High-dose CHOP plus etoposide (MegaCHOEP) in T

original article
Annals of Oncology 20: 1977–1984, 2009
doi:10.1093/annonc/mdp211
Published online 1 July 2009
High-dose CHOP plus etoposide (MegaCHOEP) in T-cell
lymphoma: a comparative analysis of patients treated
within trials of the German High-Grade Non-Hodgkin
Lymphoma Study Group (DSHNHL)
M. Nickelsen1*, M. Ziepert2, S. Zeynalova2, B. Glass1, B. Metzner3, M. Leithaeuser4,
H. K. Mueller-Hermelink5, M. Pfreundschuh6 & N. Schmitz1
1
Department of Hematology and Stem Cell Transplantation, Asklepios Hospital St Georg, Hamburg; 2Institute of Medical Informatics, Statistics and Epidemiology,
University of Leipzig; 3Clinic for Oncology and Hematology, Klinikum Oldenburg; 4Department of Hematology and Oncology, University of Rostock; 5Institute of
Pathology, University of Wuerzburg and 6Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany
Received 3 February 2009; accepted 13 March 2009
Background: T-cell lymphomas (T-NHL) generally carry a poor prognosis. High-dose therapy (HDT) and autologous
stem cell transplantation (ASCT) are increasingly used to treat younger patients.
dose-escalated CHOP plus etoposide (MegaCHOEP) necessitating repeated ASCT. Outcomes of patients with
mature T-NHL (excluding anaplastic lymphoma kinase-positive anaplastic large cell lymphoma) and aggressive B-NHL
were compared using multivariate Cox regression analysis.
Results: Compared with 84.4% of B-NHL patients, 66.7% of T-NHL patients were able to receive all treatments; the
rates of progressive disease were 27.3% in T-NHL and 16.3% in B-NHL patients. At 3 years, event-free survival (EFS)
and overall survival were significantly worse for T-NHL [25.9% confidence interval (CI) 10.4% to 41.4% and 44.5%
CI 26.5% to 62.5%) than for B-NHL patients (60.1% CI 52.1% to 68.1%; P < 0.001 and 63.4% CI 55.4% to 71.4%;
P = 0.016). In multivariate analysis, T-NHL was a strongly significant adverse risk factor for EFS (relative risk 2.2,
P = 0.001).
Conclusions: MegaCHOEP for T-NHL patients was no better than other high-dose regimens and was unable to
address the major problems of HDT/ASCT: neither early progressions nor early relapses were reduced. This study
sheds some doubt on expectations that HDT/ASCT will significantly improve outcomes for patients with T-NHL.
Key words: autologous transplantation, MegaCHOEP, T-cell lymphoma
introduction
In the Western world, 10%–15% of non-Hodgkin lymphomas
are of T-cell origin [1]. The median age at diagnosis usually is
>55 years and the majority of patients present with advanced
disease [2–4]. Prognosis is generally poor: among 1314 cases of
T-cell lymphoma reported to the International Peripheral T-Cell
and Natural Killer/T-Cell Lymphoma Study, the 5-year failurefree survival and overall survival (OS) were 18%–36% and 32%–
49%, respectively [1], when primary cutaneous and anaplastic
lymphoma kinase-positive (ALK+) anaplastic large cell
lymphoma (ALCL) were excluded. The T-cell phenotype
conveyed a worse outcome as compared with B-cell lymphoma
[2, 3] even before rituximab significantly improved the prognosis
*Correspondence to: Dr M. Nickelsen, Department of Hematology and Stem Cell
Transplantation, Asklepios Hospital St Georg, Lohmühlenstrasse 5, D-20099 Hamburg,
Germany. Tel: +49-40-1818-85-2005; Fax:+49-40-1818-85-4226; E-mail:
[email protected]
of aggressive B-cell lymphomas. The only exception is ALK+
ALCL which has a prognosis comparable to or even better than
aggressive B-cell lymphomas [5, 6]. We and others demonstrated
that patients with T-cell lymphoma receiving conventional
chemotherapy do poorly [7–10]. Therefore, nowadays many
patients receive high dose chemotherapy (HDT)/autologous
stem cell transplantation (ASCT) as part of first line therapy.
Many HDT studies, however, were retrospective and included
only patients who actually received HDT. This clearly
overestimates the role of HDT as first-line therapy because 30%
or more of T-cell lymphoma patients progress or do not achieve
complete response (CR)/partial response (PR) with conventional
chemotherapy and thus will not proceed to HDT/ASCT [11, 12].
