R-ICE Versus R-DHAP in Patients Aged 18-65 With Relapse Diffuse Large B-cell Lymphoma
R-ICE Versus R-DHAP in Patients Aged 18-65 With Relapse Diffuse Large B-cell Lymphoma
The primary objective of this study is to evaluate the efficacy and safety of induction
 therapy R-ICE in comparison to R-DHAP after 3 cycles adjusted to successful mobilization of
 stem cells in patients with previously treated diffuse large B-cell lymphoma CD20.

 The goal is to detect a difference in mobilization adjusted response rate of 15% between
 R-ICE and R-DHAP.

 The other objective is to evaluate the efficacy and safety of MabThera maintenance therapy
 after transplantation as measured by the event free survival.

 The goal is to obtain a 15% increase of event free survival at 2 years.
In vitro, the addition of rituximab to standard anticancer drugs increases cell lyses even in
 chemoresistant cell lines. This chemosensitization effect was also demonstrated in vivo by
 the results of the GELA trial in elderly patients with DLCL. Reported phase II study results
 on the RICE regimen for treatment of patients with relapsed DLCL and comparison with
 historical controls being treated with ICE suggests that this effect (15% improvement in
 response rate) is likely in relapsing DLCL and had led the SWOG to stop a randomized trial
 comparing ICE vs RICE in patients with relapsed aggressive lymphoma.

 In the setting of relapsed DLCL, high dose therapy (HDT) followed by autologous stem cell
 transplantation (ASCT) remains the standard to improve survival in highly selected
 chemosensitive patients. In the Parma study, only 58% of the patients with relapsed
 aggressive NHL were good responders after DHAP and 24% were in complete remission. Moreover,
 the quality of response depended on prognostic factors such as IPI and relapse > 12 months
 after treatment, and only patients responding to salvage therapy benefited from HDT + ASCT.
 As shown in the PARMA study. The goal in relapsed DLCL is to improve complete response rates
 before transplantation as it is the main parameter for eligibility for HDT + ASCT and the
 main prognostic factor. Unlike first line treatment with CHOP, no standard chemotherapy
 exists for relapsing patients. DHAP has been the most frequently used regimen for decades but
 incorporates only two drugs, and has dose-limiting renal toxicity. The ICE regimen was
 developed at several dosages and studies consistently produced CR rates that were 10-15%
 superior to DHAP. It is expected that this difference will remain the same with the addition
 of rituximab to both regimens. Recent phase II data in patients with relapsed DLCL not
 previously treated with rituximab showed that RICE produced a response rate of 78% with a
 complete remission rate of 58% and was active in primary refractory disease as well as in
 intermediate-high risk patients (IPI 2-3). Association of DHAP to Rituximab, R-DHAP has been
 done on small series of patients by investigators, including patients relapsing after
 autotransplant. Despite numerous phase II studies, no randomized study has been performed
 comparing the two regimens (DHAP/ICE) or others in relapsing DLCL. Treatment of first line
 DLCL has been changed in the past 10 years with more intensive regimens, often followed by
 ASCT, and very recently with the addition of rituximab to chemotherapy and therefore the
 population of relapsing patients might be different from the one in the initial PARMA study.
 A large lymphoma intergroup study working on a large prospective data base might help to find
 the best salvage regimen and to assess the role of retreatment with monoclonal antibodies in
 these patients. Finally, the role of rituximab maintenance therapy after HDT + ASCT in
 prolonging second complete response should be evaluated.
Inclusion Criteria:

 -  Patients with CD20-positive diffuse large B-cell lymphoma. Disease must be
 histologically proven in case of relapse or partial response.

 -  Aged 18 to 65 years

 -  First relapse after complete remission (CR), less than partial remission (PR) or
 partial response to first line treatment not achieving documented or confirmed
 complete remission.

 -  Eligible for transplant

 -  Previously treated with chemotherapy regimen containing anthracyclines with or without
 rituximab.

 -  ECOG performance status 0 to 2.

 -  Minimum life expectancy of 3 months.

 -  Signed written informed consent prior to randomization.

 Exclusion Criteria:

 -  Burkitt, mantle-cell and T-cell lymphoma.

 -  CD20-negative diffuse large cell lymphoma

 -  Documented infection with HIV and hepatitis B virus [HBV] (in the absence of
 vaccination)

 -  Central nervous system or meningeal involvement by lymphoma.

 -  Not previously treated with anthracycline-containing regimens

 -  Prior transplantation

 -  Contra-indication to any drug contained in the chemotherapy regimens.

 -  Any serious active disease or co-morbid condition (according to the investigator's
 decision and information provided in the Investigational Drug Brochure [IDB]).

 -  Poor renal function (creatinine level > 150µmol/l or 1.5-2.0 x upper limit of normal
 [ULN]); poor hepatic function (total bilirubin level > 30mmol/l [> 1.5 x ULN],
 transaminases > 2.5 maximum normal level) unless these abnormalities are related to
 the lymphoma; poor bone marrow reserve as defined by neutrophils < 1.5G/l or platelets
 < 100G/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.

 -  Treatment with any investigational drug within 30 days before planned first cycle of
 chemotherapy and during the study.

 -  Pregnant women

 -  Adult patients unable to provide informed consent because of intellectual impairment.