Al-Jarrad, Ahmad

Introduction: The combination of chemotherapy and immunotherapy, commonly referred to as chemo-immunotherapy (CIT), has long been a cornerstone in the treatment of lymphoma. Although this approach has resulted in successful treatments for many patients (pts), a significant number continue to experience unfavorable results, underscoring the urgency for improved treatments. There is still a significant gap in knowledge about the immune profile of lymphoma pts, specifically in terms of (1) how their immune phenotype compare to those of healthy individuals and (2) how treatment affects their immune system. This study aimed to compare the immune profiles of lymphoma pts (at baseline) to that of matched healthy controls, and track the changes in the immune system during and after lymphoma treatment. Methods: Pts with newly diagnosed, untreated lymphoma, without prior history of cancer or autoimmunity were enrolled in the Dyna-RISC study. Whole blood samples were collected at baseline (BL), on day 1 of cycle 2 (C2D1), on day 1 of last cycle (CLD1), and 6 months after completion of therapy (6mo). Age- and gender-matched healthy individuals provided blood for baseline comparison. Samples were stained fresh with a pre-mixed lyophilized cocktail containing 30 metal-tagged monoclonal antibodies (Maxpar Direct Immune Profile Assay), fixed and cryopreserved. Samples were barcoded and acquired in batches on the Helios CyTOF (cytometry by time-of-flight) system. Cytometry data was analyzed using OMIQ. Differential abundance analysis was performed using relative frequencies of cell subsets (% of parent) using a false-discovery rate of 0.05 to account for multiple comparisons. Results: Between 11/2020 and 06/2021, 15 lymphoma pts were enrolled. Median age was 62 years (range 43-86), 5 pts (33%) were female. Five pts had follicular lymphoma (FL), 3 had diffuse large B-cell lymphoma (DLBCL),1 had primary mediastinal B-cell lymphoma (PBML), 1 had classic Hodgking lymphoma (cHL), 1 had mantle cell lymphoma (MCL), 1 had plasmablastic lymphoma (PBL), 1 had splenic marginal zone lymphoma (SpMZL), 1 had ALK- anaplastic large cell lymphoma (ALCL), 1 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Four pts received bendamustine plus rituximab (BR) and 7 pts received R-CHOP. In total, more than 30 million cellular events were acquired, resulting in over 18 million analyzable live single-cell events after expert manual gating. A total of 27 cell subsets were identified within 9 major immune cell compartments. At baseline, lymphoma pts showed significant reduction (p<0.05) of CD4+ naïve T cells (median 1.37%, range 0.33%-9.01%) compared to controls (median 9.28%, range 3.44-21.3%). Concurrently, lymphoma patients at baseline had significant elevation (p<0.05) of intermediate monocytes (median 2.1%, range 0.64%-5.73%) compared to controls (median 0.8%, range 0.2%-2.73%). Naïve cytotoxic T cells were significantly increased (p<0.05) in lymphoma pts at the 6mo timepoint (median 2.08%, range 0.7%-7.46%) compared to baseline (median 0.23%, range 0.03%-4.79%). A sub-group analysis restricted to patients who received either BR or R-CHOP with 6mo timepoint samples available (n=10), showed a significant reduction (p<0.05) in the frequency of CD4+ central memory T cells in the BR group (median 0.76%, range 0.06%-1.02%) compared to the R-CHOP group (median 3.3%, range 2.19%-5.0%). Additional results describing the details of the immune profile dynamics at intermediate timepoints (C2D1, CLD1) will be presented at the conference. Conclusion: Our results suggest that lymphoma patients have an unfavorable immune profile (high intermediate monocytes combined with low naïve CD4+ T cells) at the time of diagnosis, compared to matched healthy individuals. Their immune profile is reshaped after treatment with increase in naïve cytotoxic T cells 6 months after therapy. Bendamustine-based treatment seems to particularly affect T cell recovery post-therapy, leading to a reduction in CD4+ central memory T cells, compared to patients treated with R-CHOP. These findings highlight the importance of studying baseline and treatment-mediated immune changes in lymphoma pts. This characterization is of special interest in the context of therapies that rely on the fitness of immune cells to mediate an effect, such as chimeric antigen receptor (CAR) T cell therapy and bispecific T cell engagers (BiTEs).

