Intensified CHOP Plus Rituximab (R-CHOP 14) Versus CHOP Plus Rituximab (R-CHOP 21) and Frontline/Prophylactic Darbepoetin Alfa Treatment Versus Usual Symptomatic Treatment of Anemia in Patients Aged 60 to 80 Years With Diffuse Large B-cell Lymphoma.
60 Years
80 Years
Both
Diffuse Large Cell Lymphoma
Trial Information
Intensified CHOP Plus Rituximab (R-CHOP 14) Versus CHOP Plus Rituximab (R-CHOP 21) and Frontline/Prophylactic Darbepoetin Alfa Treatment Versus Usual Symptomatic Treatment of Anemia in Patients Aged 60 to 80 Years With Diffuse Large B-cell Lymphoma.
In patients aged 60 to 75 years with diffuse large B-cell lymphoma, the shortening of
interval between the courses of CHOP combination (CHOP-14), improves the complete response
rate, the progression free survival and the overall survival.
The addition of Rituximab to standard CHOP (R-CHOP) has also been shown to improve complete
remission rate (CR), event-free survival (EFS) and overall survival (OS) in elderly patients
with B-DLCL.
The aim of this study is to test the hypothesis that the increase of the dose intensity by
shortening the interval between two courses of R-CHOP (R-CHOP-14)could further improve the
results of the R-CHOP.
Anemia is frequent at diagnosis and during the treatment of aggressive lymphoma. In the
previous LNH 98-5 study, 72 % of the patients had, at the diagnosis, a hemoglobin level
inferior to 13 g/dl. Moreover, during the treatment, 92 % of the patients had a hemoglobin
level less than 13 g/dl and 30 % were transfused. The presence of anemia at diagnosis is an
indicator of poor prognosis in multivariate analysis. This prognosis impact could probably
be explained at cellular level on the tumor. Tumoral hypoxia is increased by the presence of
anemia. Due to this hypoxia, the expression of tumor growth factor may be increased: e.a
VEGF and the induction of expression of multi drug resistance (MDR1) is observed. This
resistance to treatment is also due to the inhibition of genotoxic activity of free radicals
induced by ionised radiation and chemotherapy. Experimentally, the negative impact of
hypoxia on the efficacy of chemotherapy has been demonstrated in sarcoma cell lines for
doxorubicin, vincristine and all most cyclophosphamide. Finally, hypoxia induced over
expression of apoptosis resistance genes and induced a growth advantage for apoptosis
resistant tumoral lines. Improvement of survival in patients receiving erythropoetin with
chemotherapy or radiotherapy was suggested in a study on patients treated with a neoadjuvant
radiochemotherapy for head and neck cancer. Erythropoetin could act to protect several
normal tissues during chemotherapy and thus could decrease treatment related morbidity.
Darbepoetin alfa is a new recombinant protein stimulating erythropoiesis. Thus, the use of
darbepoetin alfa, in association with chemotherapy, could increase CR rate, EFS and OS in
patients treated for diffuse large B-cell lymphoma.
This study is a multicentric, phase III open-label, randomized trial evaluating the efficacy
and safety of R-CHOP given every 14 days compared to R-CHOP given every 21 days in
association or not with darbepoetin alfa in order to maintain hemoglobin above 13 g/dl,
compared to classical symptomatic treatment of anemia in patients aged 66 to 80 years with
not previously treated diffuse large B-cell lymphoma with at least one adverse prognostic
factor of the age adjusted IPI.
Inclusion Criteria:
Patients with histologically proven CD20+ diffuse large B cell lymphoma (WHO
Classification).
Aged 66 to 80 years old. Patients not previously treated. Ann Arbor stage II, III, IV.
ECOG performance status 0 to 2. Age-adjusted IPI equal to 1, 2, or 3. With a minimum life
expectancy of 3 months. Negative HIV, HBV and HCV serologies test < 4 weeks (except after
vaccination for HBV).
Having signed a written informed consent.
Exclusion Criteria:
Any other histological type of lymphoma. Any history of treated or non-treated indolent
lymphoma. However, patients not previously diagnosed and having a diffuse large B-cell
lymphoma with some small cell infiltration in bone marrow or lymph node may be included.
Central nervous system or meningeal involvement by lymphoma. Contra-indication to any drug
contained in the chemotherapy regimens. Any serious co-morbid active disease (according to
the investigator's decision).
Poor renal function (creatinin level > 150 micromol/l), poor hepatic function (total
bilirubin level > 30mmol/l, transaminases > 2.5 maximum normal level) unless these
abnormalities are related to the lymphoma.
Poor bone marrow reserve as defined by neutrophils < 1.5 G/l or platelets < 100 G/l,
unless related to bone marrow infiltration.
Any history of cancer during the last 5 years with the exception of non-melanoma skin
tumors or stage 0 (in situ) cervical carcinoma.
Uncontrolled hypertension. Known hypersensitivity to erythropoietin. Myocardial infarction
during last 3 month, or unstable coronary disease, or uncontrolled cardiac insufficiency.
Venous thrombosis or pulmonary embolism during last 3 months. Treatment with any
investigational drug within 30 days before planned first cycle of chemotherapy and during
the study.
Pregnant or lactating women. Adult patient under tutelage.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Efficacy of R-CHOP 14 vs R-CHOP 21 measured by event-free survival (EFS)
Outcome Time Frame:
event-free survival
Safety Issue:
No
Principal Investigator
Richard Delarue, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Lymphoma Study Association
Authority:
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Study ID:
LNH03-6B
NCT ID:
NCT00144755
Start Date:
December 2003
Completion Date:
December 2011
Related Keywords:
- Diffuse Large Cell Lymphoma
- lymphoma, diffuse large B-cell
- rituximab
- chemotherapy
- erythropoetin
- darbepoetin alfa
- Lymphoma
- Lymphoma, Large B-Cell, Diffuse
- Lymphoma, Non-Hodgkin
- Lymphoma, B-Cell
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