Moderate Increase of Secondary Hematologic Malignancies After

Transcrição

VOLUME 22 䡠 NUMBER 24 䡠 DECEMBER 15 2004
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Moderate Increase of Secondary Hematologic Malignancies
After Myeloablative Radiochemotherapy and Autologous
Stem-Cell Transplantation in Patients With Indolent
Lymphoma: Results of a Prospective Randomized Trial of
the German Low Grade Lymphoma Study Group
Georg Lenz, Martin Dreyling, Eva Schiegnitz, Torsten Haferlach, Joerg Hasford, Michael Unterhalt,
and Wolfgang Hiddemann
From the Departments of Internal
Medicine III and Medical Informatics,
Biometrics and Epidemiology (IBE),
Ludwig-Maximilians University,
Munich, Germany.
Submitted June 2, 2004; accepted
September 21, 2004.
Supported as part of the Competence
Network Malignant Lymphoma (BMBF
grant No. 01 GI 9994).
Presented in part at the 45th Annual
Meeting of the American Society of
Hematology, San Diego, CA,
December 6-9, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of
this article.
Address reprint requests to Georg
Lenz, MD, University Hospital
Grosshadern, Department of Internal
Medicine III, Ludwig-MaximiliansUniversity, Marchioninistrasse 15,
81377 Munich, Germany; e-mail:
[email protected].
© 2004 by American Society of Clinical
Oncology
0732-183X/04/2224-4926/$20.00
DOI: 10.1200/JCO.2004.06.016
A
B
S
T
R
A
C
T
Purpose
An increased risk of therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid
leukemia (t-AML) after high-dose therapy and autologous stem-cell transplantation (ASCT) for
malignant lymphoma has been described by several studies, reporting a highly variable incidence
ranging from 1% to 12%. To assess this risk more precisely, the German Low Grade Lymphoma
Study Group investigated the incidence of t-MDS/t-AML after ASCT on the basis of a randomized
comparison of ASCT versus interferon alfa (IFN-␣) maintenance in indolent lymphoma.
Patients and Methods
Between 1996 and 2002, 440 patients with indolent lymphoma were randomly assigned
after a cyclophosphamide, doxorubicin, vincristine, and prednisone–like induction therapy
regimen to myeloablative radiochemotherapy followed by ASCT or IFN-␣. The incidence of
secondary hematologic malignancies was determined by standardized follow-up of all study
patients. Bone marrow samples from patients with proven or suspected t-MDS/t-AML were
centrally reviewed.
Results
After a median follow-up of 44 months, 431 patients were assessable. Five of 195 patients
developed a secondary hematologic malignancy after ASCT. Two of these patients developed
a secondary AML. Accordingly, the estimated 5-year risk for secondary hematologic neoplasias after ASCT was 3.8%. In contrast, in the IFN-␣ arm, the 5-year risk of hematologic neoplasias
was 0.0% (P ⫽ .0248).
Conclusion
The data of this randomized trial demonstrate an increased risk of secondary hematologic
malignancies after myeloablative radiochemotherapy and ASCT compared with conventional
chemotherapy. However, as ASCT significantly improves progression-free survival, it is
currently not evident to what extent the higher rate of t-MDS/t-AML will diminish the benefit
of ASCT in indolent lymphoma.
J Clin Oncol 22:4926-4933. © 2004 by American Society of Clinical Oncology
INTRODUCTION
Myeloablative chemo- or radiochemotherapy followed by autologous stem-cell
transplantation (ASCT) is increasingly applied in the treatment of patients with ma-
lignant lymphomas. ASCT has been
accepted as the treatment of choice in patients with relapsed aggressive lymphoma.1
In addition, it is frequently applied as consolidation therapy in indolent lymphoma
both in first- or second-line treatment. This
4926
Downloaded from ascopubs.org by 78.47.27.170 on January 20, 2017 from 078.047.027.170
Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
Secondary Neoplasias After ASCT
approach is supported by promising results of several phase
II studies2,3 and two recently completed randomized trials of
the German Low Grade Lymphoma Study Group and the
Groupe d’Etudes des Lymphomes de l’Adulte.4,5 These studies
showed a significantly longer progression-free (PFS) or overall
survival after ASCT as compared with conventional chemotherapy when applied in first remission of follicular lymphoma. Comparable results were also reported from a
similarly designed trial of the European Mantle-Cell Lymphoma Network in mantle-cell lymphoma.6
These highly encouraging results are hampered by
the potentially increased risk of therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia
(t-AML) after ASCT, as suggested by several retrospective
evaluations.7-10 In these studies, the incidence of secondary
hematologic malignancies varied substantially. Hence,
Micallef et al7 reported an incidence of 12% for t-MDS/
t-AML after a median follow-up of 6 years, whereas other
studies described a lower frequency of 1% to 3%.8,9 All of
