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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3562-3568
The International Prognostic Index Correlates to Survival in
Patients With Aggressive Lymphoma in Relapse: Analysis of the PARMA
Trial
By
J.-Y. Blay,
F. Gomez,
C. Sebban,
T. Bachelot,
P. Biron,
C. Guglielmi,
A. Hagenbeek,
R. Somers,
F. Chauvin, and
T. Philip on
behalf of the PARMA Group
From the PARMA Cooperative Group (with Fédération
Nationale des Centres de Lutte Contre le Cancer [FNCLCC], Dutch
Haemato-Oncology Working Party [HOVON], European Organization for
Research and Treatment of Cancer [EORTC], Groupe d'Etude des
Lymphomes Adultes [GELA], and non-Hodgkin's Lymphoma Italian
Groups); Centre Léon Bérard, Lyon, France; Dipartimento Di
Biotecnologie Cellulari ed Ematologia, Università "La
Sapeinza," Roma, Italy; the University Hospital Rotterdam, Daniel
Den Hoed Cancer Center, Department of Hematology, Rotterdam, The
Netherlands; and University Hospital Utrecht, Department of Hematology,
Utrecht, The Netherlands; Antonie Van Leeuwenhoek Huis, The Netherlands
Cancer Center Institute, Internal Medicine Department, Amsterdam, The
Netherlands; and the Academic Medical Center, Internal Medicine
Department, Amsterdam, The Netherlands.
 |
ABSTRACT |
The objectives of the present study were to investigate the
prognostic value of the International Prognostic Index (IPI) at relapse
in the 215 patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) included in the PARMA trial. The IPI at relapse was
available in 204 (95%) of these patients. Response rates to 2 courses
of DHAP were 77%, 54%, 55%, and 42% in patients with an IPI of 0, 1, 2 and 3, respectively (P < .02), whereas complete response
(CR) rates were 33%, 29%, 20%, and 0% in the same groups of
patients (P < .03). With a median follow-up period of 79 months, overall survival (OS) at 5 years was 46%, 25%, 25%, and 11%
in these four groups (P < .001). One hundred nine patients
responding to 2 courses of DHAP were randomized to receive either BEAC
(carmustine, etoposide, cytarabine, cyclophosphamide and mesna)
followed by autologous bone marrow transplantation (ABMT)
or 4 additional courses of DHAP: IPI at relapse was found highly
correlated to OS in patients treated in the DHAP arm (5-year OS: 48%,
21%, 33%, and 0% for IPI 0, 1, 2, and 3, respectively; P = .006), but not in the BEAC arm (5-year OS: 51%, 47%, 50%, and 50%
for IPI 0, 1, 2, and 3, respectively; P = .90). OS was
significantly superior in the BEAC arm as compared with the DHAP arm in
patients with an IPI >0 (P < .05), but not in patients with
an IPI of 0. In conclusion, these results show that IPI correlates to
response and overall survival in patients with aggressive NHL in
relapse and enables us to identify patients with a significantly
different outcome among those treated with conventional chemotherapy
alone.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
THE PROGNOSIS OF aggressive
non-Hodgkin's lymphoma (NHL) in relapse treated with conventional
chemotherapy is poor, with a 5-year survival less than 20% in most
series.1-6 Since 1978, several pilot studies have suggested
that high-dose chemotherapy (HDCT) followed by hematopoietic stem cell
transplantation may improve the survival of patients with NHL in
relapse.7-16 Recently, the international prospective
randomized phase III PARMA trial demonstrated that consolidation with
HDCT improves both overall survival (OS) and progression-free survival
(PFS) in patients with intermediate- or high-grade NHL responding to
conventional salvage chemotherapy.17 However, still 40% to
80% of these patients experience a subsequent relapse and will die of
their disease after HDCT.6-17
Prognostic factors correlated to response to chemotherapy and survival
after the date of relapse have been identified: serum lactate
dehydrogenase (LDH) and clinical stage have been found correlated to response rate and survival in patients with aggressive lymphoma treated with conventional5 and high-dose
chemotherapy.7,11,12,14 The international prognostic index
(IPI) for aggressive lymphoma at initial diagnosis has been recently
described on a series of 3,273 previously untreated patients with
aggressive lymphoma.18,19 This index relies on five
different adverse prognostic factors (age >60 years; performance
status [PS] >1; LDH >normal; clinical stage >2;
and extranodal sites >1) and enables us to distinguish patients with
different response rates, patients who are progression free, and OS at
initial diagnosis. For patients less than 60 years of age,
an age-adjusted index relying solely on 3 prognostic factors (PS, LDH,
and clinical stage) was also reported.18
The objective of the present study was to investigate the prognostic
value of the IPI determined at the date of relapse in the 215 patients
with intermediate- or high-grade NHL in relapse treated in the
prospective PARMA trial.
| |
MATERIALS AND METHODS |
Patients.
