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ORIGINAL ARTICLE
Outcome of Relapsed Non-Hodgkin’sLymphoma Patients After Allogeneicand Autologous Transplantation
Ulka Vaishampayan, M.D.,* Chatchada Karanes, M.D.,
Wei Du, Ph.D., Mary Varterasian, M.D., and
Ayad Al-Katib, M.D.
Division of Hematology and Oncology, Department of Internal Medicine,
Barbara Ann Karmanos Cancer Institute, Wayne State University,
Detroit, Michigan
ABSTRACT
A retrospective review of 58 patients with non-Hodgkin’s lymphoma (NHL) relapse
or progression after autologous bone marrow transplantation (auto BMT),
peripheral stem cell transplantation (PSCT), or allogeneic bone marrow
transplantation (allo BMT) between November 1988 and December 1997 was
performed. Forty-six (79%) patients had autologous transplant and 12 (21%)
patients had allogeneic transplant. Median time to relapse post-transplant was
4.8 months with 49 relapses within 12 months after transplant. Overall 5-year
survival was 22% (auto BMT or PSCT 25%, allo BMT 18%, p ¼ 0:38) with a
median survival of 10 months (auto BMT or PSCT 10.2 months, allo BMT 7 months,
p ¼ 0:38). Thirty-five patients received salvage therapy and, of these, 13
demonstrated objective response. The 3-year survival of responders and non-
responders was 55 and 14% and median survivals were 27.8 and 8 months,
respectively (p ¼ 0:02). Interval between BMT and relapse (p ¼ 0:0001), and
response to salvage therapy (p ¼ 0:02) were the only significant predictors of
survival.
303
Copyright q 2002 by Marcel Dekker, Inc. www.dekker.com
*Corresponding author. Current address: Harper Hospital, Room 511 Hudson, 3990 John R Road, Detroit, MI 48201. Fax: (313)
993-0559; E-mail: [email protected]
Cancer Investigation, 20(3), 303–310 (2002)
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INTRODUCTION
Non-Hodgkin’s lymphoma (NHL) is initially treated
with conventional chemotherapy and/or radiation. At the
time of relapse, myeloablative therapy followed by
stem-cell transplantation is considered an accepted
method of salvage, mainly in intermediate and high-
grade disease, based on randomized trials (1–4). In
low-grade NHL, the transplant procedure remains
investigational with a marginal advantage although it
may induce some long-term remissions (5). Bone
marrow and peripheral blood stem cell transplants,
inspite of being curative modalities in NHL, are
associated with considerable mortality.
A common cause of mortality after transplantation in
NHL remains disease progression. Overall, about 50–
60% of patients demonstrate progressive disease post-
transplant (6–8). The management of this group of
patients presents a challenge due to the aftermath toxicity
of the transplant procedure and the relative chemo-
resistance of the disease. We reviewed the data on 58
patients at our institution with relapse or progression of
NHL post-autologous or allogeneic transplant. This was
undertaken with the aim of gaining additional insight into
the time and pattern of progression, prognostic factors
predictive of survival, and overall outcome in this patient
population. In this study, we focus on the effectiveness of
salvage therapy post-transplant, and how it affected the
clinical course and outcome in progressive or relapsed
NHL.
MATERIALS AND METHODS
A total of 161 patients underwent autologous or
allogeneic transplant for NHL at Wayne State University
between November 1988 and December 1997. Of these,
60 (37.2%) patients had recurrence of NHL or
progressive disease post-transplant. The medical records
of these 60 patients were reviewed in detail for
information regarding time, site, and pattern of relapse,
response to subsequent therapy administered, and overall
survival. The pre-transplant characteristics including
age, sex, performance status, disease histology, stage,
presence of extranodal involvement, therapy, type of
transplant, and preparative regimen used were also
evaluated. A signed informed consent was obtained from
all patients. The diagnosis of NHL was confirmed by
pathology review of the original specimen and by a
positive biopsy of appropriate tissue specimen at the time
of clinical relapse. Two patients were excluded from the
analysis as their biopsies at relapse demonstrated
Hodgkin’s disease.