these studies were retrospective and included patients with
different lymphoma subentities. In addition, intensity, duration, and number of chemotherapeutic regimens applied
before ASCT varied to a large degree. These and other
factors, such as age or the application of total-body irradiation (TBI) as part of the conditioning regimen, are known
to influence the risk of developing secondary hematologic
neoplasias after ASCT.7,9-12 Additionally, no randomized
comparison with patients receiving standard-dose chemotherapy is currently available, as t-MDS and t-AML are
well-known long-term complications after conventionaldose chemotherapy as well.13,14 The exact frequency of
t-MDS/t-AML after ASCT remains therefore uncertain and
needs to be determined more precisely on the basis of a
prospective randomized evaluation of ASCT versus conventional chemotherapy.
Such an analysis was performed by the German Low
Grade Lymphoma Study Group in a randomized comparison of myeloablative radiochemotherapy followed by ASCT
to interferon alfa (IFN-␣) maintenance after initial cytoreductive chemotherapy in patients with indolent lymphoma.
The incidence of secondary hematologic malignancies in
both study arms was evaluated by standardized follow-up
data and detailed questionnaires.
PATIENTS AND METHODS
Inclusion Criteria
Eligible patients included previously untreated patients up to
60 years of age (65 years for patients with mantle-cell lymphoma)
with advanced Ann Arbor stage III and IV follicular lymphoma, mantle-cell lymphoma, marginal zone lymphoma, or
lymphoplasmacytic lymphoma according to the current WHO
classification.15 The histologic classification was confirmed by a
central pathology review. The study protocol was approved by the
local ethics committees of the participating centers, and all patients had given an informed consent before enrollment in accordance with the Declaration of Helsinki.
Treatment Schedule
Patients were initially randomly assigned to different induction chemotherapy regimens and received either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP;
cyclophosphamide 750 mg/m2 administered intravenously [IV]
on day 1, doxorubicin 50 mg/m2 IV on day 1, vincristine 1.4
mg/m2 [maximum 2 mg] IV on day 1, and prednisone 100 mg/m2
orally [PO] on days 1 through 5) or mitoxantrone, chlorambucil,
and prednisone (MCP; mitoxantrone 8 mg/m2 IV on days 1 and 2,
chlorambucil 3 ⫻ 3 mg/m2 PO on days 1 to 5, and prednisone 25
mg/m2 PO on days 1 to 5). Since May 2000, patients were randomly assigned either to CHOP or to the combination of CHOP
and the anti-CD20 antibody rituximab (375 mg/m2). All patients
achieving at least a partial remission after induction therapy were
centrally randomly assigned to myeloablative radiochemotherapy
followed by ASCT or to IFN-␣ maintenance. Patients achieving a
complete remission after four cycles of initial cytoreductive chemotherapy proceeded immediately to consolidation therapy; all
other patients received six cycles of induction therapy (Fig 1).
Patients in the ASCT arm received intensified mobilization
chemotherapy with dexamethasone 3 ⫻ 8 mg PO on days 1
through 10, carmustine 60 mg/m2 IV on day 2, melphalan 20
mg/m2 IV on day 3, etoposide 75 mg/m2 IV on days 4 to 7,
cytarabine 2 ⫻ 100 mg/m2 IV on days 4 to 7, and granulocyte
colony-stimulating factor initiated day 11) for subsequent stem
cell collection. Conditioning high-dose therapy was performed
within 2 months of mobilization and consisted of TBI (12 Gy on
days ⫺6 to ⫺4) and high-dose cyclophosphamide (60 mg/kg of
body weight administered IV on days ⫺3 and ⫺2). The previously
collected peripheral-blood stem cells were reinfused on day 0.
Patients randomly assigned to IFN-␣ maintenance received
two additional courses of conventional chemotherapy to balance
the mobilization scheme (dexamethasone, carmustine, melphalan, etoposide, cytarabine, and granulocyte colony-stimulating
factor). Subsequently, IFN-␣ was applied at 5 ⫻ 106 U administered subcutaneously three times weekly until progression or the
occurrence of intolerable side effects (Fig 1).
Diagnosis of t-MDS and t-AML
Standardized follow-up was performed every 3 months after
ASCT or IFN-␣ and induced the assessment of the remission
status by ultrasound and computed tomography scans as well as a
differential CBC count. In addition, the participating centers received a detailed questionnaire concerning the development of
secondary malignancies.
t-MDS and t-AML were diagnosed according to the current
WHO classification.15 Bone marrow aspirates of all patients with
suspected t-MDS or t-AML, as well as aspirates from patients
with persistent abnormal blood counts, were centrally reviewed
in a blinded fashion to confirm or reject the diagnosis.
Statistics
The main parameter was the time from initiation of consolidation therapy until the diagnosis of a secondary malignancy.