A total of 215 patients, 18 to 60 years of age at the time of the first
relapse (188 patients) or second relapse (27 patients), with diffuse
centroblastic (n = 73, 34%), diffuse immunoblastic (n = 40,19%),
diffuse mixed small and large cells (n = 43, 20%), follicular large
cell (n = 12, 6%), diffuse small cleaved cell (n = 8, 4%),
lymphoblastic (n = 7, 3%), small noncleaved cell NHL (n = 5, 2%), and
diffuse histologies not otherwise specified (n = 27, 12%) NHL were
initially registered in the study between July 1987 and June 1994 in 51 participating centers.17
To be eligible, patients were required to have been previously treated
with a doxorubicin-containing regimen and to have had a first complete
response during at least 4 weeks. Relapses while on and while off
therapy were defined by the investigators. Central nervous system (CNS)
and bone marrow (BM) involvement at the time of relapse were considered
as exclusion criteria. Informed consent, according to the PARMA
protocol and to the rules of each institution and country, was obtained
from each patient.
Treatment.
All patients received the DHAP regimen (dexamethasone, cisplatin, and
cytarabine).4,17 After 1 course of DHAP, BM was harvested
under general anesthesia (except in 41 patients with clearly
progressive disease) and frozen, unless the marrow had been stored
previously (24 patients). BM biopsies taken at the time of harvesting
were normal in all patients. No patient received growth factors before
harvesting the BM and peripheral blood stem cells were collected in
none of these patients. Twenty days after a second course of DHAP,
patients with complete or partial responses were defined as having
chemotherapy-sensitive relapses and were eligible for random assignment
to one of the treatment groups: the autologous BM transplantation
(ABMT) arm or the conventional arm.17 The
conditioning regimen in the ABMT arm was BEAC (carmustine, etoposide,
cytarabine, cyclophosphamide, and mesna) with or without involved field
radiotherapy, followed by BMT.17 The conventional treatment
consisted of 4 additional courses of DHAP administered at intervals of
3 to 4 weeks. Radiotherapy was indicated if the sites of bulky disease
at the time of relapse were  5 cm in diameter or if extranodal T3 or
T4 lesions (according to the European Organization for Research and
Treatment of Cancer) were recorded. Details of all treatments were
given in a previous report.17
After randomization, each patient was evaluated in the allocated arm,
even if treatment was incomplete. In both arms, additional treatment
was allowed if the patient failed to respond to the assigned
treatment. Such additional treatment included high-dose chemotherapy and ABMT for patients in the DHAP conventional arm. No
specific conditioning regimen was recommended at this stage.
IPI at relapse and at initial diagnosis.
The analysis was performed with the data base updated at the end of
1995, with a median follow-up period of 79 months.
Only age-adjusted IPI was used in this cohort of patients 60 years of
age or less.18,19 The IPI was calculated from the available
data at the date of registration, ie, serum LDH, clinical stage, and
performance status at that date. Serum LDH, clinical stage, and
performance status were available in, respectively, 208 (97%), 213 (99%), and 213 (99%) of the 215 patients at the date of relapse and
184 (86%), 214 (99%), and 213 (99%) at initial diagnosis,
respectively. The IPI at initial diagnosis and relapse were thus
available respectively in 181 (84%) and 204 (95%) of the 215 patients.
Statistical methods.
Survival curves were computed according to the method of Kaplan and
Meier20 and compared using the two-sided log
rank test21 at the .05 significance level using the
LIFETEST procedure of the SAS statistical package (SAS
Institute Inc, Cary, NC). Other comparisons were performed using the
 2 of Pearson and Fisher exact tests.22
Correlation between IPI at diagnosis and at relapse was examined using
the Spearman correlation coefficient. Analysis of variance was
performed to compare time from initial diagnosis to relapse in the
different IPI subgroups. Because of insufficient number of patients,
subgroups of patients with different IPI were grouped together for
comparisons of survival.
| |
RESULTS |
Description of patients.
