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From www.bloodjournal.org by guest on December 29, 2014. For personal use only.
Evidence of a Graft-Versus-Lymphoma Effect Associated With
Allogeneic Bone Marrow Transplantation
By Richard J. Jones, Richard F. Ambinder, Steven Piantadosi, and George W. Santos
The existence of an immunologic antileukemia reaction associated with allogeneic bone marrow transplantation (BMT) is
well established. However, a similar graft-versus-tumor effect against lymphomas has not been demonstrated. We
analyzed the results of BMT in 118 consecutive patients with
relapsed Hodgkin‘s disease or aggressive non-Hodgkin’s
lymphoma. The 38 patients less than 50 years of age with
HLA-matched donors had allogeneic marrow transplants,
and the other 80 patients received purged autologous grafts.
The median age was 26 years in both the allogeneic and the
autologous graft recipients. The patient’s responset o conventional salvage therapy before transplant was the only factor
that influenced the event-free survival after BMT (P < .001).
Both the patient’s response t o salvage therapy before BMT
(P < .001) and the type of graft (P = .02) significantly influ-
enced the probability of relapse after BMT. The actuarial
probability of relapse in patients who responded t o conventional salvage therapy before BMT was only 18% after
allogeneic BMT compared with 46% after autologous BMT.
However, the actuarial probability of event-free survival at 4
years was the same, 47% versus 41%. for patients with
responsive lymphomas who received allogeneic and autologous transplants, respectively (P = .8).The beneficial antitumor effect of allogeneic BMT was offset by its higher transplant-related mortality (P = .01), largely resulting from graftversus-host disease. Allogeneic BMT appears t o induce a
clinically significant graft-versus-lymphoma effect. The magnitude of this effect is similar t o that reported against
leukemias.
0 1991 by The American Society of Hematology.
A
involvement by lymphoma at the time of BMT. All patients gave
informed consent for study participation as approved by the Johns
Hopkins Joint Committee on Clinical Investigation.
Treatment protocol. Patients less than 50 years old with an
HLA-identical (or one antigen mismatched) family member received allogeneic marrow transplants. All other patients received
autologous transplants. Autologous bone marrow was obtained,
treated with 4-hydroperoxycyclophosphamideor pan-T cell monoclonal antibodies (four patients), and stored before beginning the
BMT preparative therapy, as previously de~cribed.’.~
Preparative
therapy consisted of busulfan followed by cyclophosphamide in
patients who had previously received over 3,000 cGy of radiation to
either their lungs or spinal cord, or cyclophosphamide followed by
total body irradiation (TBI) in the other patients, as described
previously?’ In addition, 10 patients undergoing BMT while in
resistant relapse (see below) after August 1986 were entered on a
dose escalation study of a preparative regimen consisting of
busulfan (4mg/kg/d, orally in four divided doses every 6 hours, for 4
consecutive days), etoposide (10 to 50 mgkg intravenously [IV] on
the fifth day), and cyclophosphamide (60 mgkg/d IV on the sixth
and seventh days). Bone marrow was infused 1 day after completing cyclophosphamide and TBI, and 2 days after completing the
busulfan-containing regimens. Supportive care, including GVHD
prophylaxis (with cyclosporine) and treatment, was provided as
previously described.’.’”
Study defmitions and statistical analysis. The patients’ disease
status was classified according to their response to a median of two
cycles (range, 1 to 12) of conventional salvage therapy administered before BMT.7s11-’3
The salvage therapy was administered by
the referring physician and was not standardized. The salvage
LLOGENEIC bone marrow transplantation (BMT) is
associated with a clinically significant antitumor effect, independent from the pretransplant cytotoxic therapy,
against acute leukemias and chronic myelogenous
1e~kemia.I’~
The mechanisms responsible for this graftversus-leukemia effect are not completely understood. Although graft-versus-host disease (GVHD), especially chronic
GVHD, accounts for much of this graft-versus-leukemia
activity,“’ allogeneic grafts appear to produce an antileukemic effect independent of clinically apparent GVHD.4*5
A similar graft-versus-tumor effect against lymphomas
has not been demonstrated after allogeneic BMT.6,7The
inability to establish a graft-versus-lymphoma effect may be
explained by biologic differences between lymphomas and
leukemias, or may be the result of the relatively small
number of patients who have received allogeneic transplants for lymphomas. We examined the results of BMT in
118 consecutive patients with relapsed Hodgkin’s disease
and intermediate-grade or high-grade nomHodgkin’s lymphoma, based on type of marrow graft, for evidence of a
graft-versus-lymphoma effect. Patients with a histocompatible donor received allogeneic grafts, while-patients without
a matched donor received autologous grafts. We also
analyzed the influence of various other prognostic factors,
including age, type of preparative regimen, and response to
standard salvage therapy before BMT, on the outcome of
BMT for lymphomas.