This parameter was monitored prospectively as a secondary end
point of a randomized comparison of myeloablative radiochemotherapy and ASCT and IFN-␣ in which the primary efficacy end
point was PFS. All randomly assigned patients were included in
the analysis if ASCT was successfully completed or IFN-␣
4927
www.jco.org
Lenz et al
Fig 1. Study profile of the German
Low Grade Lymphoma Study Group trial.
CHOP, cyclophosphamide, doxorubicin,
vincristine, and prednisone; PR, partial response; CR, complete response; DexaBEAM, dexamethasone, carmustine,
melphalan, etoposide, cytarabine, and
granulocyte colony-stimulating factor;
TBI, total-body irradiation; ASCT, autologous stem-cell transplantation.
maintenance was initiated. Evaluation was performed as treated
according to common practice for safety assessments.
Point estimates for the cumulative risk of developing a secondary malignancy were calculated using the Kaplan-Meier method.
Patients without secondary neoplasia were censored at the date of
last follow-up. Because, according to the protocol, ASCT was applied
as salvage therapy in a proportion of patients who experienced relapse
in the IFN-␣ arm, these patients were censored at the date of transplantation. In addition to the Kaplan-Meier estimates, the cumulative
incidence of secondary neoplasias was calculated as described previously,16 considering death as a competing event. The influence of
continuous covariates on the risk of secondary neoplasias was analyzed by the Cox regression model.
PFS was defined as the time from the end of successful induction therapy until relapse or death. PFS was analyzed using the
Kaplan-Meier method. Patients without event were censored at
the date of the last follow-up. 95% CIs for the PFS and the risk of
secondary neoplasias were calculated according to Greenwood’s
formula. Group comparisons for the risk of secondary neoplasias
and for the PFS were conducted by means of the two-sided logrank test. The significance level was set to alpha ⫽ 0.05. All statistical calculations were performed with the SAS system (version
8.02; SAS Institute, Cary, NC).
RESULTS
Patient Characteristics
Four hundred forty consecutive patients treated either
with myeloablative radiochemotherapy followed by ASCT
or IFN-␣ were included in this analysis. Three patients in
the ASCT group and six in the interferon arm were excluded, as the original diagnosis was not confirmed in the
pathology review. Of the 431 assessable patients, 195 received ASCT and 236 received IFN-␣ maintenance. The
number of included patients in the two study arms differs
slightly, because in the ASCT study group, a sufficient number of stem cells could not be collected in all patients, and
ASCT was refused in some cases. The vast majority of patients were diagnosed with follicular lymphoma (75%),
17% had mantle-cell lymphoma, 2% had marginal-zone
lymphoma, and 7% had a lymphoplasmacytic lymphoma.
Clinical characteristics of patients in the two study arms
were comparable and are summarized in Table 1.
PFS
To assess the impact of ASCT versus IFN-␣ maintenance in indolent lymphoma, we analyzed the PFS in the
two cohorts. In patients receiving ASCT, the PFS was 83.7%
after 2 years (95% CI, 78.4% to 88.9%) and 60.2% after 5
years (95% CI, 51.1% to 69.3%) in comparison to only
56.8% (95% CI, 50.3% to 63.2%) after 2 years and 31.6%
(95% CI, 24.5% to 38.8%) after 5 years in the IFN-␣ study
arm, respectively (P ⬍ .0001; two-sided log-rank test).
Incidence and Onset of Secondary
Hematologic Neoplasias
At a median follow-up of 44 months (45 months for
patients treated with myeloablative radiochemotherapy followed by ASCT and 44 months in the IFN-␣ maintenance
arm), five secondary hematologic neoplasias were observed
and confirmed by the central cytological review. The characteristics of patients developing t-MDS or t-AML are summarized in Table 2.
In the ASCT arm, five cases of t-MDS were detected,
resulting in an estimated 5-year risk of secondary hematologic neoplasias of 3.8% (95% CI, 0.4% to 7.3%). All cases
presented with pancytopenia. Two of these patients proceeded into a secondary AML, from which they died shortly
after diagnosis. One patient with t-MDS received an allogeneic transplantation as salvage treatment and is currently in
ongoing complete remission, whereas the other two patients are still alive with stable blood counts. In addition, in
another patient of the ASCT group, a t-MDS was diagnosed
4928
Table 1. Patient Characteristics
IFN-␣
No. of Patients
No. of patients
Not assessable, n
Qualifying patients, n
Histology
Follicular lymphoma
Mantle-cell lymphoma
Lymphoplasmacytic lymphoma
Marginal-zone lymphoma
Induction therapy
MCP
CHOP
CHVP
R-CHOP
Age, years
Median
Range
Sex, male
Ann Arbor stage IV
ASCT
%
No. of Patients
242
6
236
Total
%
No. of Patients
198
3
195
%
440
9
431
180
39
14
3
76
17
6
1
142
34
15
4
73
17
8
2
322
73
29
7
75
17
7
2
40
162
1
33
17
