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Randomized Study of ICE Plus RITUXIMAB Versus DHAP Plus Rituximab in Previously Treated Patients With Diffuse Large B-Cell Lymphoma, Followed by Randomized Maintenance With Rituximab

Phase 3
18 Years
65 Years
Not Enrolling
Lymphoma, Large-Cell, Diffuse

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Trial Information

Randomized Study of ICE Plus RITUXIMAB Versus DHAP Plus Rituximab in Previously Treated Patients With Diffuse Large B-Cell Lymphoma, Followed by Randomized Maintenance With Rituximab

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

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

- 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.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MARR (mobilization adjusted response rate) and EFS (event free survival)

Principal Investigator

Christian Gisselbrecht

Investigator Role:

Principal Investigator

Investigator Affiliation:

Lymphoma Study Association


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:




Start Date:

June 2003

Completion Date:

October 2008

Related Keywords:

  • Lymphoma, Large-Cell, Diffuse
  • Lymphoma
  • Chemotherapy
  • rituximab
  • Lymphoma
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse



Memorial Sloan Kettering Cancer Center New York, New York  10021