Transplant Procedure and Follow-Up
All patients had normal major-organ function as
defined by the following criteria: FEV1 and
FVC . 70% of predicted, left ventricular ejection
fraction . 50%, transaminases # 3 times of upper
limit of normal, creatinine clearance . 60 cc/min, and
performance status by Zubrod’s score of #3. Patients
received one of the two preparative regimens: CVB or
Cy/TBI. The CVB regimen consisted of cyclopho-
sphamide 1.8 g/m2/day for four days and etoposide
200 mg/m2 every 12 hr for four days, followed by
BCNU at 600 mg/m2. The Cy/TBI preparative regimen
consisted of cyclophosphamide 1800 mg or
2200 mg/m2/day for two days followed by total body
irradiation at a dose of 1200 cGy fractionated at 300 cGy
daily for four days or 200 cGy twice daily for three
days. The allogeneic grafts were obtained from bone
marrow of the donor, whereas the sources of the
autologous grafts were either peripheral stem cells or
bone marrow or both. None of the grafts were purged or
pretreated.
After complete hematopoietic reconstitution, patients
were evaluated for tumor progression at least monthly for
the first six months. Computed tomography was obtained
during the first year, at three month intervals post-
transplant and earlier if indicated clinically. Bone
marrow biopsies were performed every three months
for the first year and then at least annually. Progression or
relapse of NHL was documented by biopsy. Therapy
after relapse was administered at the discretion of the
individual physician.
Statistical Methods
Overall survival and progression-free survival were
measured from the date of bone marrow transplan-
tation (BMT) to the date of the event. Actuarial
survival curves and median survival durations were
calculated using the Kaplan–Meier product-limit
method, and for the univariate comparison of survival
curves, log-rank tests were used. Cox’s proportional
hazard regression was performed to assess the joint
effect of prognostic factors multivariately. Patient
follow-up was complete through July 1998. All
statistical analyses and graphics were produced by
SAS 6.12.
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RESULTS
Patient Characteristics
The clinical characteristics of the patients are
summarized in Table 1. Majority of the patients were
of Caucasian origin with a predominance of males
(62%). Median age of this patient group was 46 years
(range 13–60 years) with 20 patients above 50 years of
age. Fourteen patients had low-grade NHL, 25 had
intermediate grade, and 19 had high-grade histology as
per the working formulation classification of NHL.
Thirty-one (53%) patients had extranodal disease site
involvement prior to transplant. Only nine patients had
early stage NHL and 49 had advanced stage disease.
Twenty-four patients had elevated serum lactate
dehydrogenase levels pre-transplant.
All patients had recurrent NHL prior to transplant and
had received at least one prior chemotherapy regimen.
Median number of chemotherapy regimens administered
pre-transplant was 2 (range 1–5). All except two of the
patients had received doxorubicin-based chemotherapy
prior to transplant. The status of disease prior to
transplant was as follows: 12 in complete remission
(CR), 32 in partial remission and 13 with progressive
disease. Eighteen patients received radiation therapy
(RT) prior to transplantation.
Of the 161 patients transplanted for NHL, 48 received
an allogeneic graft and 113 received an autologous graft.
Of the population receiving allogeneic transplantation,
43 received a sibling marrow graft of which one had an
identical twin donor, and 5 received a matched unrelated
donor graft. Progressive disease post-transplant was
demonstrated in 46 of the 113 autologous transplant
patients and 12 (25%) of the 48 allogeneic graft patients.
Seventy-two percent of the patients had Cy/TBI as the
preparative regimen and the remaining had CVB.