The characteristics of patients at relapse are given in
Table 1. Fifty-two patients (25%) were in the low-risk
group, 82 (40%) in the intermediate- to low-risk group, 51 (25%) in
the intermediate- to high-risk group, and 19 (9%) in the high-risk group. The correlation between IPI at initial diagnosis and IPI at
relapse was investigated among the 177 patients with an IPI evaluable
both at initial diagnosis and relapse. Only a limited correlation was
observed (Spearman's correlation coefficient = .33), because 23% of
patients with an IPI 0-1 had an IPI 2-3 at relapse, whereas 29% of
patients with an IPI 2-3 at initial diagnosis had an IPI 0-1 at relapse
(Table 2). Time from initial diagnosis to
relapse was not significantly different according to IPI at relapse:
median times were 15, 14, 13, and 15 months for IPI 0, 1, 2, and 3, respectively.
Prognostic value of IPI at relapse in the whole cohort.
The overall response rate and complete response rate were compared in
patients from the different risk groups
(Table 3). Response rates ranged from 75%
to 42% for patients with 0, 1, 2, or 3 risk factors (P < .02), whereas complete response rates in the same groups ranged from
33% to 0% (P < .03).
OS from the date of the first course of DHAP was compared in the
patients with an IPI 0, 1, 2, and 3 at relapse. Results are presented
in Fig 1. The median OS from the date of
relapse of the low-, intermediate- to low-, intermediate- to high-, and
high-risk groups were 58, 16, 9, and 5 months, respectively
(P < .001), indicating that IPI at relapse enables
us to discriminate patients with a significantly different OS after
relapse.
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| Fig 1.
OS of the 204 patients according to IPI at relapse. 0:
IPI = 0, low-risk group; 1: IPI = 1, intermediate- to low-risk
group; 2: IPI = 2, intermediate- to high-risk group; and 3: IPI = 3, high-risk group. Survival is calculated from the first day of the
first course of DHAP.
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OS according to the IPI at relapse and treatment arm.
One hundred nine patients in partial or complete response after 2 courses of DHAP were randomized and received either 4 additional courses of DHAP or a single course of HDCT with the BEAC regimen. Of
these 109 patients, IPI at relapse was available in 106 (97%). The OS
of patients treated in the DHAP and ABMT arms according to their IPI is
shown in Fig 2A and B. The 5-year OS of
patients treated in the DHAP arm were 48%, 21%, 33%, and 0% for IPI
0, 1, 2, and 3, respectively (P = .009). In contrast, in the
ABMT arm, the 5-year OS were 51%, 47%, 50%, and 50% for IPI 0, 1, 2, and 3, respectively (P = .90).
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| Fig 2.
OS of the 106 randomized patients according to IPI at
relapse. Survival is calculated from the first day of the first course
of DHAP. (A) Survival of patients in the DHAP arm according to the IPI.
(B) Survival of patients in the ABMT arm according to the IPI. (C)
Patients with IPI = 0, DHAP versus ABMT arm. (D) Patients with IPI
= 1-3, DHAP versus ABMT arm.
|
|
Figure 2C and D shows the outcome of the 106 patients from the low-risk
group (Fig 2C) or the intermediate- to low-, intermediate- to high-,
and high-risk groups (Fig 2D) according to their randomization arm. The
OS of patients in the low-risk group was slightly superior in the ABMT
arm, but the difference was not significant (Fig 2C; P = .59).
In contrast, patients with IPI >0 had a significantly superior
survival in the ABMT arm (Fig 2D; P < .05).
PFS according to the IPI at relapse and treatment arm.
The PFS of randomized patients was then investigated. The 5-year PFS of
patients treated in the DHAP arm were 21%, 14%, 0%, and 0%,
respectively, for IPI 0, 1, 2, and 3 (P = .03). In contrast, in
the ABMT arm, the 5-year PFS were 40%, 49%, 61%, and 100% for IPI
0, 1, 2, and 3, respectively (P = .51); it is noteworthy that there were only 2 patients in the IPI 3 subgroup with a 100% PFS, including 1 who died without disease at 16 months postregistration. Figure 3A and B show the PFS of patients
from the low-risk group (Fig 3A) or the intermediate- to low-,
intermediate- to high-, and high-risk groups (Fig 3B) according to
their randomization arm. The PFS of patients in the low-risk group was
slightly superior in the ABMT arm, but the difference was not
significant (Fig 3A; P = .50). In contrast, patients with IPI
>0 had a significantly superior survival in the ABMT arm (Fig 3B,
P < .0001). There were not significant differences in
patients with an IPI 0 treated in the DHAP and ABMT arms in terms of
histological subtypes or tumor mass (Table
4). Thirteen of the 17 IPI 0 patients randomized in the DHAP arm
relapsed subsequently; 7 of these patients received ABMT and 2 of them
are alive 19 and 73 months after registration in the PARMA; 6 patients
were not grafted and 2 of them are reported to be alive 10 and 82 months after registration in the PARMA.