69
0
14
28
132
0
35
14
68
0
18
68
294
1
68
16
68
0
16
51.1
30-64
125
181
50.5
27-64
53
77
111
149
50.9
27-64
57
76
236
330
55
77
Abbreviations: IFN-␣, interferon alfa maintenance; ASCT, autologous stem-cell transplantation; MCP, mitoxantrone, chlorambucil, and prednisone; CHOP,
cyclophosphamide, doxorubicin, vincristine, and prednisone; CHVP, cyclophosphamide, doxorubicin, vinblastive, and prednisone; R-CHOP, CHOP plus rituximab.
by bone marrow biopsy. However, the central hematology
review detected myelodysplastic features in a previous bone
marrow biopsy before myeloablative radiochemotherapy.
Consequently, we did not include this case in our analysis.
In contrast, the estimated 5-year risk for secondary
hematologic neoplasias in the IFN-␣ study arm was 0.0%,
as no patient in the IFN-␣ group developed a t-MDS (one
patient in the IFN-␣ study arm who developed a t-MDS was
censored, as he received a secondary ASCT as salvage therapy). Thus the estimated 5-year risk for t-MDS was significantly higher in the ASCT cohort as compared with the
IFN-␣ group (P ⫽ .0248, two-sided log-rank test; Fig 2).
In addition, we analyzed the estimated 5-year cumulative
incidence rate of t-MDS or t-AML considering death as a
competing event. The estimated 5-year incidence rate
was 3.5% in the ASCT study arm and 0.0% in the IFN-␣
group, respectively.
The median time to development of t-MDS and t-AML
was 38 months (range, 13 to 56 months) after diagnosis of
non-Hodgkin’s lymphoma and 30 months (range, 9 to 51
months) after initiation of myeloablative radiochemotherapy followed by ASCT. The median latency after start of
consolidation was slightly shorter for t-MDS (30 months;
range, 9 to 51 months) in comparison to t-AML (42
months; range, 40 to 44 months).
Initial Chemotherapy and Risk for t-MDS
or t-AML
To assess the impact of the conventional chemotherapy, we analyzed the incidence of secondary hematologic
Table 2. Clinical Characteristics of Patients Developing Therapy-Related Myelodysplastic Syndrome or Therapy-Related AML
Patient
No.
Age at Consolidation
(years)
Sex
Lymphoma
Subtype
Induction
Regimen
1
58
F
FL
CHOP
ASCT
2
64
M
MCL
MCP
ASCT
3
4
5
43
39
47
M
F
M
FL
FL
FL
CHOP
MCP
R-CHOP
ASCT
ASCT
ASCT
Consolidation
WHO
Classification
Latency
(months)
MDS RA
3 AML
MDS RA
3 AML
MDS RA
MDS RAEB
MDS RA
9
44
36
40
51
20
30
Clinical
Status
Dead
Dead
Alive
Alive
Alive
Abbreviations: FL, follicular lymphoma; MCL, mantle-cell lymphoma; ASCT, autologous stem-cell transplantation; AML, acute myeloid leukemia; MDS,
myelodysplastic syndrome; RA, refractory anemia; RAEB, refractory anemia with excess blasts; CHOP, cyclophosphamide, doxorubicin, vincristine, and
prednisone; MCP, mitoxantrone, chlorambucil, and prednisone; R-CHOP, CHOP plus rituximab.
4929
www.jco.org
Lenz et al
Fig 2. Cumulative risk of therapy-related myelodysplastic syndrome or
therapy-related acute myeloid leukemia after myeloablative radiochemotherapy followed by autologous stem-cell transplantation (ASCT) or interferon (IFN) alfa maintenance.
Fig 3. Cumulative risk of therapy-related myelodysplastic syndrome or
therapy-related acute myeloid leukemia after mitoxantrone, chlorambucil,
and prednisone (MCP) and cyclophosphamide, doxorubicin, vincristine, and
prednisone (CHOP).
neoplasias according to the respective induction therapy.
Sixty-eight patients received the CHOP-like regimen MCP,
and 362 patients received CHOP. In 68 of the CHOP patients, the anti-CD20 antibody rituximab was additionally
applied. Only three of 362 patients in the CHOP group
developed a secondary hematologic malignancy. In contrast, three of 68 patients developed a t-MDS or t-AML after
MCP induction therapy. As in this analysis, patients in the
IFN study arm were not censored because of secondary
ASCT as salvage therapy, and six cases of secondary t-MDS
were observed. Accordingly, the estimated 5-year risk for
secondary hematologic neoplasias was 5.1% (95% CI, 0.0%
to 10.7%) after MCP. Because the MCP study arm was
closed in 1998, patients receiving MCP had a longer median
follow-up as compared with the total group of patients
receiving CHOP. Thus we compared the MCP group with
patients receiving CHOP in the same time period with a
similar median follow-up (61 months for MCP, 62 months
for CHOP). In this CHOP cohort, only one of 104 patients
developed a secondary hematologic malignancy, and the
estimated 5-year risk was 1.3% (95% CI, 0.0% to 3.7%).
However, this difference was not significant, possibly because
of the small number of assessable patients (P ⫽ .1449; Fig 3). In
subsequent analyses, age, sex, and histology (mantle-cell lymphoma v follicular lymphoma) were not associated with an
increased risk of a secondary MDS or AML.
malignancies. After a median follow-up of 44 months, five
of 195 patients developed a t-MDS/t-AML after ASCT in
first remission. The estimated 5-year cumulative risk of
