a proportion of patients mayexperience prolonged disease-free survival. The mostimportant problem with this procedure is TRM. Thiscould be diminished by a careful selection of the pa-tients and, particularly, by reducing the intensity ofthe conditioning regimen, an avenue that is being ac-tively investigated [21,22]. Taking into account thedismal prognosis of patients relapsing after a firsttransplant, as well as the high TRM associated withsecond regular transplants, the so-called ‘mini-trans-plants’ (or transplants with non-myeloablative regi-mens) are worth investigation.
Acknowledgements
This work has been supported in part by grantsSGR 1998/00111 from the Comissionat per a Univer-sitats i Recerca (Generalitat Catalunya), FISS-98/995,98/0380, and 99/0189 from the Fondo de Investiga-ciones Sanitarias de la Seguridad Social, SpanishMinistry of Health, and FIJC-00/P-CR and FIJC-00/P-EM from the Jose Carreras International Founda-tion. We wish to thank Anna Bauer for the Englishgrammar review of the manuscript.
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