The MegaCHOEP protocol designed by the German High
Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL)
represents a new concept of HDT which delivers high doses and
dose intensities of active drugs as early as possible after
diagnosis [13]. This strategy has been successfully used in
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
original
article
Design and methods: We treated patients <61 years with high-risk aggressive lymphoma with four to six courses of
original article
Annals of Oncology
younger patients with aggressive B-cell lymphoma [14]. Here
we show that the efficacy of MegaCHOEP seems more limited
in patients with mature T-cell lymphoma.
for DL III arm B) of MegaCHOEP. The 10 patients who were treated in the
phase III trial received four cycles of MegaCHOEP at DL II.
assessment of hematologic and extramedullary
toxic effects
design and methods
patients and methods
Eligible patients had to have a primary diagnosis of aggressive lymphoma
according to the World Health Organization (WHO) classification [15]
confirmed by a panel of expert hematopathologists, stages II–IV disease, age
18–60 years, and high-risk disease as defined by a lactate dehydrogenase
(LDH) level above the normal value (phase II studies) or an age-adjusted
international prognostic index (aaIPI) ‡2 (phase III study). The study
protocols were approved by the independent ethics committees at all
participating sites and patients gave informed consent. Patients with
lymphoma of the central nervous system, bone marrow infiltration >25%
by histology, known HIV infection, or any major organ dysfunction were
excluded. From January 1997 to February 2006, a total of 498 patients from
75 centers were enrolled into subsequent phase II trials [13, 14] and a phase
III trial which is still running for aggressive B-cell lymphoma. (http://
www.clinicaltrials.gov/ct2/show/NCT00129090). All consecutive 33 patients
with mature T-cell lymphoma excluding ALK+ ALCL were analyzed.
Results were compared with 147 patients with aggressive B-cell lymphoma
who had been treated with MegaCHOEP [13, 14].
staging
Patients were staged according to the Ann Arbor criteria. Individual histories,
physical examination, and blood tests were taken from all patients. We
required a bone marrow biopsy as well as thoracic and abdominal computed
tomography scans; further imaging procedures were optional. Other
diagnostic procedures were carried out when clinically indicated.
chemotherapy
Three consecutive phase I/II trials were run by the DSHNHL in order to
evaluate the feasibility, safety, and efficacy of the MegaCHOEP program.
The overall results of dose levels (DL) I and II and DL III have been
published [13, 14]. Briefly, chemotherapy consisted of either four courses
(DL I, DL II, and DL III arm A) or six courses (DL III arm B) of
cyclophosphamide (CY), adriamycin, vincristine, etoposide, and
prednisone given at high doses and short time intervals (Figure 1). The
doses of drugs varied between DLs and individual treatment courses as
described. The last three courses of HDT were followed by transplantation
of autologous blood stem cells which had been harvested after stimulation
with granulocyte colony-stimulating factor after courses 1 and 2 (3 and 4
PBPC
Organ toxic effects were evaluated according to the Bearman criteria [16];
infections were classified using WHO criteria. Patients on DLs I and II were
to receive the next course of MegaCHOEP as soon as they had achieved
a platelet count >80/nl, had cleared any active infection, and toxic effects of
heart, bladder, kidney, lungs, central nervous system, gastrointestinal tract,
and stomatitis were graded 0; liver toxicity could be either 0 or1. Patients
treated on DL III and on the phase III trial continued treatment on day 21 if
toxic effects had resolved.
response evaluation and definitions
Response was assessed 3 months after therapy had ended. Patients with
disappearance of all pathologic lesions for at least 2 months after final
restaging were considered complete responders. Patients with lesions
representing residual masses after therapy but no indication of active
disease necessitating further therapy were classified as unconfirmed CR
(CRu). PR was defined by a ‡50% regression at all tumor sites. Progressive
disease was defined as tumor growth at at least one site of more than 25%.
Tumor regression of £50% at all sites or tumor growth of maximal 25% was
defined as stable disease (SD). All patients who did not reach CRu at final
restaging were deemed failures and were candidates for salvage therapy at
the discretion of the treating physician. Routine positron emission
tomography scans were not required.
statistical analysis
OS was measured from the beginning of therapy to death from any cause.
Event-free survival (EFS) was defined as the time from the beginning of
therapy to disease progression, initiation of salvage therapy, or additional
(off-protocol) treatment, relapse, or death from any cause. Patients without
an event in OS or EFS were censored. The Kaplan–Meier method was used
to compare OS and EFS of B and T-cell patients. The estimators at 3 years
are given with 95% confidence intervals. Differences between Kaplan–Meier
curves were assessed using the log-rank test. Multivariate analysis of OS and
EFS was carried out using the Cox proportional hazards model. We
adjusted for the factors of the aaIPI: performance status according to the
Eastern Cooperative Oncology Group (ECOG) classification (0, 1 versus
‡2) and stage (I/II versus III/IV). Serum LDH was not included because
elevated LDH had been an inclusion criterion for the phase II studies.
Binary data from the patient’s characteristics were compared using chisquare tests and, if required, Fisher’s exact tests. Age was compared using
PBPC
mCHOEP 1
mCHOEP 2
mCHOEP 3
CYC 1500
ADR 70
VCR 2
ETO 450 (600)
PRD 500
CYC 4500
ADR 70
VCR 2
ETO 600 (960)
PRD 500
CYC 4500
ADR 70
VCR 2
ETO 600 (960)
PRD 500
PBPC
mCHOEP 4
CYC 6000
ADR 70
VCR 2
ETO 1480
PRD 500
Figure 1. Study design of MegaCHOEP dose levels (DLs) I and II. The etoposide doses of DL II are given in parentheses. At DL III patients received either 1
cycle with the dose of the first cycle of DLs I (yellow) followed by 3 cycles identical to the last cycle of DLs I and II (red, 4 courses total), or 3 courses of cycle
1 DL II (yellow) followed by 3 cycles identical to the last 3 cycles of DL II (orange and red, 6 courses total).
1978 | Nickelsen et al.
