British Journal of Haematology 1999, 104, 763–769
A prospective study of risk-adapted therapy
for large cell non-Hodgkin’s lymphoma with VACOP-B
followed by high-dose CBV and autologous progenitor cell
transplantation for high-risk patients in remission
R OLF A. S TA HE L , 1 L O R E N Z M. J OST, 1 T HO M AS K RONER , 6 C O RI NA D O M M AN N -S CHE RRER , 3 R OB E RT M AU R E R , 5
C H R ISTOPH G L AN ZM AN N , 2 E M A NU E L J ACK Y, 1 G ABRIEL LA P ICH ERT, 1 B ER N HA R D P ES TAL OZZI , 1 B O RU T M AR IN CEK , 2
C H R ISTIA N S AU TER 1 A ND H AN SPE TER H O NE G G E R 4 1Division of Oncology, Department of Medicine, 2Department of
Radiology, and 3Institute of Pathology, University Hospital Zürich, 4Institute of Oncology and 5Institute of Pathology,
Stadtspital Triemli, Zürich, and 6Medizinische Poliklinik, Kantonsspital Winterthur, Switzerland
Received 27 August 1998; accepted for publication 7 December 1998
Summary. Several centres reported a favourable outcome
after high-dose chemotherapy with autologous progenitor
cell transplantation in selected patients with high-risk large
cell non-Hodkgin’s lymphoma in first remission. Based on
these observations, we wanted to prospectively determine the
outcome of a risk-adapted therapy for patients with large cell
lymphoma. Patients aged 60 years or less received 12 weeks
of VACOP-B chemotherapy. For high-risk patients in remission this was immediately followed by high-dose chemotherapy with cyclophosphamide, carmustine and etoposide
and autologous progenitor cell transplantation. High-risk
criteria were defined before the establishment of the
International Index and included large cell lymphoma
stage III or IV or mediastinal large lymphoma with sclerosis
stage II or higher, and the presence of bulky tumours and/or
an elevated LDH. 89 patients fulfilled the clinical selection
criteria and were entered onto this multicentre study. 82
patients were evaluable after confirmation of large cell
histology by pathology review. Of these, 51 were considered
to be in the low-risk group and 31 in the high-risk group.
The 3-year event-free survival for all patients was 68%. The
3-year event-free survival was 76% for the low-risk and 55%
for the high-risk group (P ¼ 0·061). Only 22/31 high-risk
patients were able to receive the high-dose chemotherapy in
first remission as intended. In conclusion, although our
study demonstrated that a risk-adapted therapy for large cell
lymphoma could be safely administered, the potential impact
on outcome of the strategy chosen here is likely to be small.
The outcome of treatment of large cell non-Hodgkin’s
lymphoma has not markedly improved over the last
decade. The comparison of conventional chemotherapy
with the CHOP regimen (cyclophosphamide, doxorubicin,
vincristine and prednisone) with so-called third-generation
regimens has demonstrated similar survival and a toxicity
profile favouring the CHOP regimen (Fisher et al, 1993). A
randomized study comparing autologous bone marrow
transplantation with salvage chemotherapy in relapse of
chemotherapy-sensitive non-Hodgkin’s lymphoma has
demonstrated an advantage for patients receiving highdose chemotherapy (Philip et al, 1993). The lack of advances
through modifications of conventional chemotherapy regimens and the possibility to identify groups of patients with a
higher likelihood of relapse has led several institutions to
perform high-dose chemotherapy with autologous progenitor cell transplantation in first remission for patients with
large cell lymphomas felt to be at high risk of relapse. The
EBMT registry reported a 70% 5-year progression-free
survival for high-grade lymphoma, excluding lymphoblastic
lymphoma treated in first complete remission (Sweetenham
et al, 1994).
Correspondence: Dr Rolf A. Stahel, Division of Oncology, Department
of Medicine, University Hospital, CH-8091 Zürich, Switzerland.
e-mail: onkstw@usz.unizh.ch.
䉷 1999 Blackwell Science Ltd
Keywords: large cell non-Hodgkin’s lymphoma, high-dose
chemotherapy, autologous progenitor cell transplantation,
high-risk patients, risk-adapted therapy.
763
764
Rolf A. Stahel et al
With the aim to prospectively determine the outcome of
therapy of large cell lymphoma stratified by two risk groups,
we initiated a three-centre study of risk-adapted chemotherapy with VACOP-B (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin), our
standard treatment at the time (Conners et al, 1990; Pichert
et al, 1992), followed by high-dose chemotherapy with CBV
(cyclophosphamide, carmustine and etoposide) and autologous progenitor cell transplantation for patients in
remsission classified to have a high risk of relapse according
to predefined histologic and clinical criteria. After a median
time of follow-up of 46 months, we report the survival
outcome according to the risk group and an analysis of the
actual treatment received.
