Repetitive High-Dose Therapy with Dose Escalated CHOP + Etoposide Followed by Autologous Stem Cell Transplantation (Mega-CHOEP) in Younger Patients with Primary Diagnosis of Aggressive NHL and Elevated LDH at Diagnosis: Final Analysis.

As a novel approach to primary treatment of aggressive lymphoma, we tested the feasibility and efficacy of a four cycle high-dose chemotherapy protocol including autologous stem cell transplantation after cycles 2, 3 and 4. In a multicenter Phase II study patients with newly diagnosed aggressive NHL, age between 18–60 years, and LDH > N at diagnosis were included. At dose level 1, cycle 1 consisted of Cyclophosphamide (CY) 1500 mg/m², Adriamycin (ADR) 70 mg/m², Vincristine 2mg, Etoposide (ETO) 450 mg/m², and Prednisone 500 mg/m². In subsequent cycles doses of CY and ETO were increased: Cycle II and III : CY 4500 mg/m² and ETO 600mg/m², cycle IV: CY 6000 mg/m² and ETO 1000 mg/m². At dose level 2 ETO was further increased throughout all cycles to 600, 960, 960 and 1480 mg/m², respectively. From February 97 to August 99, 124 patients were enrolled 14 patients had to be excluded mostly due to correction of initial diagnosis. 110 patients were evaluable with a median observation time of 55 months. 81.8% of patients completed therapy as per protocol. There were 5 cases of treatment related mortality (4.5%), and one of these deaths was due to secondary leukemia (0.9%). Overall survival at 5 years was 67.2 % and freedom from treatment failure was 62.1 %. The following factors were tested with respect to their impact on time to treatment failure (TTTF): age, sex, extranodal disease, bulky disease, performance status, B-symptoms, stage, age-adjusted IPI and LDH. In univariate analysis, only the risk factors of the age-adjusted IPI and IPI itself showed a significant impact on TTTF: see table 1. In a Cox regression multivariate analysis, LDH remained the only independent risk factor with a relative risk of 2.0 (p=0.046). Mega-CHOEP is feasible and effective treatment in younger pts. with aggressive lymphoma. Elevated LDH has major prognostic significance in patients receiving repetitive high-dose therapy and autologous stem cell transplantation. A phase III study comparing Mega-CHOEP + Rituximab to conventional chemotherapy in younger pts. with aggressive NHL is ongoing.

Table 1