The Effects of Rituximab Added to Front-Line or Salvage Chemotherapy in Diffuse Large B-Cell Lymphoma (DLBCL) Undergoing High-Dose Chemotherapy (HDC) and Autologous Stem Cell Transplant (ASCT).
Authors: Ashraf Umeer , Mahajan Ritika , Hahn Theresa , Smiley Shannon L , McCarthy Philip L. , Bernstein Zale P. , Chanan-Khan Asher Alban , Battiwala Minoo , Czuczman Myron S. , Hernandez-Ilizaliturri Francisco J. 
Published: April 2020

Abstract
Despite the improved outcome in patients with DLBCL treated with rituximab (R) in combination with systemic chemotherapy (R + chemotherapy), a significant number of patients either relapse or fail to respond as a consequence of resistant disease. HDC and ASCT is the best therapeutic strategy to rescue relapsed/refractory DLBCL. It has been postulated that R+chemotherapy may lead to the selection of highly resistant lymphoma cells diminishing the clinical benefit of HDC and ASCT. Preliminary data from the CORAL study (Gisselbrecht et al Blood2007; 11:517a) suggest that overall response rates (ORR) and 2-year event free survival (EFS) are lower in R+chemotherapy relapsed/ refractory DLBCL when compared to DLBCL treated with chemotherapy alone. However the second randomization of this study to observation versus R-maintenance may affect the interpretation of the data. We retrospectively studied the difference in the outcomes of relapsed/refractory DLBCL patients following HDC and ASCT according to the front line therapy utilized (R+chemotherapy versus chemotherapy). Using the Roswell Park Cancer Institute (RPCI) Tumor Registry and the RPCI Blood and Marrow Transplant (BMT) Database we identified 130 patients with relapsed/refractory NHL who underwent for HDC + ASCT from 1991 to 2008. After excluding patients with a diagnosis other than B-cell DLBCL (patients with transformed NHL were excluded) and those patients receiving allo-BMT after progression from ASCT, the analysis included 63 refractory/ relapsed DLBCL. Demographic characteristics, clinical data, treatment history in the front line and salvage setting were collected. In addition response to salvage therapy and disease status at day +100 from ASCT was recorded for each subject. Progression free and overall survival were calculated from ASCT. Differences in clinical outcomes between patients receiving R as part of first line or salvage treatment and those treated with chemotherapy alone were evaluated by multivariate analysis, adjusting for significant univariate predictors of survival. The patient cohort included 34 males and 29 females with median age of 46 yrs (14.4 to 69.4). Two-thirds of the patients had advance disease and the majority had a Karnofsky performance status (KPS) of 80–100% at diagnosis. R+chemotherapy was given in the front line setting to 25 pts and while 38 received chemotherapy alone. In the salvage setting, 35 pts (55%) received R+chemotherapy. Most relapses (44 pts) occurred within 6 months of completion of front line therapy (17 pts with vs. 27 pts without R). The use of R in the front line setting was associated with significantly higher response rates (PR + CR) to salvage chemotherapy (P = 0.036) and better disease control on day +100 post-ASCT (P = 0.016) when compared to chemotherapy alone. In our cohort, there have been 32 deaths, 23 in chemotherapy treated DLBCL in contrast to 9 deaths in R+chemotherapy treated patients There was a significantly higher response rate post-ASCT for R+chemotherapy treated (as front-line or salvage) DLBCL versus chemotherapy alone (P = 0.007). A multivariate analysis demonstrated that achieving a CR pre-ASCT was the most important predictor of post-ASCT progression free and overall survival . In summary, our data suggest that the use of R + chemotherapy during frontline therapy and in the salvage setting yields better disease control and less incidence of chemo-resistant disease at the time of BMT. Applying the natural selection theory, the use of R+chemotherapy is expected to result in the development of resistant lymphomas. The length of time and the amount of R therapy that will render lymphoma cells resistant to chemo-immunotherapy remain to be determined. Standard doses of R (6 to 8 doses) do not appear to affect response to salvage therapy or autologous BMT outcomes. In our single institution analysis over the last 18 years, it appears that HDC + ASCT is an effective and viable option for patients with R +/− chemotherapy relapsed/refractory DLBCL.