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| Fig 3.
PFS of the 106 randomized patients according to IPI at
relapse. PFS is calculated from the first day of the first course of
DHAP. (A) Patients with IPI = 0, DHAP versus ABMT arm. (B) Patients
with IPI = 1-3, DHAP versus ABMT arm.
|
|
Prognostic value of IPI at relapse in patient refractory to DHAP.
The outcome of patients with aggressive NHL in relapse refractory to
salvage chemotherapy is very poor in all series of the literature. Even
with HDCT and hematopoietic stem cell transplantation, only 10% to
15% of these patients are alive disease-free at 5 years.10
IPI at relapse was available in 84 of the 90 (91%) DHAP-refractory
patients. Among these refractory patients, OS was not significantly different (P = .64) in the different IPI subgroups
(Fig 4).
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| Fig 4.
OS of the 84 patients refractory to DHAP according to IPI
at relapse. 0: IPI = 0, low-risk group; 1: IPI = 1, intermediate-
to low-risk group; 2: IPI = 2, intermediate- to high-risk group; 3:
IPI = 3, high-risk group.
|
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Information on the salvage treatment after failure of DHAP were
available in 88 of these 90 patients. The OS from the date of relapse
is significantly superior in the 18 patients who latter received HDCT
(Fig 5A; P = .01). It must be noted
that this treatment was not randomized, because patients were excluded
from the PARMA study at that point. Finally, IPI at relapse was
available in 82 of the 88 DHAP-refractory patients in whom information
on salvage treatment after DHAP was available. Seventeen of these 82 patients received HDCT as salvage treatment within the 3 months after
exclusion from PARMA, despite the absence of response to DHAP, and 65 received conventional chemotherapy (Fig 5B and C). Patients with an IPI 0-1 who were treated with HDCT were found to have a very significantly superior survival as compared with patients who had not received HDCT
(P = .01; Fig 5B), whereas the OS of patients with an IPI 2-3 at relapse who were treated with HDCT was comparable to that of other
patients (P = .4; Fig 5C). Because this was not randomized, these results do not demonstrate the superiority of HDCT over conventional salvage chemotherapy in patients with an IPI 0-1 at
relapse not responding to DHAP, although this hypothesis deserves to be
tested in a randomized trial.
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| Fig 5.
OS of the 84 refractory patients according to IPI at
relapse and the randomization arm. (A) Patients treated with HDCT
versus others among refractory patients. (B) Patients treated with HDCT
versus others among refractory patients with an IPI 0-1. (C) Patients
treated with HDCT versus others among refractory patients with an IPI
2-3. Of note, the sum of patients in (B) and (C) is not equal to the
total number of patients in the new (A), because IPI at relapse was not
available in 6 patients for whom information on treatment after failure
of DHAP was available (1 received HDCT and 5 received conventional
chemotherapy after failure of DHAP).
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| |
DISCUSSION |
This study was undertaken to investigate the prognostic value of the
IPI at relapse in a prospective cohort of patients with aggressive NHL
in relapse treated in a multicentric phase III protocol. The objectives
were also to evaluate the benefit of HDCT in the different prognostic
subgroups to identify patients who still have a poor outcome despite
HDCT and who therefore could be candidates for pilot studies with new
therapeutic approaches.
The results presented here show that the IPI at the date of relapse
enables us to distinguish patients with a very different response rate
to the DHAP regimen and a different survival. The proportion of
patients in each risk group was comparable to that reported in the
initial report of the IPI.18 However, it must be noted that
the PARMA trial selected a population of favorable patients without BM
or CNS involvement. In published series, 25% or more of relapsing
patients have either BM or CNS involvement10,11; therefore,
the incidence of patients in the unfavorable IPI subgroups is likely to
be higher in an unselected population. Previous reports have shown that
the response rate of patients with relapsing aggressive NHL is in the
range of 50% and, therefore, notably inferior to that of untreated
patients.1-7 Accordingly, the overall and complete response
rate to chemotherapy were found to be inferior to those observed for
untreated patients of the same IPI group.18 Importantly, the response rate, in particular complete response rate, decreased significantly according to the risk index. The complete response rate
in particular was 0% in patients with an IPI of 3, a subgroup that
should be proposed for other salvage regimens.