Volume 20 | No. 12 | December 2009
original article
Annals of Oncology
the Mann–Whitney U-test. Statistical analyses were carried out using the
statistical software package SPSS/PC+ V10.0. All P values £0.05 were
considered to be significant.
results
patients
From January 1997 to February 2003, 312 patients were enrolled
into the MegaCHOEP phase I/II trials. Twenty-three patients with
mature T-cell lymphoma (no ALK+ ALCL) who had been treated
on these trials were eligible for this analysis. Furthermore, 10
patients with T-cell lymphoma out of 186 patients included into
the MegaCHOEP phase III trial from February 2003 to February
2006 are included. Of these 33 patients, 13 patients (39.4%) had
ALK2 ALCL, 11 (33.3%) had peripheral T-cell lymphoma
unspecified, four (12.1%) had angioimmunoblastic T-cell
lymphoma, three (9.1%) had NK/cytotoxic T-cell lymphoma, and
one patient (3.0%) each had intestinal T/NK cell lymphoma or Tlymphoblastic lymphoma. The histological subtypes and
characteristics of patients with T- and B-cell lymphomas are
shown in Tables 1 and 2. The median age of all patients was 46
years; median observation time for EFS was 4.4 years. Patients
with B-cell or T-cell lymphoma did not statistically differ with
respect to age, gender, aaIPI, LDH, performance status, extranodal
disease, number of extranodal sites, and B-symptoms. The only
statistically significant differences were a higher proportion of
patients with stage III/IV disease (84.4% versus 66.7%; P = 0.039)
and a lower proportion of patients with bulky disease (24.2%
versus 69.9%; P < 0.001) in the T-cell lymphoma group (Table 1).
treatment outcome
There was no difference in outcome of T-cell lymphoma
patients treated on phase II or phase III trials. Therefore, all 33
patients were analyzed together. Twenty-two of 33 patients
(66.7%) received all planned therapy. Reasons for early
termination of therapy were progressive or SD in four patients
(12.1%), extensive toxicity in six patients (18.2%), and
protocol violation in one patient (3.0%). Sixteen of 33 patients
(48.5%) achieved a CR or CRu, two patients (6.1%) achieved
a PR, three patients (9.1%) had SD, nine patients (27.3%)
progressed within 2 months after final restaging or during
therapy, one patient had an unknown response at the end of
treatment, and two therapy-related deaths were observed.
Table 1. Histological subtypes
T-NHL subtypes
n = 33 (%)
B-NHL subtypes
n = 147 (%)
ALCL/ALK2
13 (39.4)
PTCL
AITL
T/NK
Intestinal T/NK
Lymphoblastic
11
4
3
1
1
DLBCL
Primary mediastinal
Follicular, centroblastic
Blastic mantle cell
Burkitt-like
Blastic marginal zone
Aggressive B-NHL
unspecified
123 (83.7)
22
4 (2.7)
3 (2.0)
2 (1.4)
1 (0.7)
14 (9.5)
(33.3)
(12.1)
(9.1)
(3.0)
(3.0)
ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase;
PTCL, peripheral T-cell lymphoma; AITL, angioimmunoblastic T-cell
lymphoma.
Volume 20 | No. 12 | December 2009
In the B-cell lymphoma group, 124 of 147 patients (84.4%)
received all planned therapy. The reasons for stopping therapy
early were as follows: progressive disease (n = 2, 1.4%), extensive
toxicity (n = 16, 10.9%), protocol violation (n = 2, 1.4%),
mobilization failure (n = 2, 1.4%), and other reason (n = 1,
0.7%). Ninety-nine of 147 B-cell lymphoma patients (67.3%)
achieved CR/CRu, 7.5% of patients had a PR (n = 11), 0.7% of
patients experienced SD (n = 1), 24 patients (16.3%) showed
primary progressive disease, and six patients (4.1%) had
unknown response at the end of treatment; there were six
therapy-related deaths (4.1%). EFS at 3 years was significantly
worse for T-cell (25.9%, 95% CI 10.4% to 41.4%) than for B-cell
lymphoma patients (60.1%, 95% CI 52.1% to 68.1%; P < 0.001)
as was OS [44.5% (95% CI 26.5% to 62.5%)] versus 63.4% (95%
CI 55.4% to 71.4%), P = 0.016, Figure 2). With a median followup of 4.4 years, 18 of 33 (54.5%) T-cell lymphoma patients and
55 of 147 (37.4%) B-cell lymphoma patients have died. The
causes of death were as follows: lymphoma (15 T-cell lymphoma
patients, 46 B-cell lymphoma patients, 45.5% versus 31.3%),
therapy related (two T-cell lymphoma patients, five B-cell
lymphoma patients, 6.1% versus 3.4%), lymphoma and therapy
related (one B-cell lymphoma patient, 0.7%), secondary
neoplasia (two B-cell lymphoma patients, 1.4%), intercurrent
disease (one T-cell lymphoma patient, 3.0%), or unknown (one
B-cell patient, 0.7%) (see Figure 3).