MATERIALS AND METHODS
Patients. We analyzed 118 consecutive patients with relapsed
Hodgkin’s disease or diffuse intermediate-grade or high-grade
non-Hodgkin’s lymphoma who underwent BMT at the Johns
Hopkins Oncology Center between January 1981 and October
1988. Some of the patients have been described previ~usly.~.’
Patients were eligible for BMT if they were less than 60 years old
and had progressed during or relapsed after standard chemotherapy. Patients with Hodgkin’s disease whose first relapse followed a
disease-free interval of greater than 12 months after chemotherapy
were not eligible until second relapse. Additional eligibilityrequirements included a Karnofsky performance status of at least 70%, no
evidence of morphologic lymphoma in the bone marrow by aspirate
and biopsy, and the absence of active central nervous system
Blood, Vol77, No 3 (February 1). 1991: pp 649-653
From The Johns Hopkins Oncology Center, The Johns Hopkins
Medical Institutions, Baltimore, MD 21205.
Submitted April IS, 1990; accepted October 4,1990.
Supported in part by National Institutes of Health Grants CA-15396
and CA-06973.
Address reprint requests to Richard J. Jones, MD, Room 2-127, The
Johns Hopkins Oncology Center, 600 N Wove St, Baltimore, MD
21205.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
0 1991 by The American Society of Hematology.
0006-4971191/7703-0027$3.0010
649
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650
JONES ET AL
therapies given to the patients with Hodgkin’s disease have been
described previously.’ For the patients with non-Hodgkin’s lymphoma, the salvage therapy was a standard first, second, or third
generation lymphoma regimen14in 47 patients, cisplatinlcytarabinebased regimens in 8 patients, and other regimens in 8 patients. A
sensitive relapse was defined as showing at least a partial response
(250% decrease in tumor size by the sum of the products of the
perpendicular diameters of all areas of known disease) to salvage
therapy immediately before BMT. Patients were defined as being
in resistant relapse if their lymphoma progressed through their
initial combination chemotherapy treatment (five patients), or if
their disease showed less than a partial response to salvage therapy
immediately before BMT.
The major statistical endpoints of this study were event-free
survival and time to relapse after BMT. Event-free survival was
defined as the time from the day of BMT until disease progression
or death from any cause. The time to relapse was defined as the
time to disease progression with deaths being censored. Because
residual masses often do not represent residual lymphoma,I5-l7
patients with both complete and partial remissions after BMT were
included in these analyses until disease progression. Event-time
distributions were estimated using the method of Kaplan and
Meier.” For categorical factors, the differences between eventtime distributions were tested using the log-rank statistic.’’ The
prognostic significance of continuously distributed variables (ie,
age) was assessed using the proportional hazards model’’ with
hazard ratios expressed per unit change. To adjust for the effect of
several prognostic factors simultaneously, the multivariate proportional hazards model was used. Hazard ratios exceeding 1.0
indicate an increased risk for death or relapse in the presence of
the prognostic factor. Similarly, hazard ratios less than 1.0 indicate
a lower risk of relapse or death with the prognostic factor. The
following prognostic factors were analyzed for their effects on the
event-time distributions: type of graft, preparative regimen, disease status at the time of BMT, number of relapses, type of
lymphoma (Hodgkin’s v non-Hodgkin’s), age, and sex. For time-toevent distributions, point estimates are given 295% confidence
intervals as determined from standard life table methods. The
association of type of graft with patient characteristics and transplant-related mortality was tested using the Chi-square test or the
Student’s t-test. All Pvalues reported are two-sided. Analyses were
performed as of April 1, 1990.
;
;
RESULTS
The actuarial probability of event-free survival for the
entire 118 patients a t 4 years after BMT was 29% (95%
confidence interval, 21% t o 37%) (Fig 1). The median
follow-up after BMT for the event-free survivors was 44
months with a minimum follow-up of 18 months. Multivariate analysis showed that the status of the lymphoma a t the
time of BMT was the only factor that influenced the
event-free survival (Table 1). Patients in sensitive relapse
had a significantly improved probability of event-free survival (Fig 1, P < .001). Whether or not the patient was in a
complete or partial remission before BMT was not a
significant prognostic factor (hazard ratio = 0.98, P = .9).
T h e overall actuarial probability of relapse after B M T was
48% (37% t o 58%). All but 3 of the 43 relapses were in
areas of prior disease. Having sensitive disease a t the time
of BMT also had a favorable influence on the probability of
relapse (Table 1). The actuarial probability of relapse after
BMT was 41% (30% t o 55%) for the patients transplanted
5
LL
g
:
0 00
IO 2 0
30 40 50
a
60 70 80 90 100 110
MONTHS
Fig 1. Actuarial probability of event-free survival after BMT for
relapsed lymphoma in the entire 118 patients (-1,
in the 80 patients
in sensitive relapse (- -1, and in the 38 patients in resistant relapse I...).