patients receiving ASCT was 3.8%, in comparison with
0.0% after IFN-␣ (P ⫽ .0248). Thus the frequency of t-MDS
and t-AML at 4 years is in the range of 1% and 3.0%, as
reported in recent studies.8,9 However, it is much lower
than suggested in a previously reported retrospective evaluation, which claimed an incidence of 12% after a median
follow-up of 6 years,7 and lower than in the randomized
GOELAMS trial, which reported a rather high incidence of
secondary tumors after a median follow-up of 56 months in
patients with follicular lymphoma after ASCT.17 In addition, the PFS for patients receiving ASCT was significantly
better as compared with those receiving IFN-␣ (60.2% v
31.6% after 5 years; P ⬍ .0001), clearly indicating the superiority of ASCT. Thus currently there is no evidence that the
moderate increase in the incidence of secondary t-MDS or
t-AML will substantially diminish the long-term benefit of
myeloablative radiochemotherapy and ASCT.
The role of TBI as part of the conditioning regimen is
not yet fully elucidated. In different retrospective studies of
lymphoma patients receiving ASCT, multivariate analyses
suggested TBI to be associated with an increased risk of
secondary hematologic malignancies.10,12,18 In contrast, in
a recently published case-control study of 56 t-MDS/t-AML
patients, TBI at doses of 12 Gy did not increase the risk of
t-MDS or t-AML.19
The data of the current study also suggest that the risk
of t-MDS after ASCT has to be evaluated in the context of
the preceding antilymphoma chemotherapy. Hence 5.1%
of patients receiving MCP developed a secondary hematologic neoplasia, in comparison with only 1.3% of patients
DISCUSSION
The current study clearly demonstrates that the application
of myeloablative radiochemotherapy followed by ASCT is
associated with an increased risk of secondary hematologic
4930
receiving CHOP. Possibly because of the rather small number of only 68 patients receiving MCP, this difference was
not significant. However, an increased risk of secondary
hematologic malignancies has been described after treatment with chlorambucil or its derivates by other investigators. Two retrospective evaluations described an increased
risk for the development of secondary leukemia after therapy with prednimustine, a 21-prednisolone ester of
chlorambucil. In patients with advanced breast cancer, a
cumulative risk for therapy-related leukemia of 25% at 37
months was reported after a combination of prednimustine, methotrexate, fluorouracil, mitoxantrone, and tamoxifen. Similarly, in a cohort study of 2-year survivors of
malignant lymphomas, an increased incidence of secondary
acute nonlymphocytic leukemia was associated with the
application of prednimustine.20,21 Similarly, mitoxantrone
has been suggested to be associated with an increased risk of
secondary hematologic neoplasias. Two recent studies in
breast cancer claimed an increased risk of t-MDS/t-AML
after mitoxantrone-based chemotherapy.22,23 In contrast,
our current study does not confirm such a high rate of
secondary neoplasias, especially because no t-MDS/t-AML
could be observed in the MCP/IFN-␣ arm. However, it is
tempting to speculate that the combination of TBI and
alkylating substances or anthracyclines might especially
contribute to the rather high incidence of t-MDS/t-AML
after high-dose consolidation.
The treatment of secondary hematologic neoplasias remains unsatisfactory, with allogeneic transplantation being the
only potentially curative approach.24,25 One patient in our
cohort with t-MDS underwent allogeneic transplantation
and is currently in complete remission. Two patients who
developed secondary AML died shortly after diagnosis. The
other two patients are still alive with stable blood counts.
In conclusion, the data of our randomized trial demonstrate a statistically significant increased risk of secondary
hematologic malignancies after myeloablative radiochemotherapy followed by ASCT compared with conventional chemotherapy in patients with indolent lymphoma. Patients
receiving the combination of TBI and alkylating agents seem to
have an especially increased risk for developing a secondary
hematologic neoplasia. Despite this moderately higher rate,
the PFS in patients receiving ASCT was significantly superior
as compared with those receiving conventional chemotherapy.
Thus at this time there is no evidence that the risk of secondary
malignancies after ASCT might substantially diminish the
long-term benefits of this therapeutic approach, which provides the perspective for a significantly prolonged PFS and
potentially overall survival as compared with conventional
therapy in the vast majority of patients.
■ ■ ■
Appendix
The following persons and institutions participated in
this study: M. Hahn, S. Müller, Praxis für Hämatologie/
Onkologie, Ansbach; J. Gensicke, P. Dravoj, Stadtkrankenhaus
Arolsen, Arolsen; G. Schlimok, M. Sandherr, Zentralklinikum