Of 14 patients with T-cell lymphoma who achieved a CR or
CRu after receiving all planned treatment, seven patients relapsed
7–46 (median 10) months after start of treatment. All relapses
were chemosensitive. Three patients achieved a second CR with
Table 2. Patient characteristics
n
Median age (range)
Male
Female
LDH above the normal value
ECOG >1
Stage III/IV
aaIPI 1
aaIPI 2
aaIPI 3
More than one EN sites
Extranodal involvement
Bulk ‡7.5 cm
B-symptoms
MegaCHOEP treatment
Phase II trial
4· dose level 1
4· dose level 2
4· dose level 3a
6· dose level 3a
Phase III trial
4· dose level 2
T-NHL, n (%)
B-NHL, n (%)
33
48
22
11
32
12
28
3
21
9
11
27
8
23
(20–60)
(66.7)
(33.3)
(97.0)
(36.4)
(84.4)
(9.1)
(63.6)
(27.3)
(33.3)
(81.8)
(24.2)
(69.7)
147
46
87
60
147
43
98
39
75
33
52
97
102
89
4
5
10
4
(12.1)
(15.2)
(30.3)
(12.1)
10 (30.3)
31
61
37
18
(18–60)
(59.2)
(40.8)
(100.0)
(29.3)
(66.7)
(26.5)
(51.0)
(22.4)
(35.6)
(66.0)
(69.9)
(60.5)
(21.1)
(41.5)
(25.2)
(12.2)
–
a
Similar total doses, but different number of cycles.
LDH, lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group;
EN, extranodal.
doi:10.1093/annonc/mdp211 | 1979
original article
Annals of Oncology
different salvage regimens (FCD—fludarabine, CY, and
dexamethasone—and radiotherapy, MTX-based salvage therapy
and allogeneic stem cell transplantation (SCT), gemcitabinebased salvage therapy, and allogeneic SCT, respectively) and are
alive and well. Two patients died after allogeneic transplantation
in PR or with unknown disease status. One patient was lost to
follow-up early after salvage treatment; one patient (with Tlymphoblastic lymphoma) had a second meningeal relapse
shortly after allogeneic SCT and died from lymphoma.
Nine of 11 patients with stable or progressive disease during
or after MegaCHOEP received salvage therapy. Two patients
achieved a CR: the first patient received five cycles of
fludarabine and CY (FC) and died from lymphoma 41 months
after diagnosis; the second died due to graft versus host disease
and infections after allogeneic transplantation. One patient
received different salvage regimens, never achieved a stable
remission, and died from a lymphoproliferative disorder after
allogeneic transplantation 21 months after diagnosis. Seven
patients did not reach any stable remission; six died from
lymphoma 2–9 months after diagnosis, one patient left
Germany in progressive disease and was lost to follow-up.
Five of 11 patients who did not complete the MegaCHOEP
program received CHOP-like treatment. Of these patients, one
reached a CR (after one course of MegaCHOEP followed by
five cycles of CHOEP-14), a second achieved CRu (after two
courses of MegaCHOEP followed by four courses of CHOP21). The second patient relapsed 10 months after diagnosis,
reached second CR after autologous transplantation and died
from cardiac disease in second relapse. Two patients achieved
PR after CHOP-like treatment, received salvage therapy
(ESHAP and radiotherapy, allogeneic SCT) and are in ongoing
first CR. One patient had SD after one cycle of MegaCHOEP,
two cycles of CHOP-14, and one cycle of CHP. He received FC
salvage therapy and died from primary progressive disease. One
further patient received six cycles of CHOP after one cycle of
MegaCHOEP and reached a CR after BEAM consolidation. The
patient relapsed and died 20 months after diagnosis.
Figure 2. Event-free survival (A) and overall survival (B).
prognostic factors
In a multivariate Cox model which analyzed EFS for the
‘histological subtypes’ T- or B-cell lymphoma, adjusted for the
aaIPI factors ‘performance status’ and ‘stage III/IV’ (LDH had
been an inclusion criterion for the phase II studies), the T-cell
lymphoma patients had a 2.2-fold increased relative risk (RR)
of any event (P = 0.001). The risk factors of the aaIPI were
significant: the RR of patients with an ECOG >1 was 1.8-fold
(P = 0.007), of patients with stage III/IV disease was 2.2-fold
(P = 0.006) higher than in patients without these risk factors
(Table 3).
discussion
Figure 3. Causes of death for patients with T- or B-cell lymphoma.
1980 | Nickelsen et al.
The MegaCHOEP regimen was developed for younger patients
with aggressive lymphoma and poor prognosis. The results for
patients with B-cell lymphomas were promising [13, 14] and
led to the design of a randomized phase III study comparing
MegaCHOEP to an intensified conventional treatment regimen
(CHOEP-14).
Volume 20 | No. 12 | December 2009
original article
Annals of Oncology
Table 3. Risk factor analysis of EFS and OSa
Factor
EFS
T-cell versus B-cell
ECOG >1
Stage III/IV
OS
T-cell versus B-cell
ECOG >1
Stage III/IV
Relative risk
95% Confidence
interval
P value
2.2
1.8
2.2
1.4–3.5
1.2–2.8
1.3–3.7
0.001
0.007
0.006
1.6
1.4
2.6
1.0–2.8
0.9–2.3
1.4–4.8
0.068
0.168
0.003
a
Cox model adjusted for international prognostic index factors.
EFS, event-free survival; OS, overall survival; ECOG, Eastern Cooperative
Oncology Group.