The proportions event-free are 29% (21% t o 37%). 42% (31% t o 53%).
and 0, respectively (P < .001). Each tick mark represents a patient
surviving in continuous complete remission.
with sensitive disease a n d 100% for the patients with
resistant disease.
Although the type of graft was not a significant prognostic factor for event-free survival after BMT, it was an
independent significant prognostic factor for the probability of relapse after BMT in the multivariate proportional
hazards model (Table 1). The median age was 26 years for
Table 1. Patient Characteristics and Their Influence o n Outcome
Hazard Ratios
Characteristics
Sex
Female
Male
Age
Type of lymphoma
Hodgkin’s
Non-Hodgkin’s
No. of relapses
1
22
Preparative regimen
Cy-TBI
Bu-Cy
BU-VP16-Cy
Disease status at BMT
Sensitive relapse
Resistant relapse
Type of graft
Allogeneic
Autologous
No. of
Patients
Event-Free
Survival
Relapse
33
85
0.74 (P = 2 3 )
0.93 (P = .82)
-
1.01 (P = .14)
0.99 (P = .48)
55
63
0.92 (P = .73)
0.65 (P = .18)
61
52
0.97 (P = .89)
1.02 (P = .96)
1.3 (P = .29)
0.81 (P = .6)
1.7 (P = .14)
1.4 (P = .6)
72
36
10
< ,001)
80
38
0.24 (P
38
80
0.84 (P = .49)
0.18 (P < ,001)
0.4 (P = .02)
P values are for the multivariate proportional hazards model. The
reference group for each categorical variable is the first patient group
listed, except for preparative regimens where the hazard ratios for
Bu-Cy and Bu-VP16-Cy are versus Cy-TBI.
Abbreviations: Cy-TBI, cyclophosphamide and TBI; Bu-Cy, busulfan
and cyclophosphamide; Bu-VP16-Cy, busulfan, etoposide, and cyclophosphamide.
From www.bloodjournal.org by guest on December 29, 2014. For personal use only.
GRAFT-VERSUS-LYMPHOMA EFFECT
651
both the autologous (range 2 to 60) and the allogeneic
(range 5 to 45) graft recipients. There were no significant
differences between the clinical features of patients in
sensitive relapse receiving either autologous or allogeneic
grafts (Table 2). The actuarial event-free survival of the
patients in sensitive relapse was 41% (28% to 53%) for the
autologous patients and 47% (24% to 67%) for the allogeneic patients (Fig 2A, P = 3 ) . However, the actuarial
probability of relapse after BMT was 46% (33% to 60%) for
patients with sensitive disease receiving autologous grafts
compared with only 18% (5% to 55%) for allogeneic graft
recipients with sensitive disease (Fig 2B, P = .02). The
difference in relapse rates between allogeneic and autologous transplants was similar for patients with Hodgkin’s
disease (24% difference) and non-Hodgkin’s lymphomas
(29%). Two patients relapsed after allogeneic BMT for a
sensitive lymphoma; neither patient had demonstrated any
evidence of acute GVHD, and one patient had developed
mild chronic GVHD involving only the mouth. Acute
GVHD developed in five of nine allogeneic patients in
sensitive relapse who survive event-free, and chronic GVHD
developed in three of these nine patients.
The type of marrow graft also influenced the transplantrelated mortality. Whereas 18 of 38 patients (47%) with
allogeneic grafts died of causes directly related to BMT, 17
of 80 patients (21%) with autologous grafts died of transplant-related causes (P = .007, Chi-square). We have previously shown that the status of the lymphoma at BMT also
influenced the peritransplant mortality, with patients in
resistant relapse having a significantly higher mortality.’
Patients in sensitive relapse also had a higher transplantrelated mortality after allogeneic BMT than following
autologous BMT; the peritransplant mortality was 42% (8
of 19) in allogeneic graft recipients compared with 13% (8
Table 2. Characteristics of Patients in Sensitive Relapse
by Type of Graft
-I
Q
2
>
U
A
I.On
3
v)
W
W
[L
t
2
w
>
w
LL
0
>
t
-I
-
m
a
m
0
[L
a
I .o-
w
cn 0.9 -
a
a 0.8-I
W
[L
0.7 -
0.6 F 0.5 -
LL
0
t
A
m
Q
m
0
[L
a
MONTHS
Fig 2. Actuarial probability of event-free survival (A) and relapse
(B) in the 61 patients who underwent autologous BMT 1-(
and the
19 patients who underwent allogeneic BMT (- -) for lymphomas in
sensitive relapse. The proportions event-free are 41% (28% to 53%)
and 47% (24% to 67%). respectively (P = .E). The probabilities of
relapse are 46% (33% to 60%) and 18% (5% to 55%), respectively
(P = .02).
