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
Authors: Holte Harald , Leppa Sirpa M. , Bjorkholm Magnus , Fluge Oystein , Jyrkkio Sirkku , Delabie Jan , Sundstrom Christer , Karjalainen-Lindsberg Marja-Liisa , Erlanson Martin , Kolstad Arne , Fossa Alexander , Östenstad Björn , Lofvenberg Eva , Nordström Marie , Möller-Pedersen Lars , Anderson Harald , Jerkeman Mats , Eriksson Mikael 
Published: October 2019

Abstract
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. 1st 2008 after the end of therapy and will be available for all patients by Dec 1st.
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.