Augsburg, Augsburg; G. Unverferth, W. Langer, F. Püschel,
Kreiskrankenhaus Aurich, Aurich; R. Paliege, P.
Majunke, Kreiskrankenhaus Bad Hersfeld, Bad Hersfeld; W.
Schultze, H. Fuss, P. Frenzel, Humaine Klinikum Bad Saarow,
Bad Saarow; D. Hennesser, Vinzenz-Pallotti Hospital,
Bergisch Gladbach; B. Dörken, G. Massenkeil, Charité/
Virchow-Klinikum,Berlin;K.Possinger,O.Sezer,Universitätsklinikum Charité/Campus Mitte, Berlin; W.D. Ludwig, H.
Harder, Robert Rössle Klinik, Berlin; H.J. Weh, B. Angrick,
Franziskus Hospital, Bielefeld; W. Schmiegel, U. Graeven,
Medizinische Universitätsklinik und KnappschaftsKrankenhaus, Bochum; H. Vetter, S. Fronhoffs, Universitätsklinikum Bonn, Bonn; E. Musch, H. Röhl, G Mann, MarienHospital Bottrop, Bottrop; B. Wörmann, G. Jordan, A. Pies,
Städtisches Klinkum Braunschweig, Braunschweig; M. Adler,
Hämatologische Praxis, Braunschweig; H. Hotz, F. Marquard,
Allgemeines Krankenhaus Celle, Celle; F. Fiedler, A. Hänel,
Klinikum Chemnitz, Krankenhaus Küchwald, Chemnitz; R.
Lohmann, Krankenhaus Coesfeld, Coesfeld; M. Lö␤ner, CarlThiem-Klinikum, Cottbus; U. v Grünhagen, Onkologische
Schwerpunktpraxis, Cottbus; D. Fritze, A. Rost, H. Schuppert,
Klinikum Darmstadt, Darmstadt; F.W. Kleinsorge, Internistische Praxis, Detmold; T.U. Hausamen, W Freund, Städtisches Krankenhaus Dortmund, Dortmund; M. Schäfers, K.
Quabeck, Internistische Praxis, Duisburg; W. Lange,
Johanniter-Krankenhaus Rheinhausen, Duisburg; R. Haas,
Universitätsklinik Düsseldorf, Düsseldorf; M. Gramatzki,
Universitätsklinikum Erlangen, Erlangen; M. Eckart, Praxis
für Hämatologie/Onkologie, Erlangen; R. Fuchs, S.
Wehle-Ilka, J. Wiegand, St-Antonius-Hospital, Eschweiler; U.
Dührsen, H. Nückel, Medizinische Klinik und Poliklinik,
Essen; S. Seeber, M.R. Nowrosian, Westdeutsches Tumorzentrum, Essen; U. v Verschuer, R. Rudolph, Hämatologische
Praxis, Essen; J.G. Saal, D. Hartwigsen, U. Strack,
St-Franziskus-Hospital, Flensburg; A. Machraoui, T. Koch,
Diakonissenkrankenhaus Flensburg, Flensburg; T. Reiber, D.
Semsek, Praxis für Innere Medizin, Freiburg; A. Ochs, U.
Brand, Evangelisches Diakoniekrankenhaus, Freiburg; R.
Mertelsmann, J. Finke, Medizinische Universitätsklinik,
Freiburg; G. Heil, E. Stelzer, Klinikum Gera, Gera; G.
Schliesser, Hämatologische Praxis, Giessen; L. Trümper,
B. Gla␤, Universitätsklinikum Göttingen, Göttingen;
H. Eimermacher, Katholisches Krankenhaus, Hagen; S. Kraus,
I. Hausbrandt, St Salvator Krankenhaus, Halberstadt; H.J.
Hurtz, R. Rohrberg, R. Behrends, Schwerpunktpraxis,
Halle/Saale; N Schmitz, P Dreger, Allgemeines Krankenhaus
St. Georg, Hamburg; A.R. Zander, N. Kröger, H. Renges,
S. Hegewisch-Becker, Universitäts-Krankenhaus Eppendorf,
Hamburg; K. Verpoort, W. Zeller, Onkologische
4931
www.jco.org
Lenz et al
Schwerpunktpraxis, Hamburg; H. Schmidt, Kreiskrankenhaus Hameln, Hameln; A. Ganser, D. Peest, Medizinische
Hochschule Hannover, Hannover; R. Mao, Hämatologische
Praxis, Hannover; R. Voigtmann, E. Schilling, Marienhospital
Herne, Herne; H. Dietzfelbinger, Privatklinik Dr R.
Schindlbeck, Herrsching; M. Prisch, M. Bach, St-ElisabethHospital, Herten; U. Basler, B. Sievers, Städtisches Krankenhaus Hildesheim, Hildesheim; D. Urbanitz, T.F. Heide,
U. Kaiser, St Bernward-Krankenhaus, Hildesheim; W.
Freier, Onkologische Schwerpunktpraxis, Hildesheim; M.
Pfreundschuh, Universitätsklinik des Saarlandes, Homburg/
Saar; A.A. Fauser, M. Kiehl, Klinik für KMT, Hämatologie/
Onkologie, Idar-Oberstein; K. Höffken, H.J. Fricke,
Universitätsklinikum Jena, Jena; J. Th. Fischer, S. Wilhelm, R.
Ehrhardt, Städtisches Klinikum Karlsruhe, Karlsruhe; J
Mezger, G. Göckel, St-Vincentius-Krankenhäuser, Karlsruhe;
W.D. Hirschmann, E.U. Steinhauer, Städtische Kliniken Kassel, Kassel; M. Kneba, Universitätsklinikum Kiel, Kiel; I.
Meuthen, G. Kunstmann, H. Spangenberger, Krankenhaus
Holweide, Köln; V. Diehl, A. Engert, M. Reiser, Universitätsklinikum Köln, Köln; S. Schmitz, T. Steinmetz, Internistische
Praxis, Köln; M. Planker, M. Busch, M. Hipp, Städtische
Krankenanstalten, Krefeld; B. Tschechne, HämatologischOnkologische Praxis, Lehrte; D. Niederwieser, W. Pönisch,
Universitätklinikum Leipzig, Leipzig; A. Aldaoud, A.
Schwarzer, Gemeinschaftspraxis, Leipzig; L. Mantovani, B.
Matthe, Städtisches Klinikum St Georg, Leipzig; H.P.
Lohrmann, H. Middeke, Klinikum Lippe-Lemgo, Lemgo; L.
Heidenreich, K.A. Jost, Dreifaltigkeitshospital, Lippstadt; F.
Bergmann, Evangelisches Krankenhaus Lippstadt, Lippstadt;
S. Fetscher, Städtisches Krankenhaus Süd, Lübeck; M.
Uppenkamp, M. Hoffmann, Klinikum der Stadt, Ludwigshafen; H. Weiss, St-Marien-Krankenhaus, Ludwigshafen; M.
Wiermann, Universitätsklinikum Magdeburg, Magdeburg; C.
Huber, T. Fischer, G. He␤, Universitätsklinikum Mainz,
Mainz; R. Hehlmann, E. Lengfelder, I. Kottke, III. Medizinische Klinik Mannheim, Mannheim; A. Neubauer, N.
Schwella, Universitätsklinikum Marburg, Marburg; M.