The IPI at relapse was also capable of distinguishing subgroups of
patients with a different survival after relapse. Interestingly, patients in the low-risk group were found to have a relatively favorable outcome, with a median survival of 56 months after relapse in
both randomization arms; 40% of these patients treated with 6 courses
of DHAP and no HDCT were alive at 6 years and 21% remained disease-free at that date. This survival rate is greater than that
usually reported for patients with aggressive NHL in relapse and
indicates that conventional chemotherapy without ABMT may be curative
in greater than 20% for patients with an IPI of 0. These results have
important consequences for the evaluation of salvage chemotherapy
regimens published in phase II trials, because the proportion of
patients within the low-risk group may strongly influence the response
rate and survival. The IPI at relapse is therefore an important
parameter to evaluate salvage chemotherapy regimens and to avoid
selection processes that would result in artificially high response
rates and OS in patients with aggressive NHL in relapse.
Although the number of patients in each subgroup is small, the results
presented here suggest that the magnitude of improvement achieved with
high-dose chemotherapy in terms of OS is different among risk groups.
HDCT apparently improved modestly the 5-year OS of patients in the
low-risk group, with an observed difference of 7% in 5-year OS between
the ABMT and the DHAP arms. Similarly, PFS was not significantly
different in the 2 groups, although it must be noted that the PFS of
IPI 0 patients treated in the DHAP arm was only 21% at 5 years
(v 40% in the ABMT arm), with 13 patients experiencing relapse
in the DHAP arm. The relatively favorable outcome of the subgroup of
IPI 0 patients treated in the DHAP arm is in part due to the fact that
4 of these patients experienced relatively prolonged survival after
relapse. In contrast, the 5-year OS and PFS of patients in the
intermediate-or high-risk subgroups were 30% to 50% higher in the
ABMT arm as compared with the DHAP arm. Although the number of patients
in each group was actually small and differences between intermediate-
and high-risk groups are only marginally significant, this result is
consistent with the recently reported conclusions of the LNH87 group 2 trial in patients receiving first-line chemotherapy.23 In
this study, patients with intermediate- or high-grade NHL with an IPI
>1 at initial diagnosis treated with HDCT were found to have a
significantly better disease-free survival and a marginally better OS
as compared with patients treated with standard consolidation
regimens.23 These results suggest that the survival
benefits of HDCT are superior in patients within the high-risk groups
as compared with those in the low-risk group. However, it must be
emphasized that these results do not indicate that low-risk group
patients do not benefit from HDCT, given the very low power of this
analysis and the absence of stratification on this criteria.
Patients who do not respond to salvage treatment have a uniformly poor
prognosis, with a 5-year survival close to 10% in all series.7-16 This indicates that response to conventional
chemotherapy in itself remains the most important prognostic factor for
OS in relapsing lymphoma patients. Eighteen patients not responding to
2 courses of DHAP received HDCT and hematopoietic stem cell (HSC) transplantation within the 3 months after the
second course of DHAP, including 17 patients with an available IPI at
relapse. These 18 patients were found to have a survival significantly superior to that of the 70 remaining patients; importantly, the difference was significant only for patients with an IPI 0-1. Despite
the well-established fact that patients refractory to salvage
chemotherapy have a very poor outcome with HDCT and are generally not
proposed for this therapeutic approach, these results suggest that
patients with an IPI 0-1 at relapse may behave differently and could
possibly benefit from HDCT, even though they are resistant to salvage
chemotherapy. This hypothesis could be tested in a prospective
randomized trial.
In conclusion, the results presented here indicate that the IPI at
relapse enables us to distinguish patients with a significantly different response rate and OS after salvage treatment. They strongly suggest that HDCT improves the survival of patients in response to DHAP
and with an IPI >0 and also possibly in nonresponding patients with
an IPI 0-1.
| |
ACKNOWLEDGMENT |
The authors thank M.D. Reynaud for expert secretarial assistance during
the making of this manuscript.
| |
FOOTNOTES |
Submitted March 11, 1998;
accepted July 8, 1998.
The PARMA study was supported by grants from the Ligue Nationale de
Lutte contre le Cancer (Ligues Départementales de la Haute-Savoie, Saône et Loire, Rhône, Ain, and
Ardèche), the University of Nebraska Medical Center, and the
"Programme Hospitalier de Recherche Clinique."
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
1734 solely to indicate this fact.
Address reprint requests to J.-Y. Blay, MD, PhD, Centre Léon
Bérard, 28, rue Laennec, 69008 Lyon, France; e-mail:
blay{at}lyon.fnclcc.fr.
| |
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Abstract
Introduction