Overall Survival
The overall survival of all the patients with
progressive/relapsed disease was 35% at two years and
22% at five years (Fig. 1). The median survival was
10 months post-transplant. The patients relapsing after
autologous BMT (auto BMT) or peripheral stem cell
transplantation (PSCT), demonstrated a five-year survi-
val of 25% and of those post-allogenic BMT (allo BMT)
it was 18% (Fig. 2). The median survivals in the auto
BMT and allo BMT arms were 10.2 and 7 months,
respectively. The type of preparative regimen (TBI or
non-TBI) utilized for transplant did not appear to affect
the outcome ðP ¼ 0:11Þ significantly The patients above
50 years of age demonstrated a longer median survival of
16.4 months than the younger patients (median survi-
val—6.8 months). However, 14 of the 20 patients above
50 years of age had low-grade NHL and this may explain
the superior survival after relapse. In a univariate
analysis of patient characteristics, including sex, race,
stage, B symptoms, lactate dehydrogenase levels, pre-
transplant disease status, histology, and extranodal
involvement, none of these factors emerged as significant
predictors of prognosis.
Table 1
Patient Characteristics
No. (%)
Age
# 50 38 (65)
. 50 20 (35)
Gender
Male 36 (62)
Female 22 (38)
Type of transplant
Auto 46 (79)
Allo 12 (21)
Time to relapse
# 12 months 49 (84)
. 12 months 9 (16)
Stage
I/II 9 (16)
III/IV 49 (84)
Histology
Low grade 14 (24)
Intermediate grade 25 (43)
High grade 19 (33)
Extranodal site
Present 31 (53)
Absent 27 (47)
Preparative regimen
Cy þ TBI 42 (72)
CVB (non-TBI) 16 (28)
Disease status at transplant
CR/PR 44 (76)
SD/PD 14 (24)
Relapse site
Nodal 16 (27)
Extranodal 42 (73)
Relapsed NHL Post-Transplant 305
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Figure 1. Overall survival of relapsed/progressive NHL.
Figure 2. The influence of type of transplant on overall survival in progressive NHL post-transplant.
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Time, Site, and Histology of Relapse
The median time from transplant to disease
progression was 4.8 months (range 1 –43 months).
Forty-nine of the 58 relapses were observed in the first
year post-transplant. Only three of these were noted
beyond two years after transplant. Disease progression
was documented by biopsy in all patients. The time to
relapse had a statistically significant impact on survival
post-transplant (Fig. 3, P ¼ 0:0001Þ:Forty-two of the 58 patients had at least one
extranodal site of relapse and had a survival inferior to
those with nodal relapses only—median 8.7 vs.
13.3 months, respectively. Pre-transplant, 31 (53%)
patients had extranodal site involvement and of these
67% relapsed at the same site. Only two patients had
central nervous system involvement with NHL and both
relapsed in the same site.
Two patients relapsed post-transplant with Hodgkin’s
disease (nodular sclerosis and mixed cellularity) and
hence were excluded from analysis. One patient had an
original histology of follicular mixed NHL and
demonstrated a relapse with mantle cell lymphoma.
Only one patient had myelodysplasia 5 months post-
relapse and died one month after this diagnosis without
receiving any therapy.
Post-Relapse Therapy
Of the 58 patients, 23 did not receive any further
treatment post-relapse, mainly due to poor performance
status. Thirty-five patients were able to receive salvage
therapy, of which 13 demonstrated either a complete or
partial response. The details of the type of therapy
administered are summarized in Table 2. None of the
patients received a second transplant. The responders had
an overall survival benefit over the non-responders with a
median survival of 27.9 months as compared with that of
8 months (Fig. 4). Hence the salvage therapy was feasible
in about 60% of the patients but survival was
significantly improved in the 37% patients who
demonstrated a response ðP ¼ 0:022Þ:
DISCUSSION
Progressive or relapsed disease post-transplant por-
tends a dismal prognosis. Salvage therapy has shown
Figure 3. The impact of the time interval between transplant and relapse on overall survival in NHL.
Relapsed NHL Post-Transplant 307
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limited benefit in relapsed NHL with two-year survival
rates in the range of 10–25% (9,10). Patients receiving
autologous or allogeneic transplant for intermediate or
high-grade NHL have equivalent outcomes in terms of
survival (11). There are two other reports reviewing the
outcome in progressive or relapsed NHL patients (9,12).