Schwonzen, H. Spangenberger, St-Walburga-Krankenhaus,
Meschede; H. Bodenstein, H.H. Wöltjen, Klinikum Minden,
Minden; H.E. Reis, D. Kohl, D. Berkovic, Kliniken Maria Hilf,
Mönchengladbach; C. Lunscken, Hämatologische Praxis,
Mülheim a.d. Ruhr; C. Peschel, C. v Schilling, Klinikum Rechts
der Isar der Technischen Universität, München; P.C. Scriba, B.
Emmerich, Medizinische Klinik Innenstadt der Universität,
München; R. Forstpointner, V.B. Nerovcic, Klinikum
Grosshadern der Ludwig-Maximilians University, München;
R. Hartenstein, N. Brack, Städtisches Krankenhaus MünchenHarlaching, München; D. Schlöndorff, J. Walther, U. Seybold,
Klinikum Innenstadt, München; W.E. Berdel, Universitätsklinikum Münster, Münster; R. Kriebel-Schmitt, V. Burstedde, B. Berning, Schwerpunktpraxis für Hämatologie/
Onkologie, Münster; J. Wehmeyer, C. Lerchenmüller,
Onkologische Schwerpunktpraxis, Münster; H. Rühle, N.
Grobe, F. Jungmichel, Klinikum Neubrandenburg, Neubrandenburg; W. Maurer, A. v Bierbrauer, Städtisches Krankenhaus, Neunkirchen; P. Ehscheidt, St-Elisabeth-Krankenhaus,
Neuwied; B. Krämer, W. Linke, Kreiskrankenhaus Nordhorn,
Nordhorn; H. Wandt, J. Wortmann, Klinikum Nord, Nürnberg; H.J. Illiger, B. Metzner, Klinikum Oldenburg, Oldenburg; L. Theilmann, B. Sandritter, Städtisches Klinikum
Pforzheim, Pforzheim; R. Pasold, F. Rothmann, A. Haas,
Ernst-Von-Bergmann-Klinik, Potsdam; G. Kautzsch, A.
Rupprecht, St Josefs-Krankenhaus Potsdam, Potsdam; R.
Andreesen, S. Krause, S. Mayer, Universitätsklinikum Regensburg, Regensburg; E. Günther, Kreiskrankenhaus Reutlingen,
Reutlingen; W. Bootsveld, Jakobi-Krankenhaus, Rheine; H.
Huff, B. Schönberger, G. Puchtler, Klinikum Rosenheim,
Rosenheim; P. Ketterer, O. Anders, Klinikum Südstadt, Rostock; M. Freund, Universitätsklinikum Rostock, Rostock;
M. Baldus, Internistische Schwerpunktpraxis, Rüsselsheim;
J. Prei␤, P. Schmidt, Caritas Klinik St Theresia, Saarbrücken;
J. Schimke, G. Jacobs, H. Daus, Praxis für Hämatologie/
Onkologie, Saarbrücken; R. Subert, D. Häling, C. Schult,
Medizinisches Zentrum der Landeshauptstadt, Schwerin; E.
Jähde, Evangelisches Jung-Stilling Krankenhaus, Siegen; W.
Gassmann, T. Gaska, St.-Marien-Krankenhaus Siegen, Siegen;
HR Ochs, G. Schütte, Marienkrankenhaus Soest, Soest; W.
Aulitzky, S. Martin, Robert-Bosch-Krankenhaus, Stuttgart; E.
Höring, M. v Ehr, M. Respondek, Praxis für Hämatologie/
Onkologie, Stuttgart; H.G. Mergenthaler, Bürgerhospital,
Stuttgart; E. Heidemann, J. Kaesberger, Diakonissenkrankenhaus, Stuttgart; H.G. Biedermann, W. Larisch, Kreiskrankenhaus Traunstein, Traunstein; C.B. Kölbel, K.J. Weber, H.
Kirchen, Krankenhaus der Barmherzigen Brüder, Trier;
M.R. Clemens, Mutterhaus der Borromäerinnen, Trier; M.
Grundheber, Praxis für Hämatologie/Onkologie, Trier; H.
Döhner, M. Bentz, Universitätsklinikum Ulm, Ulm; W.
Brugger, I. Funke, Medizinische Klinik VillingenSchwenningen, Villingen; L. Labedzki, H.J. Bias, Kreiskrankenhaus Waldbröl, Waldbröl; N. Frickhofen, H.G. Fuhr, G.
Müller, Dr.-H.-Schmidt-Kliniken Wiesbaden, Wiesbaden;
K.M. Josten, Deutsche Klinik für Diagnostik, Wiesbaden; A.
Köhler, Deutsche Klinik für Diagnostik, Wiesbaden; U.
Rasenack, A. Körfer, Stadtkrankenhaus Wolfsburg, Wolfsburg; M. Sandmann, G. Becker, Kliniken St Antonius,
Wuppertal; C. Maintz, Praxis für Hämatologie/Onkologie,
Würselen; K. Wilms, H. Rückle-Lanz, M. Wilhelm, U. Gunzer,
Universitätsklinikum, Würzburg; G. Schott, Heinrich-BraunKrankenhaus Zwickau, Zwickau, Germany.
Authors’ Disclosures of Potential
Conflicts of Interest
The authors indicated no potential conflicts of interest.
4932
REFERENCES
1. Philip T, Guglielmi C, Hagenbeek A, et al:
Autologous bone marrow transplantation as
compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s
lymphoma. N Engl J Med 333:1540-1545, 1995
2. Horning SJ, Negrin RS, Hoppe RT, et al:
High-dose therapy and autologous bone marrow
transplantation for follicular lymphoma in first
complete or partial remission: Results of a phase
II clinical trial. Blood 97:404-409, 2001
3. Colombat P, Cornillet P, Deconinck E, et
al: Value of autologous stem cell transplantation
with purged bone marrow as first-line therapy for
follicular lymphoma with high tumor burden: A
GOELAMS phase II study. Bone Marrow Transplant 26:971-977, 2000
4. Lenz G, Dreyling M, Schiegnitz E, et al:
Myeloablative radiochemotherapy followed by
autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: Results of a prospective
randomized trial of the German Low-Grade Lymphoma Study Group (GLSG). Blood 104:26672674, 2004
5. Sebban C, Belanger C, Brousse N, et al:
Comparison of CHVP ⫹ interferon with CHOP
followed by autologous stem cell transplantation
with a TBI conditioning regimen in untreated
patients with high tumor burden follicular lymphoma: Results of the randomized GELF94 Trial
(GELA Study Group). Blood 102:354, 2003 (abstr
354)
6. Hiddemann W, Dreyling MH, Pfreundschuh M, et al: Myeloablative radiochemotherapy
