Page 169 - 18F-FDG PET as biomarker in aggressive lymphoma; technical and clinical validation

Rituximab intensification during R-CHOP in DLBCL
DLBCL,rapid tumor control is critical to improve outcome by avoiding development of refractory disease on or after R-CHOP, because patients with refractory disease have poor prognosis [17]. Several phase II studies have explored optimization of rituximab for the treatment of DLBCL. In the DENSE-R-CHOP-14 trial, early dose-intensification of rituximab in combination with R-CHOP-14 was tested in 124 elderly patients with DLBCL [7]. In this study, 4 additional rituximab administrations were added during the first 3 weeks. Compared with a historical control population (RICOVER-60 population), no differences in outcome were observed for the whole population. Subgroup analysis revealed that patients with high-intermediate and high IPI scores had higher CR/unconfirmed CR (CRu) rates after rituximab intensification, but this did not translate into better survival outcome. A high rate of grade 3 and 4 infectious complications was reported, which improved after mandatory prophylaxis with acyclovir and cotrimoxazole was instituted. In the SMARTE-R-CHOP-14 study, a prolonged exposure time of rituximab using a loading schedule of 2 rituximab administrations before the first CHOP cycle and 3 additional rituximab administrations after completion of R-CHOP was investigated in 189 elderly patients with DLBCL [8]. Compared with the RICOVER-60 population, survival outcome was not significantly better for the complete study population, and subgroup analysis showed that patients with high-intermediate and high IPI scores had higher CR/CRu rates and better 3-year PFS (71% v 59%) and OS (80% v 67%) rates. Elderly male patients showed a significantly faster rituximab clearance than elderly female patients, resulting in a shorter rituximab serum elimination half-life, lower serum levels, and shorter rituximab exposure times [8,10]. Because in the RICOVER-60 study elderly male patients seemed to benefit to a lesser extent from addition of rituximab to CHOP than elderly female patients, an increased dose of 500 mg/m2 of rituximab for male patients and the standard dose of 375 mg/m2 for female patients were investigated in 271 elderly patients with DLBCL in the SEXIE-R-CHOP-14 study [2,18]. No survival differences were found, and the authors concluded that the increased rituximab dose may have abrogated the negative effect in elderly male patients. These phase II studies in elderly patients with DLBCL supported the notion that patients with DLBCL with poor prognosis would be most likely to benefit from adapted rituximab schedules.
In our study, trough rituximab levels were indeed consistently higher during the first 4 cycles in the RR-CHOP-14 arm than in the R-CHOP-14 arm, and they
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