Vose et al. reported on progression after autologous
transplantation in NHL (9). Our series included both
autologous and allogeneic transplants and demonstrated
an overall survival of 35% at 2 years and median survival
of 10 months. This is longer than the overall and median
survivals of 25% and 3 months observed by Vose et al.
The better results in this review could be explained by a
proportion (24%) of patients with low-grade histology in
our population. In the report by Apostolidis et al. (12), the
median survival of patients with follicular NHL who had a
relapse post-BMT was 33 months and this is consistent
with the median survival of 30 months observed in our
low-grade histology population. The recent advances in
supportive care are likely to be contributing factors for the
enhanced survival observed in our study population.
Table 2
Salvage Therapy and Response
Type of Therapy CR/PR SD/PD Total
Chemotherapy 6 14 20
EPOCH-3a EPOCH-4
DHAP-2b DHAP-4
ESHAP-1c ESHAP-4
IFN-1d
Flud-1e
Radiation therapy 5 6 11
Chemotherapy and
radiation therapy
2 2 4
DHAP-1 Flud-1
IFN-1 EPOCH-1
a EPOCH—etoposide, prednisone, doxorubicin, cyclophosphamide,
and vincristine continuous infusion.b DHAP—dexamethasone, cytarabine, and cisplatin.c ESHAP—etoposide, methylprednisolone, cytarabine, and cisplatin.d IFN—interferon alpha.e Flud—fludarabine.
Figure 4. The difference in overall survival between responders to salvage therapy vs. non-responders.
Vaishampayan et al.308
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Early relapse is more common in NHL than in
Hodgkin’s disease (9,13). The interval between trans-
plant and relapse has been demonstrated to be a
significant predictor of overall outcome in the previous
reports (9,12). This is confirmed in our study. The rapid
progression of disease indicates aggressive nature of
relapsed NHL and its relative resistance to chemother-
apy. A longer time interval elapsed between transplant
and progression is a sign of sensitivity to chemotherapy
and allows for recovery from transplant-related toxi-
cities. There is also a gradual improvement in
performance status, which makes the patient more
amenable to further therapy considerations. This could
account for the better outcome in late relapses.
It would be ideal to predict in advance the patients
who have a higher probability of early relapse post-
transplant. Stable or progressive disease prior to
transplant, extranodal disease status, and advanced age
have been shown in some studies to predict a higher
probability of relapse and worse prognosis (14). Factors
assessed by univariate analysis in this study include age,
sex stage, LDH, extranodal disease, and status at
transplant. This study, however, depicted that none of
these pre-transplant criteria were significantly predictive
of relapse. Hence, based on current evidence, only time
interval between transplant and relapse significantly
influences outcome in progressive NHL.
There are no specific recommendations regarding
choice of therapy once the patients relapse after
transplant. Treatment is feasible in about 40% of patients
as shown by our review. A number of confounding
factors such as debilitation from recent transplant
procedure and impaired organ function makes the
delivery of further therapy a challenge. Second transplant
is a consideration in cases with adequate performance
status and available donor. This has shown successful
results in sporadic cases (15). Traditionally, if the relapse
is localized, then RT is a good option. Eleven of the 35
patients treated with salvage therapy after relapse,
received RT alone. In cases of disseminated disease, the
choice of chemotherapy agents is based on prior
regimens administered and the predominant cumulative
toxicities observed. Hence, a variety of chemotherapy
regimens were administered after relapse. Twenty
patients received chemotherapy and four received a
combination of chemotherapy and radiation. Eight
patients received etoposide, prednisone, doxorubicin,
cyclophosphamide, and vincristine continuous infusion
(EPOCH), seven received dexamethasone, cytarabine,
and cisplatin (DHAP), five received etoposide, methyl-
prednisolone, cytarabine, and cisplatin (ESHAP), two
received interferon and two received fludarabine (Flud).
