Optimization of Rituximab for Treatment of DLBCL in Young, High-Risk Patients -Results of the Dense-R-CHOEP Trial of the German High-Grade Lymphoma Study Group

Background. The German High-Grade Non-Hodgkin Lymphoma Study Group published several studies performed in order to optimize the use of Rituximab (R) in conjunction with CHOP chemotherapy in older patients (pts) with diffuse large B-cell lymphoma (DLBCL) (Pfreundschuh et al., J Clin Oncol 2014, 32, 4127; Murawski et al., Ann Oncol 2014, 25, 1800). The prospective, randomized

R-MegaCHOEP study reported 3-yr-PFS and –OS rates of 74 and 85 %, respectively, in young, high-risk pts (aaIPI 2, 3) treated with 6 x R and 8 x CHOEP-14 (Schmitz et al., Lancet Oncol. 2012,13,1250). We wanted to further improve treatment results in young, high-risk pts. by doubling the number of R infusions from 6 to 12.

Methods. Pts. with aggressive B-NHL (90 % DLBCL), age 18-60 yrs., aaIPI 2 or 3, received treatment  with 8 x CHOEP-14. In contrast to the randomized study reported previously, where R (375 mg/ m2) had been administered only six times (days 0, 15, 29, 43, 71 and 99) R was administered twelve times (days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 99) after an amendment. Event-free survival (EFS) (primary endpoint) and overall survival (OS) achieved with 12 x R vs. 6 x R were compared.

Results. Between 10/ 2010 and 02/ 2014 seventy-nine pts (median age 47 yrs., 53 % males) were registered, 78 pts were analyzed. Sixty-six pts (85 %) presented with aaIPI 2 and 11 pts. presented with aaIPI 3. Feasibility (86 % of pts. received all study treatment) and safety (TRM 0 %) of this intense regimen was excellent. CR/ CRu rate was 77 %, 2-yr-EFS 69% (95% CI:59-80%), 2-yr-PFS 76% (95% CI: 66-86%) and 2-yr OS 82% (95% CI: 73-92%). After a median observation time of 24 months  12 patients have died,  8 patients from lymphoma, 2 pts. from toxicity of salvage therapy, and 2 from other causes. Comparing these results to those achieved in 130 pts. treated with 6 x R and 8 x CHOEP-14 2-yr-EFS (71% (95% CI: 63-79%), p=0.766), 2-yr-PFS (75% (95% CI: 67-83%), p=0.871) and 2-yr-OS (85% (95% CI: 78-91%), p=0.843) did not significantly differ. These results could be confirmed in multivariate analyses adjusted for factors of aaIPI, bulk and gender. Interestingly, in pts. with aaIPI 3 12 x R + 8 x CHOEP-14 resulted in 2-yr-EFS and -OS rates of 72% (95% CI: 44-99%) and 91% (95% CI: 74-100%), respectively. These remarkable results, however, were not significantly different from those achieved with 6 x R + 8 x CHOEP-14 because only 11 pts. with aaIPI 3 had received 12 x R. Conclusions. In contrast to the significant improvements of EFS and OS achieved with the SMARTE-R- CHOP-14 regimen (Pfreundschuh et al. 2014) but in agreement with the results of the DENSE-R-CHOP-14 trial (Murawski et al, 2014) in older pts. (60-80 years) with high-risk disease (IPI 3-5) increasing the number of R infusions from 6 to 12 in young, high-risk pts. did not result in a significant improvement of EFS and OS in pts. with aaIPI 2 and overall.  This may reflect the necessity of longer R exposure of tumor cells in order to achieve optimal results. EFS and OS in pts. with aaIPI 3 were surprisingly good but improvement was not statistically significant because only 11 pts. with aaIPI 3 had been enrolled; more pts. with aaIPI 3 need to be investigated. Among other possible explanations for the lack of further improvement by doubling the number of R infusions,  the more aggressive chemotherapy (CHOEP vs. CHOP), the different timing of R in pts. receiving 6 and 12 R infusions, and differences in pharmacokinetics between younger and older patients may be responsible.