R-ICE Versus R-DHAP in Patients Aged 18-65 With Relapse Diffuse Large B-cell Lymphoma

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.