followed by autologous blood stem cell transplantation leads to a significant prolongation of
the event-free survival in patients with mantle
cell lymphoma (MCL): Results of a prospective
randomized European Intergroup study. Blood
98:861, 2001 (abstr 3572)
7. Micallef IN, Lillington DM, Apostolidis J, et
al: Therapy-related myelodysplasia and secondary
acute myelogenous leukemia after high-dose therapy with autologous hematopoietic progenitor-cell
support for lymphoid malignancies. J Clin Oncol
18:947-955, 2000
8. Howe R, Micallef IN, Inwards DJ, et al:
Secondary myelodysplastic syndrome and acute
myelogenous leukemia are significant complications following autologous stem cell transplantation for lymphoma. Bone Marrow Transplant
32:317-324, 2003
9. Sobecks RM, Le Beau MM, Anastasi J, et
al: Myelodysplasia and acute leukemia following
high-dose chemotherapy and autologous bone
marrow or peripheral blood stem cell transplantation. Bone Marrow Transplant 23:1161-1165,
1999
10. Milligan DW, Ruiz De Elvira MC, Kolb HJ,
et al: Secondary leukaemia and myelodysplasia
after autografting for lymphoma: Results from
the EBMT: EBMT Lymphoma and Late Effects
Working Parties—European Group for Blood and
Marrow Transplantation. Br J Haematol 106:
1020-1026, 1999
11. Krishnan A, Bhatia S, Slovak ML, et al:
Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation
for lymphoma: An assessment of risk factors.
Blood 95:1588-1593, 2000
12. Armitage JO, Carbone PP, Connors JM, et
al: Treatment-related myelodysplasia and acute
leukemia in non-Hodgkin’s lymphoma patients.
J Clin Oncol 21:897-906, 2003
13. Tucker MA, Coleman CN, Cox RS, et al:
Risk of second cancers after treatment for
Hodgkin’s disease. N Engl J Med 318:76-81,
1988
14. Travis LB, Curtis RE, Boice JD Jr, et al:
Second cancers following non-Hodgkin’s lymphoma. Cancer 67:2002-2009, 1991
15. Jaffe ES, Harris NL, Stein H, et al: World
Health Organisation Classification of Tumours:
Tumours of the Haemopoitic and Lymphoid Tissues. Lyon, France, IARC Press, 2001
16. Marubini E, Valsecchi M: Analysing Survival Data From Clinical Trials and Observational
Studies. New York, NY, Wiley & Sons, 1995
17. Deconinck E, Foussard C, Bertrand P-P, et
al: Value of autologous stem cell transplantation
in first-line therapy of follicular lymphoma with
high tumor burden: Final results of the random-
ized GOELAMS 064 Trial. Blood 102:246, 2003
(abstr 865)
18. Darrington DL, Vose JM, Anderson JR, et
al: Incidence and characterization of secondary
myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation
for lymphoid malignancies. J Clin Oncol 12:25272534, 1994
19. Metayer C, Curtis RE, Vose J, et al: Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: A
multicenter case-control study. Blood 101:20152023, 2003
20. Andersson M, Philip P, PedersenBjergaard J: High risk of therapy-related leukemia and preleukemia after therapy with
prednimustine, methotrexate, 5-fluorouracil, mitoxantrone, and tamoxifen for advanced breast
cancer. Cancer 65:2460-2464, 1990
21. Travis LB, Curtis RE, Stovall M, et al: Risk
of leukemia following treatment for nonHodgkin’s lymphoma. J Natl Cancer Inst 86:
1450-1457, 1994
22. Linassier C, Barin C, Calais G, et al: Early
secondary acute myelogenous leukemia in
breast cancer patients after treatment with mitoxantrone, cyclophosphamide, fluorouracil and
radiation therapy. Ann Oncol 11:1289-1294,
2000
23. Saso R, Kulkarni S, Mitchell P, et al: Secondary myelodysplastic syndrome/acute myeloid leukaemia following mitoxantrone-based
therapy for breast carcinoma. Br J Cancer 83:9194, 2000
24. de Witte T, Suciu S, Peetermans M, et al:
Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid
leukemia (sAML) following MDS of more than 6
months duration: A pilot study by the Leukemia
Cooperative Group of the European Organisation
for Research and Treatment in Cancer (EORTCLCG). Leukemia 9:1805-1811, 1995
25. Kantarjian HM, Keating MJ, Walters RS, et
al: Therapy-related leukemia and myelodysplastic syndrome: Clinical, cytogenetic, and prognostic features. J Clin Oncol 4:1748-1757, 1986
4933
www.jco.org

Moderate Increase of Secondary Hematologic Malignancies After

Transcrição

Documentos relacionados

High-dose CHOP plus etoposide (MegaCHOEP) in T

Proceedings of the 33rd World Small Animal Veterinary

v8 n2 - BJVP - Brazilian Journal of Veterinary Pathology

Transcript - Patient Power

Non-Hodgkin lymphoma as a cause of acute intestinal obstruction

From Irrational Numbers to Perfect Matchings

Information for Doctors - Zentrum für Psychiatrie Calw

Programme - Fachbereich Mathematik und Informatik

ESMO_valencia2016_intranet2 [Kompatibilitätsmodus]

Geometrical Modelling for an Automated Faceting

Clonal relation in a case of CLL, ALCL, and Hodgkin

clicking here - Cutaneous Lymphoma Foundation

3rd workshop therapy erectile dysfunction _A4_LangDin Flyer.indd