Here we present an analysis of T-cell lymphoma patients
treated with MegaCHOEP. In contrast to 84.4% of B-cell
lymphoma patients, only 66.7% of T-cell lymphoma patients
were able to complete therapy as per protocol. This is
comparable to other prospective HDT studies where the rate of
patients proceeding to transplantation after conventional firstline therapy was between 41% and 74% [11, 12, 17–19], the
main reason for early drop-outs being primary progressive
disease. The studies published by Corradini et al. [17], Reimer
et al. [11], and Mercadal et al. [12] included ALK2 patients
with a more favorable risk profile (aaIPI > 1 in 44%–72% of
patients compared with 91% of patients, elevated LDH in 54%–
63% of patients compared with 97% in our study, respectively).
The rates of early failures in these studies were 24% [17], 30%
[11], and 44% [12] resulting in 3-year OS of 48% and 50% [11,
17] and 4-year OS of 39% [12], respectively. Three- or 4-year
progression-free survival was <40% in all these studies.
d’Amore et al. [19] published an abstract on a large series of Tcell lymphoma patients treated with six cycles of CHOEP-14
followed by BEAM and ASCT. About 55% of patients presented
with an aaIPI ‡2 F. d’Amore (personal communication) and
the rate of patients actually receiving transplantation (75%) was
relatively high; this study has not been fully published so far.
Although the rate of patients with progressive or SD under
treatment was relatively low (12.1%) with MegaCHOEP, the
CR/CRu rate at restaging 3 months after end of therapy was
only 48.5%; the rate of primary progressive disease had
increased to 27.3%. Furthermore, MegaCHOEP could not be
completed in 18.2% of patients due to excessive toxicity.
Patients with early treatment failure had a poor outcome. No
patient with SD or progressive disease at restaging (n = 12) was
finally cured. At the time of the analysis, only 10 patients were
in ongoing first CR after MegaCHOEP (n = 7), CHOP-like
therapy (n = 1), or alternative treatment (n = 2). These results
are comparable to those from other studies: Rodriguez et al.
[20] published a DFS of 60% for patients in CR after HDT, but
these patients had better prognostic factors: only 60% of
patients presented with an aaIPI >1 compared with 91% in our
study. Additionally, 20% of patients in the published analysis
had ALCL without discrimination between ALK+ and ALK2
patients. The GELA [21] presented data on a cohort of mature
T-cell lymphoma patients younger than our population
Volume 20 | No. 12 | December 2009
(median 36 years) but otherwise comparable (28 patients, no
ALCL, 75% aaIPI > 1). OS and EFS for patients who had been
transplanted in first CR were 49% and 45%, respectively. In
contrast to our population, patients had reached CR before HD
therapy. Corradini et al. [17] published long-term follow-up
data on ALK2 patients treated with HDT and reported 12-year
OS and EFS of 21% and 18%, respectively. All prospective
studies published so far show that <40% of the patients with Tcell lymphomas were cured by HDT/ASCT. Prospective
randomized studies comparing HDT/ASCT with conventional
chemotherapy are warranted before HDT/ASCT may be
considered standard therapy for younger patients [22]. The
majority of T-cell lymphoma patients fail first-line treatment
and will need alternative therapy. Recently, several retrospective
analyses showed promising results with allogeneic
transplantation [23–25] while the efficacy of new drugs awaits
further study [26, 27].
In conclusion, the results obtained with the MegaCHOEP
protocol in patients with T-cell lymphoma were no better than
other phase II studies using HDT/ASCT as part of first-line
therapy. The foremost goal of the protocol—applying increased
doses and dose intensity of active drugs as early as possible [14]
to improve results by preventing early progression—was not
achieved. Therefore, the DSHNHL decided to stop recruitment
of T-cell lymphoma patients into the MegaCHOEP phase III
trial. A phase III study which will compare classical
chemotherapy followed by conventional HDT/ASCT to reduced
intensity conditioning followed by allogeneic transplantation in
patients with T-cell lymphoma will start shortly.