PATIENTS AND METHODS
This prospective three-centre study was open from July 1991
to December 1995. The participating centres were the
Division of Oncology, Department of Medicine, University
Hospital, Zürich, the Institute of Oncology, Stadtspital
Triemli, and the Medizinische Poliklinik, Kantonsspital
Winterthur. Virtually all eligible patients seen at the
participating centres agreed to be treated in this study.
Patient selection. All patients aged 16–60 with previously
untreated large cell non-Hodgkin’s lymphoma stage I–IV
were offered VACOP-B chemotherapy. Exclusion criteria were
documented CNS disease, HIV infection, and a history of
prior malignancy. Histology in all cases was reviewed by a
panel of pathologists from the Institute of Pathology,
University Hospital of Zürich and the Institute of Pathology,
Stadtspital Triemli. The Kiel classification was used. Radiographs were reviewed by a staff member of the Department of
Radiology, University Hospital, together with the investigators. High-risk patients were candidates for high-dose
chemotherapy and autologous haemopoietic progenitor cell
transplantation, if a complete remission (CR) or a complete
remission with residual disease of unknown significance
(CRu, < 5 cm in diameter in previous bulk lesion) was
documented after VACOP-B and oral informed consent was
obtained. The high-risk group was defined as follows: large
cell lymphoma stage III or IV or mediastinal large cell
lymphoma with sclerosis stage II or higher, and the presence
of a lesion of > 10 cm in one dimension and/or with an
elevated serum LDH. Of the 89 fulfilling the clinical selection
criteria, large cell histology was confirmed in 82. Seven were
excluded because of mantle cell lymphoma (three patients),
unclassifiable bone marrow disease only (two patients),
lymphoplasmocytic or centroblastic-centrocytic lymphoma
(one patient each).
Regimens. The VACOP-B regimen was used as described
before (Conners et al, 1990; Pichert et al, 1992).
After documentation of response, high-risk patients underwent bone marrow harvest or later in the study
peripheral progenitor cell harvest after mobilization with
cyclophosphamide and filgrastim. For the progenitor cell
transplantation in first remission, unpurged bone marrow
was used in 15 patients, unpurged peripheral progenitor
cells in four patients and CD34-selected followed by CD10,
CD19 and CD20 purged peripheral progenitor cells in two
patients (Pichert et al, 1998). High-dose chemotherapy with
the CBV regimen consisted of cyclophosphamide (total
dose 6 g/m2 i.v.), etoposide (total dose 900 mg/m2 i.v.),
carmustine (total dose 300 mg/m2 i.v.), and mesna (total
dose 3·75 g/m2 i.v.). At least 0·2 × 105 CFU-C/kg were
reinfused. All but one patient received 5–20 mg/kg filgrastim
s.c. starting the day after bone marrow reinfusion until
granulocyte recovery, some patients as part of two
consecutive clinical studies (Stahel et al, 1994, 1997).
In addition to standard supportive care, patients received
a Pneumocystis carinii prophylaxis with cotrimoxazole for
3 months.
All patients not undergoing high-dose chemotherapy with
stage I or II disease and a tumour bulk >10 cm or patients
with extranodal involvement of the head and neck
region were to receive involved field irradiation to a dose of
36 Gy after completion of chemotherapy. Patients intended
for high-dose chemotherapy were discussed individually at
study entry with the radiotherapist involved in the study.
For patients with a single bulk lesion, in particular
mediastinal bulk, the intention was to administer consolidating radiotherapy with 36 Gy to this area after high-dose
chemotherapy.
After completion of therapy patients were followed
clinically every 3 months during the first 2 years, then
every 6 months up to 4 years and then yearly by the
participating centres. Radiological follow-up of previously
involved areas was performed every 6 months up to 2 years
and than yearly.
Statistical analysis. All patient data were entered into a
computerized data base after periodic review by the members
of the study group. Event-free survival was calculated from
start of therapy to either treatment failure, relapse from
achieved remission, death due to any cause, or the last
control documenting survival without evidence of disease.
Overall survival was calculated from start of therapy to
either death due to any cause or the last control documenting survival. Probabilities of event-free and overall survival
were calculated using the method of Kaplan-Meier. Survival
differences between subgroups were analysed by the logrank
test with a P value for significance set at 0·05.
