R-CHOEP-14 X 6 Followed by Systemic CNS Prophylaxis for Diffuse Large B-Cell Lymphoma (DLBCL)/Follicular Lymphoma (FL) Grade 3 with Age Adjusted IPI Score 2–3: Preliminary Results of a Nordic Lymphoma Group (NLG) Phase 2 Study Including 160 Patients Aged 18- 64 Years

CHOP – based chemotherapy for aggressive lymphomas in patients with age-adjusted International Prognostic Index (IPI) score of 2–3 resulted in a historical 3-year progression free survival of approximately 30% in a previous Nordic phase III study. The aim of the present study is to determine whether an intensified regimen with chemoimmunotherapy and CNS prophylaxis improves outcome.

Methods. From October 2004-June 2008 patients in Norway, Finland, Sweden and Denmark were included in a phase II study.

Inclusion criteria: Age 18–64 years, newly diagnosed de novo DLBCL or FL grade III, no clinical sign of CNS disease and negative CSF cytology/flow cytometry by lumbar puncture, HIV negative, WHO performance status grade 0–3, adequate organ functions.

Schedule: Six courses of rituximab and CHOP with the addition of etoposide 100 mg/m² day 1–3 by i.v. route given every 14 day. Pegfilgrastim 6 mg sc. day 4 of each cycle. One course of cytarabine 12 g/m² (6 g/m² for patients 60–64 years). One course of methotrexate 3 g/m² (1.5 g/m² for patients 60–64 years). Biopsy and/or ¹⁸FDG PET/CT exam. of residual masses after fulfilled therapy was recommended, but not mandatory. Radiotherapy was given to residual masses of uncertain significance.

Results. Demographic data: 160 patients were included (99 males). Median age: 54 years (range 20–64). Histology: DLBCL: 148, FL grade 3: 12. Age adjusted IPI score: 2: 120; 3: 40. Stage 3–4: 154 patients. LDH elevated: 154 patients. Performance status 2–3: 53 patients. B-symptoms were registered in 40% of the patients, more than one extranodal site in 23%, and bulky lesions (≥ 10 cm) in 43%. Data on toxicity and response rates were registered for 127 patients by Aug. 1^st 2008 after the end of therapy and will be available for all patients by Dec 1^st.

Toxicity: Two toxic deaths were registered, one after large bowel perforation and one after an acute toxic necrosis of the liver. Hematological toxicity grade 4 was seen in 78% of the patients, infection grade 4 in 8%. Seven patients (5.5%) had major protocol deviations due to toxicity.

Response: Two of the patients were non-responders at evaluation after 3 courses and were taken off therapy. Radiotherapy was given to 25 patients (20%). Response rates at end of therapy: CR: 54 (43%), CRu: 38 (30%), PR: 27 (21%), SD: 1 (1%), PD: 7 (5%). The majority (23/27) of the PR patients were considered to have residual masses and not viable tumor tissue and were observed without further treatment.

Conclusions: Preliminary data indicate a low rate of toxic deaths despite intensive therapy. Remission rates are highly satisfactory for this subgroup of patients. Data are too premature for survival analysis at this time point.