acknowledgements
We like to thank the ‘Deutsche Krebshilfe’ for supporting the
MegaCHOEP phase III trial and Mrs Kristina Kocksch for data
management of the phase III trial and Beate Mann and Ulrike
Schoenwiese for data management of the phase II trials. The
following investigators and institutions are members of the
German High Grade Lymphoma Study Group:
Saarland University Medical School, Homburg,
Germany—M Pfreundschuh; University Hospital,
Magdeburg, Germany—M Mohren; Mannheim Hospital,
Mannheim, Germany—E Lengfelder; University
Hospital, Köln, Germany—M Reiser; Großhadern der LMU
Hospital, München, Germany—C Nickenig; Hospital
Maternity House of Borromäerinnen, Trier, Germany—MR
Clemens; Carl-Thiem Hospital, Cottbus, Germany—N Peter;
University Hospital Eppendorf, Hamburg, Germany—M
deWit; St Josefs and St Marien Hospital, Hagen, Germany—H
Eimermacher; Medical Hospital, Ruprecht-Karls University,
Heidelberg Germany—A Ho; Stadt Ludwigshafen Hospital,
Ludwigshafen, Germany—M Hoffmann; University Hospital,
Freiburg, Germany—R Mertelsmann; AK St Georg, Hamburg,
Germany—N Schmitz; Georg August University, Göttingen,
Germany—L Trümper; Evangelisches Krankenhaus
Hamm, Germany—L Balleisen; University Hospital,
Münster, Germany—R Liersch; Städtische Hospital, Oldenburg,
Germany—B Metzner; Evangelisches Diakonie-Krankenhaus,
Bremen, Germany—KH Pflüger; University Hospital, Essen,
Germany—U Dührsen; Städtisches Krankenhaus Martha-Maria,
doi:10.1093/annonc/mdp211 | 1981
original article
Halle/Saale, Germany—W Schütte; St Bernward Krankenhaus,
Hildesheim, Germany—U Kaiser; Städtisches Hospital,
Karlsruhe, Germany—M Bentz; Katharinen Hospital,
Stuttgart, Germany—HG Mergenthaler; University Hospital,
Ulm, Germany—S Wessendorf; University Hospital Clinic,
Bonn, Germany—T Sauerbruch; St Antonius Hospital,
Eschweiler, Germany—R Fuchs; Klinikum rechts der Isar,
München, Germany—C Peschel; Dr Horst-Schmidt Hospital,
Wiesbaden, Germany—N Frickhofen; University Hospital
Charité, Berlin, Germany—G Dölken; University Hospital
Benjamin Franklin, Berlin, Germany—E Thiel; University
Hospital, Rostock, Germany—M Freund; Helios Hospital,
Wupperta, Germany—A Raghavachar; Städtisches Klinikum St
Georg, Leipzig, Germany— L Mantovani-Löffl er; Krankenhaus
Maria-Hilf II Franziskushaus, Mönchengladbach, Germany—U
Graeven; Rostock Südstadt Hospital, Rostock, Germany—B
Krammer-Steiner; St Marien Hospital, Amberg, Germany—L
Fischer von Weikersthal; Zentralklinikum, Augsburg,
Germany—G Schlimok; Krankenhaus Nordwest Frankfurt,
Frankfurt/Main, Germany—E Jäger; joint medical practice:
Aldaoud/Schwarzer, Leipzig, Germany—A Aldaoud; Sana
Kliniken Lübeck GmbH, Krankenhaus Süd, Lübeck,
Germany—S Fetscher; St Antonius Hospital, Wuppertal,
Germany—M Sandmann; Rigshospitalet, DK-Kopenhagen,
Germany—M Hansen; Städtische Krankenanstalten, Krefeld,
Germany—T Frieling; University Hospital Schleswig-Holstein,
Lübeck, Germany—T Wagner; St Vincentius Hospitals,
Karlsruhe, Germany—J Mezger; Altstadt Hospital, Magdeburg,
Germany—E Kettner; Oncological Priority Practice, Münster,
Germany—C Lerchenmüller; St Marienkrankenhaus, Siegen,
Germany—T Gaska; Kreiskrankenaus, Aurich, Germany—W
Langer; Märkische Hospital, Lüdenscheid, Germany—G Heil;
University Hospital Regensburg, Regensburg, Germany—R
Andreesen; Allgemeines Krankenhaus, Celle, Germany—S
Hollerbach; Ernst von Bergdamm Hospital, Potsdam,
Germany—G Maschmeyer; Kantonsspital, CH-St Gallen,
Germany—T Cerny; Municipal Hospital, Braunschweig,
Germany—B Wörmann; Franz Hospital, Dülmen, Germany—G
Dresemann; Johann-Wolfgang-GoetheUniversity Hospital,
Frankfurt/Main, Germany—L Bergmann; Municipal Hospital,
Fulda, Germany—H G Höff kes; Ernst-Moritz-Arndt University,
Greifswald, Germany—G Dölken; Amtssygehuset i Herlev, DKHerlev, Germany—H Johnsen; St Vincenz-Krankenhaus,
Limburg, Germany—KP Schalk; Bürgerhospital, Stuttgart,
Germany—HG Mergenthaler; Krankenhaus der Barmherzigen
Brüder, Trier, Germany—C B Kölbel; Kantonsspital, CH-Baden,
Germany—J H Beer; Ceske Budesovice Hospital, CZBudesovice, Germany—J Fischer; Allgemeines Krankenhaus,
Hagen, Germany—T Scholten; St Elisabeth and St Barbara
Krankenhaus, Halle/Saale, Germany—R Willenbrock; St
Marienhospital, Hamm, Germany—H Dürk; Medizinische
Hochschule, Hannover, Germany—A Ganser; Municipal
Hospital, Hildesheim, Germany—F Schmitz; KMT-Klinik, IdarOberstein, Germany—A A Fauser; Evang Stift St Martin,
Koblenz, Germany—HH Dormeyer; Municipal Hospital,
Nettetal, Germany—M Pauw; joint medical practice: Otremba/
Reschke/Hinrichs, Oldenburg, Germany—B Otremba; Diakonie
Hospital, Stuttgart, Germany—R Mück; Kreiskrankenhaus,
Waldbröl, Germany—S Brettner; joint medical practice: Hahn/
1982 | Nickelsen et al.