RESULTS
Patient characteristics
Eighty-two eligible patients entered the study between July
1991 and December 1995 and were included in this
analysis. The patient characteristics are summarized in
Table I. The median age was 42 years; 42 patients were
male, 40 female. 31 patients (38%) were classified as highrisk; these included 26 patients with stage III or IV disease
who had bulky tumours and/or an elevated LDH at diagnosis
and five patients with stage II mediastinal large cell
lymphoma with sclerosis who had bulky tumours and/or
elevated LDH. The International Index (Shipp, 1994) derived
from the International non-Hodgkin’s Lymphoma Project
was published towards the end of accrual into our study.
䉷 1999 Blackwell Science Ltd, British Journal of Haematology 104: 763–769
Risk-adapted Therapy of Large Cell Lymphoma
765
Table I. Patient characteristics, histology, and predefined risk factors.
Patient demographics
Low-risk
group
High-risk
group
All
patients
No. of patients
51
31
82
Age (years)
Median
Range
45
19–60
35
16–59
42
16–60
Sex (no.)
Male/female
28/23
14/17
42/40
Histology (no.)
Centroblastic
Centroblastic-centrocytic diffuse
Mediastinal B-cell with sclerosis
Immunoblastic
Anaplastic Ki-1 positive
Other/unclassifiable
28
2
2
6
10
3
18
1
8
0
0
4
46
3
10
6
10
7
Immunophenotype
B-cell differentiation
T-cell differentiation
Not classified
39
7
5
26
4
0
65
11
5
Stage (no.)
I
II
III
IV
20
23
4
4
0
5
3
23
20
28
7
27
Presence of extranodal disease
Head and neck region
GI tract
6
5
1
0
7
5
ECOG performance score (no.)
0
1
2
3
4
32
14
3
2
0
9
10
3
7
2
41
24
6
9
2
Predefined risk factors (no.)
Elevated LDH
Tumour bulk >10 cm
12/50
10
28/30
24
40/80
34
Age-adjusted international index (no.)
Low risk
Low-intermediate risk
High-intermediate risk
High risk
27
22*
2
0
0
5
17*
9
27
27
19
9
* In one patient each missing LDH value at diagnoses were presumed normal.
To allow for comparison, a classification of our patients
according to the age-adjusted International lndex is included
in Table II.
Treatment results
The median potential time of follow-up for the 82 patients
was 46 months (range 20–73 months). The event-free and
overall survival at 3 years for all patients were 68% (95%
confidence interval [CI], 56–72%) and 73% (CI 61–81%),
respectively (Fig 1).
Fifty-one patients were classified as low-risk. Their eventfree and overall survival at 3 years were 76% (CI 61–86%)
and 83% (CI 70–91%), respectively. 48 patients in the lowrisk group completed 12 weeks of VACOP-B chemotherapy.
In one patient, treatment was withheld in complete
remission after 7 weeks because of acute and eventually
fatal viral hepatitis C. In one patient treatment was stopped
after 8 weeks because of cardiomyopathy and another
received early salvage therapy because of lack of response
after 6 weeks. Two patients received salvage therapy
䉷 1999 Blackwell Science Ltd, British Journal of Haematology 104: 763–769
766
Rolf A. Stahel et al
Table II. Results compared with the age-adjusted international
prognostic index.
This study
Index data
Risk group
No.
2-year survival
2-year survival
Low
Low-intermediate
High-intermediate
High
27
27*
19*
10
93%
78%
79%
44%
90%
79%
59%
37%
* One patient each with missing LDH value presumed normal.
following 12 weeks of VACOP-B because of insufficient
response and one patient with only partial remission
declined further therapy until symptomatic progression.
20/25 patients received the intended involved field irradiation
after completion of VACOP-B chemotherapy.
Thirty-one patients were classified as high-risk. Their
event-free survival and overall survival at 3 years were 55%
(CI 36–70%) and 53% (CI 31–70%), respectively. Three of
the high-risk patients did not complete VACOP-B chemotherapy as intended. One patient with T-cell nasal lymphoma
died of gastric bleeding and a syndrome of haemophagocytosis after the first week of chemotherapy. In one patient
VACOP-B was terminated after 8 weeks due to pulmonary
toxicity and one patient was switched to a salvage regimen
because of disease progression under VACOP-B.