The types of salvage therapy administered, and the
responses observed, are summarized in Table 2. In the
patients responding to salvage therapy, the median
survival was improved from 8 to 27.9 months. The 3-year
survival was 52% in responders as compared with 11% in
non-responders. This study thus demonstrates that
therapy for progressive or relapsed NHL post-transplant
offers a major survival benefit to responding patients.
Future therapy choices would be in keeping with recent
advances. Monoclonal antibodies, immunotherapy, mini-
transplant, evaluation of newer agents such as paclitaxel,
gemcitabine, and topotecan are some considerations.
In summary, progression of NHL post-transplant is
usually rapid and terminal. There are very few reports to
date addressing the clinical course of patients with
progressive NHL and it is not known if further treatment
is justified and whether it has an impact on the outcome
in this patient population. This review indicates that
salvage therapy benefits about one quarter of the patients
with relapsed NHL and hence should be administered if
clinically feasible. Attempts to reduce toxicity and
improve the efficacy of salvage therapy should be the
focus of future research.
REFERENCES
1. Haioun, C.; Lepage, E.; Gisselbrecht, C.; Bastion, Y.;
Coiffier, B.; Brice, P.; Bosly, A.; Dupriez, B.; Nouvel, C.;
Tilly, H.; Lederlin, P.; Biron, P.; Briere, J.; Gaulard, P.;
Reyes, F. Benefit of Autologous Bone Marrow Trans-
plantation over Sequential Chemotherapy in Poor Risk
Aggressive Non-Hodgkin’s Lymphoma: Updated Results
of the Prospective Study LNH87-2. J. Clin. Oncol. 1997,
15, 1131–1137.
2. Santini, G.; Salvagno, L.; Leoni, P.; Chisesi, T.; De Souza,
C.; Sertoli, M.R.; Rubagotti, A.; Congiu, A.M.;
Centurioni, R.; Olivieri, A.; Tedeschi, L.; Vespignani,
M.; Nati, S.; Soracco, M.; Porcellini, A.; Contu, A.;
Guarnaccia, C.; Pescosta, N.; Majolino, I.; Spriano, M.;
Vimercati, R.; Rossi, E.; Zambaldi, G.; Mangoni, L.;
Rizzoli, V.; et al. VACOP-B versus VACOP-B Plus
Autologous Bone Marrow Transplantation for Advanced
Diffuse Non-Hodgkin’s Lymphoma: Results by the Non-
Hodgkin’s Lymphoma Cooperative Study Group. J. Clin.
Oncol. 1998, 16, 2796–2802.
3. Nimer, S.; Zelentz, A.; Portlock, C. Bone Marrow
Transplantation versus Chemotherapy in Non-Hodgkin’s
Lymphoma. N. Engl. J. Med. 1995, 333, 728–732.
4. Philip, T.; Guglielmi, C.; Hagenbeek, A.; Somers, R.;
Van der Lelie, H.; Bron, D.; Sonneveld, P.; Gisselbrecht,
C.; Cahn, J.Y.; Harousseau, J.L.; et al. Autologous Bone
Relapsed NHL Post-Transplant 309
Can
cer
Inve
st D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y M
ichi
gan
Uni
vers
ity o
n 10
/26/
14Fo
r pe
rson
al u
se o
nly.
Marrow Transplantation as Compared with Salvage
Chemotherapy in Relapses of Chemotherapy-Sensitive
Non-Hodgkin’s Lymphoma. N. Engl. J. Med. 1995, 333
(23), 1540–1545.
5. Armitage, J.O. Bone Marrow Transplantation for Indolent
Lymphomas. Semin. Oncol. 1993, 20, 136–142.
6. Petersen, F.; Appelbaum, F.; Hill, R.; Fisher, L.D.;
Bigelow, C.L.; Sanders, J.E.; Sullivan, K.M.; Bensinger,
W.I..; Witherspoon, R.P.; Storb, R.; et al. Autologous
Marrow Transplantation for Malignant Lymphoma: A
Report of 101 Cases from Seattle. J. Clin. Oncol. 1990, 8
(4), 638–647.