Annals of Oncology
Müller, Ansbac, Germany—M Hahn; Kreiskrankenhaus am
Plattenwald, Bad Friedrichshall, Germany—D Bürkle;
Ermstalklinik, Bad Urach, Germany—M Schmelz; Oncology
Institute of Svizzera Italiana, CH-Bellizona, Italy—E Zucca;
Practice for Haematology and Oncology, Freiburg, Germany—T
Reiber; Practice for Haematology and Oncology, Freiburg,
Germany—D Semsek; University Hospital Halle-Wittenberg,
Halle/Saale, Germany—H J Schmoll; medical practice: Hahnfeld,
Jena, Germany—S Hahnfeld; Landshut Hospital, Landshut,
Germany—B Kempf; University Hospital, Motol, Prague, Czech
Republic—J Prausova; University Hospital, Würzburg,
Germany—H Einsele; DRK Kliniken Berlin Köpenick, Berlin,
Germany—C Rudolph; Vivantes Neukölln Hospital, Berlin,
Germany—C Mayr; Zentralkrankenhaus Reinkenheide,
Bremerhaven, Germany—W Kurtz; Oncology Priority Practice,
Celle, Germany—F Marquard; Municipal Hospital, Esslingen,
Germany—M Geissler; St Josef Hospital, Gelsenkirchen,
Germany—G Meckenstock; Kreis Herford Hospital, Herford,
Germany—U Schmitz-Huebner; Westpfalz-Klinikum,
Kaiserslautern, Germany—H Link; joint medical practice: Siehl/
Söling, Kassel, Germany—U Söling; Municipal Hospital, Kiel,
Germany—M Kneba; joint medical practice: Schmitz/Steinmetz/
Gabor, Köln, Germany—S Schmitz; joint medical practice:
Stauch/Uhle, Kronach, Germany—M Stauch; CaritasKrankenhaus, Lebach, Germany—S Kremers; Onkologische
Schwerpunktpraxis, Leer—L Müller; Klinikum Lippe-Lemgo
GmbH, Lemgo—F Hartmann; Dreifaltigkeitshospital,
Lippstadt—L Heidenreich; joint medical practice: Schröder/Sieg,
Mülheim/Ruhr—J Schröder; Städtisches Krankenhaus
München- Harlaching, München—L Lutz; Oncology Priority
Practice, Neumarkt, Germany—E Ladda; Kreiskrankenhaus,
Neumarkt, Germany—F Tympner; Oncology Priority Practice,
Neunkirchen, Germany— P Schmidt; joint medical practice:
Balló/Böck, Off enbach/Mai, Germany—P Böck; General
University Hospital, Prague Czech Republic—P Klener; MartinLuther-Krankenhaus, Schleswig, Germany—M Schoettler;
Helios Hospital, Schwelm, Germany—U Müschenborn; joint
medical practice: Demandt/Ernstberger, Straubing,
Germany—M Demandt; joint medical practice: Rendenbach/
Laubenstein, Trier, Germany—B Rendenbach; joint medical
practice: Forstbauer/Ziske, Troisdorf, Germany—H Forstbauer;
St Marienhospital, Vechta, Germany—J Diers; Triemli City
Hospital, Zürich, Switzerland—H Honegger; joint medical
practice: Weinberg/Tummes/Guggenberger, Aachen,
Germany—D Tummes; Kantonsspital, CH-Aarau,
Germany—W Mingrone; Kreiskrankenhaus Bad Säckingen, Bad
Säckingen, Germany—G Lunke; Institute for Medical Oncology,
Inselspital, Bern, Switzerland—M F Fey; Krankenhaus
Bietigheim, Bietigheim, Germany—G Dietrich;
Knappschaftskrankenhaus, Bottrop, Germany—G Trenn;
Practice for Haematology and Oncology, Burgwedel,
Germany—G Obst; Municipal Hospital, Darmstadt,
Germany—D Fritze; Hans-Susemihl-Krankenhaus, Emden,
Germany—H Becker; GMP Tesch/Grunewald/Klippstein/
Knauf, Frankfurt/Main, Germany—H Tesch; Krankenhaus
Gummersbach, Gummersbach, Germany—M Sieber; St
Salvator-Krankenhaus, Halberstadt, Germany—W Kraus;
Marienhospital, Herne, Germany—D Strumberg; Klinikum
Kempten-Oberallgäu, Kempten, Germany—O Prümmer;
Volume 20 | No. 12 | December 2009
original article
Annals of Oncology
Practice for Haematology and Oncology, Krefeld, Germany—M
Neise; Onkologische Praxis am Diakonissenhaus, Leipzig,
Germany—B Peuser; University Hospital, Mainz, Germany—C
Huber; Practice for Internal Medicine, Naunhof, Germany—J
Uhlig; Practice for Haematology and Oncology, Norderstedt,
Germany—R Hoffmann; Marienhospital, Osnabrück,
Germany—M Müller; Practice for Haematology and Oncology,
Regensburg, Germany—R Dengler; Leopoldina-Krankenhaus,
Schweinfurt, Germany—S Kanzler; joint medical practice:
Springer/Fiechtner, Stuttgart, Germany—G Springer; Spital
Uster, Uster, Switzerland—G Tscherry; University Hospital,
Zürich, Switzerland—A Knuth; Heinrich-Braun-Krankenhaus/