Overall, only 22/31 patients (71%) received the high-dose
chemotherapy and autologous progenitor cell transplantation in first remission as intended. The median time from
start of chemotherapy to autologous bone marrow transplantation in first remission was 15 weeks. For the 22
patients transplanted in first remission, the median time
to recovery of granulocytes to 0·5 × 109/l was 11 d (range
9–19 d) and the median time to recovery of platelets
to 50 × 109/l was 20 d (range 10–29 d) after autologous
progenitor cell transplantation. The median time of
hospitalization was 23 d (range 19–48 d). There was no
treatment-related mortality. Eight patients relapsed after
high-dose therapy. The 3-year event-free survival and overall
survival of these 22 patients was 62%. There was no
difference of event-free survival or overall survival between
the eight patients transplanted in CR and the 14 patients
transplanted in CRu (logrank analysis, P ¼ 0·94 and 0·65,
respectively). Nine patients in the high-risk group received
the intended radiotherapy to initially single bulky lesions
after high-dose chemotherapy.
Nine of the 31 high-risk patients did not receive treatment
as intended. Reasons for not undergoing immediate highdose chemotherapy were death under VACOP-B (one
patient), insufficient response to VACOP-B (six patients),
pulmonary toxicity of VACOP-B (one patient) and patient
refusal (two patients). One patient with insufficient response
to VACOP-B received high-dose chemotherapy after salvage
treatment. The 3-year event-free survival for these nine
patients was 33%. The survivors included the two patients who
refused high-dose chemotherapy and the patient unable to
undergo high-dose chemotherapy because of pulmonary
toxicity.
Fig 2. Comparison of the calculated event-free survival (A) and
overall survival (B) between patients in the low-risk group (n ¼ 51)
and patients in the high-risk group (n ¼ 31).
Fig 1. Calculated event-free and overall survival after risk-adapted
therapy of 82 patients with large cell lymphoma.
A comparison of the survival after risk-adapted therapy
between the low and the high-risk group is depicted in Fig 2.
There was a trend, but not a significant difference, in eventfree survival between the low- and the high-risk group
(logrank analysis, P ¼ 0·061). Overall survival, however,
remained significantly better in the low-risk group (logrank
analysis, P ¼ 0·005).
䉷 1999 Blackwell Science Ltd, British Journal of Haematology 104: 763–769
Risk-adapted Therapy of Large Cell Lymphoma
DISCUSSION
The main purpose of this study was to prospectively
determine the outcome of a risk-adapted treatment for
large cell lymphoma. All patients received VACOP-B chemotherapy. Patients with large cell lymphoma stage III or IV and
patients with mediastinal large cell lymphoma with sclerosis
stage II or higher, with the presence of a tumour bulk and/or
elevated LDH at diagnosis were to receive high-dose
chemotherapy with CBV and autologous progenitor cell
transplantation in first complete remission. Since we set the
age limit of high-dose chemotherapy at 60 years, only
patients up to this age were included in the study. The 3-year
event-free and overall survival for all patients were 68% and
73%, respectively.
To define a group of high-risk patients, we used criteria
available in the literature at the time, including stage III or
IV, tumour bulk and elevated LDH (Shipp et al, 1986;
Jagannath et al, 1986; Coiffier et al, 1991). Two reasons
prompted us to include stage II mediastinal large cell
lymphoma with bulk or elevated LDH in the high-risk
group: the difficulty to classify the parenchymal lung
involvement often seen in this tumour as stage IIE or IV
and a report suggesting this particular histology to be of
high risk for treatment failure (Haioun et al, 1989). Using
our criteria, 62% of our patients were classified as low-risk
and 38% as high-risk. The 3-year event-free and overall
survival for the low-risk group were 76% and 83%,
respectively.
Previous single-centre studies on high-dose chemotherapy
in first complete remission in patients felt to be at high risk
for relapse reported very favourable data with relapse-free
survival of >80% in small numbers of patients (Nademanee
et al, 1992, 1997; Jackson et al, 1994). The EBMT registry
reported a 5-year progression-free survival of 70% in a series
of 102 patients with high-grade lymphoma, excluding
lymphoblastic lymphoma, receiving high-dose chemotherapy in first remission at various centres (Sweetenham
et al, 1994). These reports are based on patients referred to a
transplant centre and therefore are likely to represent a
favourable selection of patients. Only a prospective study
including as a denominator all patients potentially considered for treatment and an analysis of the results by treatment
intention will allow better definition of the outcome of highdose therapy in first remission. In our prospective study the
3-year event-free and overall survival for the 31 patients in
the high-risk group were 55% and 53%, respectively, by
intention to treat analysis. The event-free survival of the 22
patients receiving the treatment as intended was 64%, which
was similar to the EBMT experience, and, as expected, it was
considerably lower for the other nine patients not receiving
high-dose chemotherapy (33%).