No. of Patients
Characteristics
Autologous
Age
0-10
6
11-20
18
21-30
11
9
31-40
9
41-50
8
51-60
No. of relapses
1
43
2
14
23
4
Type of lymphoma
Hodgkin’s
20
Non-Hodgkin’s
41
Preparative regimen
Cy-TBI
46
Bu-Cy
15
Interval from diagnosis to BMT
(mean 2 SEM)
23 2 2.1 mo
*Chi-square test.
tstudent’s t-test.
Allogeneic
PValue
1
2
10
3
3
0
.09*
10
5
4
.16*
9
10
.38*
14
5
.79*
27 2 3.2 mo
.31t
of 61) in autologous graft recipients (P = .01, Chi-square).
Acute GVHD developed in 24 of the 38 allogeneic patients
(63%), and chronic GVHD developed in 8 of 25 allogeneic
patients (32%) who survived at least 100 days. The majority
of deaths resulting from allogeneic BMT (11 of 18 patients
overall and 5 of 8 patients in sensitive relapse) were related
to GVHD.
DISCUSSION
Our results show that for both Hodgkin’s disease and
non-Hodgkin’s lymphoma, the probability of relapse after
allogeneic BMT is decreased compared with autologous
BMT. All the autologous marrow grafts were morphologically free of lymphoma at the time of BMT, and were
purged ex vivo in an attempt to eradicate any occult
lymphoma cells that might have been present in the graft.
Nevertheless, it is possible that the difference in relapse
rates between autologous and allogeneic BMT was the
result of infusing viable lymphoma cells with the autologous
grafts. The relapse rates after autologous BMT for patients
From www.bloodjournal.org by guest on December 29, 2014. For personal use only.
652
JONES ET AL
with lymphomas in this report and others that use marrow
purging2‘,=are similar to studies that did not use p~rging.6,’”’~
However, the pattern of relapse in all of these studies
suggests that failure to eradicate lymphoma in the patient is
a more important cause of disease progression than infusion of occult lymphoma cells with the autologous marrow
graft, although we cannot completely discount that areas of
prior disease are “permissive” sites for the growth of tumor
cells infused with the autologous marrow graft. Therefore,
it is very unlikely that much of the difference in relapse
rates between autologous and allogeneic BMT is a consequence of reinfusingviable lymphoma cells with the autologous grafts; the decreased lymphoma recurrence after
allogeneic BMT likely results largely from an immunologic
graft-versus-lymphoma effect.
Previous studies have failed to show a graft-versuslymphoma effect with allogeneic BMT.6,7This is probably a
consequence of the limited statistical power of small sample
sizes rather than the result of differences in the biology of
the graft-versus-tumor effect between lymphomas and leukemias. In fact, both studies6,’ showed a trend toward a
lower relapse rate after allogeneic BMT. In addition, the
magnitude of the graft-versus-lymphoma effect in our
patients is similar to the reported graft-versus-leukemia
effect associated with allogeneic BMT.’s3.’ Allogeneic BMT
was associated with a 28% lower relapse rate than autologous BMT in our patients with sensitive lymphomas,
compared with 23% to 25% lower relapse rates than
syngeneic or autologous BMT in patients with acute leukemias in remission.'^^
The mechanisms responsible for the graft-versus-tumor
effect associated with allogeneic BMT are not completely
understood. Both acute and chronic GVHD appear to
generate antitumor activity.’.’ However, there also appears
to be a graft-versus-tumor effect with allogeneic BMT
separate from clinically apparent GVHD.4.’ There are too
few relapses in our patients who received allogeneic grafts
for sensitive lymphomas to evaluate the role of GVHD in
the graft-versus-lymphoma effect. The tumor cell kill provided by the graft-versus-tumor effect, although qualitatively very important, is probably quantitatively rather
small. Animal models suggest that a 25% to 50% improvement in relapse rate, as occurs with the graft-versus-tumor
effect, probably represents no more than 1 to 2 logs of
additional tumor cell kill over that provided by the preparative
However, this small amount of additional
tumor cell kill likely represents the most drug-resistant
population of cells.
As seen with acute leukemia: the improved control of
lymphoma with allogeneic BMT did not lead to an improvement in event-free survival (Fig 2). The beneficial graftversus-lymphoma effect with allogeneic BMT is offset by
increased peritransplant mortality, largely resulting from
GVHD. Nevertheless, its superior antitumor activity makes
allogeneic BMT an important approach for continued study
in patients with lymphoma, especially in those patients at
low risk for the complications of GVHD.
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From www.bloodjournal.org by guest on December 29, 2014. For personal use only.
1991 77: 649-653
Evidence of a graft-versus-lymphoma effect associated with allogeneic
bone marrow transplantation
RJ Jones, RF Ambinder, S Piantadosi and GW Santos
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