Dose Intensification with Rituximab, MTX and CHOP Results in Superior Results for Young High Risk DLBCL Patients Than Primary Autologous Transplantation
Authors: Marks Reinhard , Strüssmann Tim , Baumgarten Alexander , Finke Jürgen 
Published: October 2019

Abstract
Despite treatment of diffuse large B cell lymphoma has improved the last decade by incorporating rituximab to CHOP therapy, outcome in young high risk patients (aaIPI 2-3) remains poor with a substantial percentage of pts achieving only a short EFS and OS. In recent years primary autologous transplantation seemed to improve results. We designed an upfront treatment schedule consisting of 6 cycles CHOP-14 as backbone, incorporating dose dense rituximab as suggested by data from Pfreundschuh at al. and high dose MTX as CNS directed approach and compared results with own controls using primary autologous transplantation. All pts aged <65 y presenting with high risk DLBCL at Freiburg University Medical Center since 2012 were treated with 6 cycles CHOP-14 and dose dense rituximab (375 mg/m²) on days 0, 1, 4, 8, 15, 22, 29, 47, 61 and 75. HD MTX (3.0 g/m²) was administered on days 30 and 76 right before standard CHOP. We reviewed all pts treated according to the protocol in an intention to treat analysis identifying 18 patients meeting the criteria. 3 pts presenting with the diagnosis of DLBCL were not treated according to the protocol. 1 pt with a double hit lymphoma was primarily intensified with HD chemotherapy and subsequent ASCT. 1 pt with a prior history of kidney transplantation received 6 cycles R-CHOP and 1 pt was however primarily intensified. Response was evaluated using PET-CT according to revised criteria for response assessment by Cheson et al. 2014. Of 18 pts, histology included DLBCL (n=17, 95 %) and follicular lymphoma grade IIIb (n=1, 5 %). Median age at diagnosis was 52 y (range 23-68 y), with 50 % female. Stage I/II vs. III/IV: 22 % vs. 78 %; Of stage I/II pts, 2 had a bulky disease, 1 pt had a testicular lymphoma and 1 pt had orbital involvement; B-symptoms: 44 %; LDH was elevated in all pts; ECOG > 1: 33 %; Extranodal site ≥ 2: 61 %; According to IPI and aaIPI 16 pts (89 %) had an intermediate high and high risk score. Median follow-up was 15.6 month (range 0.4 - 35.9). 16 pts (89 %) completed the protocol. No treatment related deaths were observed. Toxicities were as expected and manageable; one pt could not receive 6th cycle CHOP due to severe infection. One early death was observed 4 days after 1st R-CHOP due to lymphoma infiltration of the heart and consecutive arrhythmia. All pts responded, 13 pts achieving a CR (72 %) and 4 pts a PR (22 %). Of 4 pts in PR by PET criteria 3 pts underwent second biopsy. 2 pts were lymphoma negative and 1 pt positive. The lymphoma positive pt underwent radiation of residual lymphoma masses, achieving a CR. The other pts did not receive any further treatment and are retrospectively in CR with a prior false positive PET-CT Scan. For all pts estimated 18m-OS was 94.5% and 2y-PFS was 94.5%. No CNS events occurred. This data compared favourable to own historic controls using an R-CHOP based induction followed by R-VCPE intensification and autologous transpplantation after BEAM in 133 high-risk patients with 3y-OS of 68%. Dose intensification with rituximab, CHOP and MTX is feasible for high risk DLBCL pts <65 y, showing promising results regarding ORR, progression-free and overall survival. In our cohort no CNS relapse was yet observed. Longer follow-up and larger cohort is required to confirm our results.

Disclosures
No relevant conflicts of interest to declare.