Background: Chemoimmunotherapy using rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin), and prednisone (R-CHOP) has been the standard of care treatment of DLBCL for over 20 years. Despite its widespread usage, there is no accepted standard for the dose of prednisone in this setting which varies from fixed-dose (100 mg daily for 5 days) to different levels of BSA-adjusted dosage (ranging from 40-100 mg/m2 daily for 5 days). BSA-adjusted dosage results in high doses of prednisone administered to patients with increased body surface area which may lead to significant adverse events. We performed a systematic review and meta-analysis to determine if fixed-dose prednisone during R-CHOP therapy results in equivalent outcomes compared to BSA-adjusted dosing. Methods: A comprehensive search of several databases from each database's inception to April 29th, 2024, English language, was conducted. The databases included Ovid MEDLINE and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The search strategy was designed and conducted by an experienced librarian with input from the study's principal investigator. Controlled vocabulary supplemented with keywords was used to search for prospective clinical studies of R-CHOP for adult patients with untreated DLBCL. Search results were reviewed independently by 2 members of the study team for final inclusion. Discrepancies were adjudicated by a third member and reviewed by the senior author. Prednisone dosage and clinical outcomes were abstracted from the available public data. Meta-analysis was performed using the metafor package in R version 4.2.2 by applying a mixed-effects model to combine results from the multiple studies. The analysis was first conducted overall to determine the general effect, and then stratified by prednisone dose (fixed- vs. BSA-adjusted) to explore dose-dependent variations in outcomes. Results: Our search resulted in 2287 entries which were individually reviewed by the study team. A total of 30 studies with a combined sample size of 3573 treated patients fulfilled the inclusion criteria and were included in the final analysis set. Nineteen (63%) studies with a combined sample size of 1930 patients (median 155, range 12-399) used fixed-dose prednisone. Eleven (37%) studies with a combined sample size of 1643 patients (median 70, range 9-439) used BSA-adjusted dosing. Overall survival (OS) at 2 years data were available for 11 (37%) of the studies. Progression free survival (PFS) at 2 years data were available for 8 studies (27%). Overall response rate (ORR) and complete response rate (CRR) data were available for 16 (54%) and 14 (47%) of the included studies, respectively. OS at 2 years for all studies was 84% (SD 78%-91%) and did not differ between fixed-dose (88%, SD 79%-97%) and BSA-adjusted dose (82%, 73%-91%). PFS at 2 years for all studies was 77% (SD 68%-85%) and did not differ between fixed-dose (80%, SD 68%-93%) and BSA-adjusted dose (74%, SD 62%-86%). ORR for all studies was 86% (SD 79%-92%) and did not differ between fixed-dose (86%, SD 76%-96%) and BSA-adjusted dosage (84%, SD 80%-88%). CRR for all studies was 70% (SD 61%-80%) and did not differ between fixed-dose (67%, SD 54%-81%) and BSA-adjusted dose (77%, SD 64%-89%). Heterogeneity tests performed according to available clinical outcomes yielded results between 0% and 76%. Conclusion: The result of our systematic review and meta-analysis combining 30 prospective studies and a total of 3573 patients with newly diagnosed DLBCL treated with frontline R-CHOP found no difference in clinical outcomes between patients treated with fixed-dose and BSA-adjusted dose prednisone. Our findings provide scientific evidence for the widespread practice of capping prednisone at the maximum dose of 100 mg daily for 5 days, potentially avoiding unnecessary adverse effects from BSA-adjusted dosing.