The International Index was published towards the end of
accrual for our study (Shipp, 1994). To place the outcome of
our risk-adapted therapy within the framework given by
the age-adjusted international index, we have recalculated
our results according the performance status, stage and
elevation of LDH. The results are depicted in Table II. The
age-adjusted index maintained its ability to separate
767
prognostic groups in our risk-adapted approach (logrank
for trend, P ¼ 0·0017). Although our results in the low,
intermediate-low and high-risk group are similar to the
results of the age-adjusted index, the results appear slightly
better in the group of intermediate-high-risk patients.
The treatment outcome for the high-risk patients in
our study is similar to three other prospective phase II
studies with shorter follow-up which used high-dose
chemotherapy in first remission after conventional chemotherapy. Pettengell et al (1996) reported the outcome of 33
patients with high-risk lymphoma defined by stage, LDH and
Karnofsky index treated with VAPEC-B for 7 weeks, followed
by ifosfamide/cytarabine and high-dose busulphan/cyclophosphamide with autologous progenitor cell transplantation. 79% of their patients completed the treatment as
intended and the 2-year event-free survival and overall
survival were 61% and 64%, respectively. These results were
better than in a previous series of patients treated with 11
weeks of VAPEC-B alone. In another study (Vitolo et al,
1997), 50 patients with high-risk large cell lymphoma
selected by similar criteria as in our study were treated with
8 weeks of MACOP-B chemotherapy, followed by mitoxantrone, high-dose cytarabine and dexamethasone, and
subsequently BEAM with autologous progenitor cell support.
Only 70% of their patients completed treatment as intended
and the failure-free and overall survival at 32 months of
follow-up were 50% and 56% respectively (Vitolo et al,
1997). The comparison of an extended series of 61 patients
receiving this regimen with a historic control group
receiving MACOP-B alone suggested a benefit in event-free,
but not in overall, survival (Cortelazzo et al, 1997).
To date, only one large prospectively randomized study
directly comparing high-dose chemotherapy in first complete
remission with continuation of sequential chemotherapy at
conventional doses has been published (Haioun et al, 1994),
which has recently been updated (Haioun et al, 1997). In
this analysis the authors retrospectively introduced the
classification of patients according to the International
Index. Although no difference in survival was found by the
analysis of all 551 patients randomized, a significant
advantage in disease-free survival of high-dose chemotherapy and autologous bone marrow transplantation
compared to sequential chemotherapy was reported for the
236 patients in the high-intermediate and high-risk group
(5-year disease-free survival 59% v 39%, P ¼ 0·01). Two
other randomized studies of 35 or fewer patients per
treatment arm examined the impact of high-dose therapy
for slow responders or for partial responders to conventional
chemotherapy and failed to show an advantage for high-dose
chemotherapy (Verdonck et al, 1995; Martelli et al, 1996).
Our and other prospective phase II studies, as well the
retrospective analysis of the large randomized LNH87-2
study according to the International Index, report event-free
survival for patients with high-risk large cell lymphoma
between 55% and 65% after treatment with high-dose
chemotherapy in first remission (Pettgengell et al, 1996;
Vitolo et al, 1997; Haioun et al, 1994). This is less than
expected after the initial reports on selected patients. Whilst
awaiting results from ongoing randomized studies, one
䉷 1999 Blackwell Science Ltd, British Journal of Haematology 104: 763–769
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Rolf A. Stahel et al
could speculate how the treatment outcome might be
further improved. Certainly, a large proportion of patients
still relapse after high-dose therapy. One could therefore
postulate that, if high-dose therapy in first remission has a
place at all, repetitive cylces of high-dose treatment might be
needed. On the other hand, in our study, as well as in others
on high-dose therapy in first remission, over a quarter of
patients did not receive the treatment as intended mainly due
to insufficient response to the initial chemotherapy. In some
of these patients an early use of high-dose therapy might
alter the outcome. Gianni et al (1997) demonstrated a
superior event-free survival of early sequential high-dose
chemotherapy over MACOP-B or B-cell lymphomas without
bone marrow involvement. Stoppa et al (1997), using early
repetitive high-dose combination chemotherapy, reported a
2-year failure-free survival of 56% in 20 patients with
intermediate-high and high-risk large cell lymphoma
according to the International Index, an outcome within
the range of results of studies using high-dose consolidation.
In conclusion, although high-dose chemotherapy in first
remission of large cell lymphoma with a higher risk of
relapse can be safely administered, our study and others
suggest that the degree of of a potential improvement in
outcome is likely to be small. Formal proof of the efficacy
of high-dose chemotherapy in large cell lymphoma will
therefore require much larger collaborative studies.
ACKNOWLEDGMENT
This study was supported by grant AKT75 of the
Krebsforschung Schweiz.
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