Städt. Klinikum, Zwickau, Germany—U Kreibich; joint medical
practice: Brudler/Heinrich/Bangerter, Augsburg, Germany—B
Heinrich; Kreiskrankenhaus Bad Hersfeld, Bad Hersfeld,
Germany—R Nowak; Helios-Klinikum Bad Saarow/
Fürstenwalde, Bad Saarow, Germany—U Wruck; joint medical
practice: Weinert/Bettinger, Bad Salzufl en, Germany—R
Weinert; joint medical practice: Ihle/Blau, Berlin, Germany—I
Blau; joint medical practice: Herrenberger/Keitel-Wittig/Kirsch,
Berlin, Germany—J Herrenberger; Evangelisches
Waldkrankenhaus Spandau, Berlin, Germany—E Aulbert;
Campus Charité Mitte, Berlin, Germany— K Possinger;
University Hospital, Bochum, Germany—W Schmiegel;
Medizinische Universitätsklinik u Poliklink I, Bonn,
Germany—I Schmidt-Wolf; Johanniter Krankenhaus,
Bonn, Germany—Y Ko; Onkologische Schwerpunktpraxis, Borken,
Germany—R Kellner; HOK, Fakultnı́ nemocnice Brno,
Brno-Bohunice, Czech Republic—I Vášová; Practice for
Haematology and Oncology, Coesfeld, Germany—M Glados;
St Johannes Hospital, Dortmund, Germany—HJ Pielken;
St Marienkrankenhaus, Frankfurt/Main, Germany—F
Hartmann; Evangelisches Diakoniekrankenhaus, Freiburg,
Germany—HP Allgaier; Klinikum Garmisch-Partenkirchen,
Garmisch-Partenkirchen, Germany—H Lambertz; joint medical
practice: Mittermüller/Göldel, Germering—J Mittermüller;
Wilhelm-Anton-Hospital, Goch—V Runde; joint medical
practice: Kollbach/Thomas, Grefrath, Germany—R Thoms;
Allgemeines Krankenhaus/Strahlenklinik, Hagen, Germany—R
Souchon; joint medical practice: Rohrberg/Hurtz/Schmidt/
Frank-Gleich, Halle/Saale, Germany—M Schmidt; AK Altona,
Hamburg, Germany—D Braumann; Marienkrankenhaus,
Hamburg, Germany—U Vanhoefer; Klinikum Region
Hannover, Germany—Krankenhaus Siloah, Hannover,
Germany—H Kirchner; Municipal Hospital, Herrsching,
Germany—H Dietzfelbinger; Evangelisches Krankenhaus,
Holzminden, Germany—C Manegold; Klinikum Hoyerswerda,
Hoyerswerda, Germany—K Gasiorek; Rotes Kreuz
Krankenhaus, Kassel, Germany—C Löser; Krankenhaus
Holweide, Köln, Germany—I Meuthen; Kliniken der Stadt Köln,
Krankenhaus Merheim, Köln-Merheim, Germany—E Stoelben;
Park-Krankenhaus Leipzig- Südost, Leipzig, Germany—U
Halm; Kreiskrankenhaus, Lörrach, Germany—HH Osterhues;
Kath Klinikum/St Vincenz-und Elisabeth-Hospital, Mainz,
Germany—W Dippold; University Hospital, Marburg,
Germany—A Neubauer; Städtisches Krankenhaus MünchenSchwabing, München, Germany—C Nerl; joint medical practice:
Abenhardt/Bojko/Bosse/Riedner, München, Germany—D
Bosse; Klinikum der Universität München Innenstadt, München,
Volume 20 | No. 12 | December 2009
Germany—F Oduncu; Städtisches Klinikum Neunkirchen,
Neunkirchen, Germany—A Bierbrauer zu Brennstein; DRKKrankenhaus Neuwied, Neuwied, Germany—W Gickler; joint
medical practice: Detken/Seraphin, Northeim, Germany—S
Detken; Klinikum Nürnberg, Nürnberg, Germany—M Wilhelm;
Schloßbergklinik, Oberstaufen, Germany—K Zellmann;
Paracelsus-Klinik, Osnabrück, Germany—S Frühauf; Asklepios
Klinik Parchim, Parchim, Germany—W Schreiber; Krankenhaus
Siloah, Pforzheim, Germany—P Weber; Fakultni Nemocnice,
Prague, Czech Republic—T Kozek; stav hematologie a krevnı́
transfuse, Prague, Czech Republic—N Mesta, P Klemer;
Sana-Klinikum Remscheid GmbH, Remscheid, Germany—A
Wehmeier; Praxis für Hämatologie und Onkologie, Rostock,
Germany—V Lakner; joint medical practice: Würmell/
Baldus/Giesder-Würmell, Rüsselsheim, Germany—M Baldus;
joint medical practice: Jacobs/Daus/Schmits,
Saarbrücken, Germany—G Jacobs; Klinikum Schwerin,
Schwerin, Germany—D Hähling; St-Lukas-Klinik,
Solingen, Germany—KH Beckers; Krankenhaus Maria-Hilf,
Stadtlohn, Germany—C Deutike; Onkologische
Schwerpunktpraxis, Trier, Germany—M Grundheber;
Masarykova Nemocnice, Usti nad Labem, Czech Republic—M
Lysy; Vejle Sygehus, DK-Vejle, O Gadeberg; Klinikum der Stadt,
Villingen-Schwenningen, Germany—W Brugger; Asklepios
Nordseeklinik, Westerland, Germany—W Nettekoven.
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