Pre-Phase Chemotherapy Followed By Ofatumumab (OFA) and Reduced Dose CHOP (OFA-mini-CHOP) for Patients over 80 Years with Diffuse Large B-Cell Lymphoma (DLBCL) – a Lymphoma Study Association (LYSA) Prospective Phase II Study (LNH09-7B)

Introduction: R-miniCHOP is the standard chemotherapy for patients over 80 years (y) with DLBCL. In the LNH 03-7B trial, the 2-year overall survival was 58.9% [95% CI: 49.3-67.2%]. Grade III/IV toxicity and deaths occurred during the two first cycles mainly (Lancet Oncol. 2011 May;12(5):460-8). In order to improve overall survival (OS) rituximab (R) was replaced by Ofatumumab (OFA), a humanised anti-CD20 monoclonal antibody. In vitro data suggest that OFA induces more potent complement-mediated cytotoxicity than rituximab, and clinical data demonstrate activity of OF in rituximab-refractory lymphomas). In addition, to reduce early toxicity a pre-phase (PP) with vincristine and prednisone (P) was tested.

Patients and methods: Patients older than 80 y with untreated CD20+ DLBCL, Ann Arbor stage I to IV, left ventricular ejection fraction > 50%, and a performance status (PS) of 0 to 4 were eligible. Patients received a PP with vincristine (1 mg TD D-7) and P (60 mg TD D-7 to D-4) before the first cycle of OF-miniCHOP. PP was followed by miniCHOP chemotherapy (cyclophosphamide: 400 mg/m² D1; doxorubicine: 25 mg/m² D1; vincristine: 1 mg total dose D1 and prednisolone 40 mg/m² by oral route from D1 to D5) plus OFA (1000 mg TD) every 21 days for 6 cycles. GCSF was optional. The primary objective was to evaluate the efficacy of PP OF-mini-CHOP as measured by the OS. Secondary endpoints were response rate (RR), progression free survival (PFS), event-free survival (EFS), disease-free survival (DFS) for complete responders and toxicities. Survival results are presented for all included patients on an intend-to-treat basis (n=120). Response to treatment was evaluated according to 1999 Cheson criteria.

Results: From June 2010 to November 2011, One-hundred-twenty-patients (male, female) were included in 41 centers of the LYSA. The median age was 83 years (range 89-95). Seventy-seven percent of patients had a stage III/IV. LDH level was elevated in 58% of patients. Age-adjusted (aa) IPI was 2-3 in 57% of patients. One-hundred-twenty patients completed the PP, 107 the first three cycles and 89 received the whole regimen. For patients who started the first cycle, the mean relative Dose-Intensity during trial was 98%, 97% and 96 % for OFA, doxorubicine and cyclophosphamide respectively. Seventy-eight percent of patient received at least one injection of GCSF. The overall RR was 67.5%, including 35.8% of complete response and 20 % of unconfirmed complete response. At the time of this analysis, in September 2013, the median follow-up time was 26.6 months. The 2-year overall survival was 64.7% [95% CI: 55.3-72.7%]. The two-year PFS, EFS and DFS were 57.2% [95% CI: 47.7-65.6%], 53.1% [95% CI: 43.7-61.6%] and 66.6% [95% CI: 54.0-76.5%] respectively. Haematological toxicity was the most common side effect. Grade 3-4 neutropenia was observed in 20.8% of the patients and grade 3-4 thrombocytopenia in 1.7%. Seven patients (5.8%) experienced at least one episode of febrile neutropenia. Infusion reaction related to OFA was reported in 12.5% of patients. Prolonged hospitalization (> or = 10 days) was observed in 17 cases (14.1%) and mainly occurred during cycle 1 to cycle 3.

Forty-five patients died during the treatment evenly distributed between lymphoma (62.2%), intercurrent and other causes (22.2%), and concurrent illness (15.6 %). No toxic death was reported. Six patients died during treatment (1 during PP, 4 during cycle 1 to cycle 3, 1 during cycle 4 to cycle 6) Thirty-nine patients died during follow-up. In univariate analysis, low aaIPI (0 /1) is the unique statistically significant prognostic factor of prolonged OS (OR 3.083, [1.458-6.517] CI95%). Instrumental Activities of Daily Living (IADL) score equal to 4 is associated with a longer PFS. By contrast, low Albuminemia level, undernutrition according to buzby index and high Charlson comorbidity index (CCI) were not predictive of survival.

Conclusion: In DLCBL patients over 80 y, immunochemotherapy with PP OFA-mini-CHOP appears to be safe and effective, confirming that a substantial proportion of very old patients can be cured. The use of a PP seems to reduce the early death risk. OFA and PP seems to improve OS comparing with the previous reported data. The combination of a PP, monoclonal antibody against CD20 and miniCHOP can be the new standard regimen for DLBCL patients over 80 y.