Early Dose Intensity Is Critical in Patients with Aggressive Lymphoma: A Randomized study Comparing Identical Doses of Cyclophosphamide, Adriamycin, Vincristine, Etoposide, and Prednisolone given as 4 or 6 cycles followed by Repetitive Transplantation of Stem Cells (Mega-CHOEP).

The German Study Group for High-Grade NHL (DSHNHL) investigated the efficacy of CHOP + Etoposide (Mega-CHOEP) at high doses for treatment of younger patients (pts) (<60y) with aggressive NHL and LDH > N. Autologous stem cells (ASC) were administered after the last 3 courses of therapy for hematopoietic rescue. At dose level (DL) 1 and 2 four courses of treatment were given: while doses of adriamycin (70 mg/m²), vincristine (2 mg), and prednisolon remained identical at all dose levels, the doses of Cyclophosphamide (C) and Etoposid (E) were set at 1500, 4500, 4500 6000 mg/m² (C), and 600, 600 (960), 600 (960), 1480 mg/m² (E) during courses 1, 2, 3 and 4 of therapy at DL1 (2). At DL 3 pts were randomized to receive either 4 (DL 3/4) or 6 courses of therapy (DL 3/6). While the cumulative doses of C and E were highest at DL 3 (C 19.5 g/m²; E 5.04 g/m²) as compared to DL 1 (C 16.5 g/m²; E 2.8 g/m²) or DL 2 (C 16.5 g/m²; E 4.0 g/m²) the administration of Mega-CHOEP with 6 courses of chemotherapy resulted in substantial prolongation of treatment (65 to 124 days) and thus loss of dose intensity (Table). From February 1997 to June 2001, 208 consecutive pts. were enrolled at DL 1–3, 31 of whom were excluded mostly due to incorrect histopathologie diagnosis. Therapy was given as per protocol in 81.8 % of pts. at DL 1 and 2, 90.2 % at DL 3/4 , and 69.2 % at DL 3/6, respectively, with treatment delays at DL 3/6 mostly due to extramedullary toxicity and, or poor performance status. Results were as follows: see table 1.

Late events were very rare with 5 relapses beyond 2 years in the whole population. Dose escalation without higher dose intensity (DL1+2 vs DL3/4) did not improve results. Dose escalation with loss of dose intensity (DL1+2 and DL 3/4 vs DL3/6) resulted in loss of efficacy. Mega-CHOEP DL2 was selected for comparison with non-transplant therapy in an ongoing phase III trial. These data underscore the importance of early dose intensity for successful treatment of aggressive NHL with high risk features.

Table 1