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
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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Efficacy of R-CHOP 14 vs R-CHOP 21 measured by event-free survival (EFS)
Richard Delarue, MD
Lymphoma Study Association
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)