7. Freedman, A.; Takvorian, T.; Anderson, K.; Mauch, P.;
Rabinowe, S.N.; Blake, K.; Yeap, B.; Soiffer, R.; Coral,
F.; Heflin, L.; et al. Autologous Bone Marrow
Transplantation in B-Cell Non-Hodgkin’s Lymphoma:
Very Low Treatment Related Mortality in 100 Patients in
Sensitive Relapse. J. Clin. Oncol. 1990, 8 (5), 784–791.
8. Takvorian, T.; Canellos, G.; Ritz, J.; Freedman, A.S.;
Anderson, K.C.; Mauch, P.; Tarbell, N.; Coral, F.; Daley,
H.; Yeap, B.; et al. Prolonged Disease-Free Survival after
Autologous Bone Marrow Transplantation in Patients
with Non-Hodgkin’s Lymphoma with a Poor Prognosis.
N. Engl. J. Med. 1987, 316, 1499–1505.
9. Vose, J.; Bierman, P.; Anderson, J.; Kessinger, A.;
Pierson, J.; Nelson, J.; Frappier, B.; Schmit-Pokorny, K.;
Weisenburger, D.D.; Armitage, J.O. Progressive Disease
after High Dose Therapy and Autologous Transplantation
for Lymphoid Malignancy: Clinical Course and Patient
Follow-Up. Blood 1992, 80 (8), 2142–2148.
10. Bolwell, B.J. Autologous Bone Marrow Transplantation
for Hodgkin’s Disease and Non-Hodgkin’s Lymphoma.
Semin. Oncol. 1994, 21 (4), 86–95.
11. Ratanatharathorn, V.; Uberti, J.; Karanes, C.; Abella, E.;
Lum, L.G.; Momin, F.; Cummings, G.; Sensenbrenner,
L.L.; Prospective Randomized Trial of Autologous
versus Allogeneic Transplantation in Patients with
Non-Hodgkin’s Lymphoma. Blood 1994, 84 (4),
1050–1055.
12. Apostolidis, J.; Foran, J.; Johnson, P.; Norton, A.; Amess,
J.; Matthews, J.; Bradburn, M.; Lister, T.A.; Rohatiner,
A.Z.; et al. Patterns of Outcome Following Recurrence
after Myeloablative Therapy with Autologous Bone
Marrow Transplantation for Follicular Lymphoma.
J. Clin. Oncol. 1999, 17 (1), 216–221.
13. Varterasian, M.; Ratanatharathorn, V.; Uberti, J.;
Karanes, C.; Abella, E.; Momin, F.; Kasten-Sportes, C.;
Al-Katib, A.; Lum, L.; Heilbrun, L.K.; et al. Clinical
Course and Outcome of Patients with Hodgkin’s Disease
Who Progress after Autologous Transplantation. Leuk.
Lymph. 1995, 20, 59–65.
14. Wheeler, C.; Strawderman, M.; Ayash, L.; Bierer, B.E.;
Elias, A.; Gilliland, D.G.; Antman, K.; Guinan, E.C.;
Eder, J.P.; et al. Prognostic Factors for Treatment
Outcome in Auto-transplantation of Intermediate and
High Grade Non-Hodgkin’s Lymphoma with Cyclo-
phosphamode, Carmustine and Etoposide. J. Clin. Oncol.
1993, 11 (60), 1085–1091.
15. De Lima, M.; Van Besien, K.W.; Giralt, S.; Khouri, I.F.;
Mehra, R.; Andersson, B.S.; Przepiorka, D.; Gajewski,
J.L.; Korbling, M.; Champlin, R.E. Bone Marrow
Transplantation after Failure of Autologous Transplant
for Non-Hodgkin’s Lymphoma. Bone Marrow Trans-
plant. 1997, 19 (2), 121–127.
Vaishampayan et al.310
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ownl
oade
d fr
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ahea
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re.c
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y M
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gan
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vers
ity o
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/26/
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