Dose-Dense Rituximab in Combination with Biweekly CHOP-14 for Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Results of a Phase-I/II and Pharmacokinetic Study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).

Biweekly application of rituximab in combination with biweekly CHOP (R-CHOP-14) results in a slow increase of rituximab serum levels up to cycle 5 and the achievement of a plateau between the 5^th and the last rituximab application suggesting a saturation kinetics of rituximab(Reiser et al., JCO 2006., 24:431s). With the aim of achieving high rituximab levels early during the treatment phase, a phase I/II and pharmacokinetic study was started in elderly patients with DLBCL. Elderly patients (61–80 years, stages I–IV) received 6 cycles of CHOP-14 together with 12 applications of rituximab (375 mg/m²) given on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. Blood samples were taken before and after rituximab, as well as 1 week, and 1, 2, 3, 6 and 9 months after the last rituximab infusion. Fresh frozen serum samples were analyzed by Xendo Lab., Groningen, The Netherlands. By June 30, 2006, 76 patients with DLBCL (median age 70 years; IPI=1: 21%, IPI=2: 24%; IPI=3: 37%; IPI=4,5: 18%) have been enrolled. Pharmacokinetic data were obtained from the first twenty patients. The median trough serum levels (mg/ml) of rituximab before each rituximab infusion were: day 0: 0; day 1: 132; day 4: 171; day 8: 172, day 15: 153, day 22: 187, day 29: 175, day 43: 153, day 57: 140, day 71: 129, day 85: 128, day 99: 154. After therapy rituximab levels were 122 at 1 month, 50 at 2 months, 25 at 3 months, with levels at 6 months and at 9 months remaining to be determined. Of the first twenty patients three died of therapy-associated complications (1 sepsis, 2 interstitial pneumonia). 4 additional patients had interstitial pneumonia. After the first 20 patients, pneumocysits carinii (co-trimoxazole) and CMV prophylaxis (acyclovir) became mandatory and no interstitial pneumonia has been observed since in patients under prophylaxis. 46 patients have completed immunochemotherapy and no progression was observed under immunochemotherapy. In summary, this schedule of early rituximab dose-densification achieves a rituximab serum level plateau already with the second application of rituximab, i.e. on day 1 of the first CHOP-14 cycle. This is in contrast to a bi-weekly application, whereby the plateau is not achieved until day 57, i. e. nearly 2 months later or compared to the conventional three-weekly application, where a plateau can be expected to be achieved even later. Infectious complications, in particular interstitial pneumonias are of concern, but appear to be controlled by pneumocystis and CMV prophylaxis. The fast and high response rate together with the apparently reduced rate of progressions under therapy are encouraging. An update of the phase-II trial will be presented.