R-CHOP Arm Research Articles

How to improve RCHOP as frontline therapy for diffuse large B-cell lymphoma: a systematic review and meta-analysis of 21 randomized controlled trials.

RCHOP is the standard of care for patients with diffuse large b-cell lymphoma (DLBCL) but failures occur in approximately 40% of them. We performed a meta-analysis of 21 randomized controlled trials (RCTs) comparing experimental regimens with RCHOP. We searched the database of PubMed with proper criteria, and data of efficacy (Progression Free Survival-PFS) in the ITT population were extracted and analyzed. Cross comparisons of RCTs were performed by using the CINEMA software. Odds ratio (OR) and 95% confidence intervals (95%, CI) are reported. The literature search yielded 21 RCTs including 5785 patients in the RCHOP arm and 5648 patients in the experimental arm. Odds ratio (OR) for PFS in the total cohort was OR (95%, CI): 0.87 (0.76-0.99), p=0.02. Among different strategies to improve RCHOP, addition of a novel agent on RCHOP improved PFS. In total 1740 patients in the RCHOP arm were compared with 1755 in the RCHOP plus a novel agent arm, and the OR (95% CI) for PFS was 0.84 (0.71-0.97), p=0.02. Indirect comparisons of nine studies adding a novel agent on RCHOP does not give prominence to any agent. Subgroup analysis according to cell of origin was performed for non-GC DLBCL patients. In this subgroup, 1546 patients treated with RCHOP were compared with 1538 patients treated with experimental regimens. The OR (95% CI) for PFS was 0.86 (0.73-1.02), p=0.34. Overall survival data extracted from 18 studies showed no superiority of experimental regimens over RCHOP. Efficacy of RCHOP backbone is marginally improved when adding a novel anti-lymphoma agent.

Final Analysis of the Randomized Phase II/III Study of Standard R-CHOP Versus CHOP Combined with Dose-Dense Weekly Rituximab for DLBCL: JCOG0601

Background: Despite several attempts of randomized phase III trial to overcome R-CHOP in overall survival (OS), R-CHOP has been continued to be a standard of care in previously untreated DLBCL. We conducted a randomized phase II/III study (JCOG0601, jRCTs031180139) that investigated the efficacy of dose-dense weekly rituximab combined with standard CHOP regimen (RW-CHOP) during the early treatment period for previously untreated DLBCL and published the results (Ohmachi K, et al. Blood Adv. 2021). Here in, we report the long-term efficacy and safety of the JCOG 0601 trial after 8 years follow-up from the end of accrual. Methods: Patients aged 20-79 years with previously untreated CD20-positive DLBCL (stage I-IV, performance status 0-2) were randomized to standard R-CHOP (CHOP-21 with eight doses of rituximab, once every 3 weeks) or RW-CHOP (CHOP-21 with eight doses of weekly rituximab). The primary endpoint of phase III part was progression-free survival (PFS). Required sample size was 422 patients, an accrual period of 7 years, and a follow-up period of 3 years with the primary analysis. An additional follow-up period was added to assess long-term outcomes, for a total of 8 years of follow-up. Results: Between December 2007 and December 2014, 422 patients were enrolled, but primary analysis was performed on 421 patients after one patient withdrew consent: 213 in the R-CHOP arm and 208 in the RW-CHOP arm. The baseline characteristics were as follows (R-CHOP arm vs. RW-CHOP arm): median age, 61 vs. 62 years; male sex, 54.5% vs. 55.8%; Ann Arbor stage I/II/III/IV, 14.6/32.9/26.8/25.8% vs. 16.3/42.8/20.2/20.7%; and International Prognostic Index score ≤2, 77.0% vs. 87.5%. At a primary analysis, there was no significant difference in PFS between the arms. At the time of final analysis with a median follow-up of 9.6 years (range: 0.3-14.9) among all patients, meaningful differences were not found in PFS and OS as well as the primary analysist (hazard ratio [HR] in PFS of RW-CHOP against R-CHOP, 0.94; 95% confidence interval [CI], 0.67 to 1.32, one-sided log-rank, P = 0.36 and HR in OS, 0.94; 95% CI, 0.63 to 1.41). Median PFS and OS were not estimable in both arms. Estimated 10 years PFS and OS of all patients was 66.9% (95% CI, 62.1 to 71.3) and 78.0% (95% CI, 73.6 to 81.7). After the first relapse or refractoriness, 126 patients received post-protocol salvage therapy: 66 in the R-CHOP arm and 60 in the RW-CHOP arm. In each arm, 3 patients received high-dose chemotherapy followed by autologous stem cell transplantation. One patient in the R-CHOP arm proceeded to allogeneic stem cell transplantation from a sibling donor. Ann Arbor stage I to II disease tended to have more favor prognosis than Ann Arbor stage III to IV disease, and no sustained relapse was observed in either stage. Of the 401 patients who underwent central pathological review, 125 were diagnosed with germinal center B-cell-like (GCB) type and 216 with non-GCB type by immunohistochemistry analysis. There was no remarkable difference in PFS between the arms for GCB type and non-GCB type. Death occurred in 95 patients: 56 from DLBCL, 2 from treatment-related cardiac toxicity, 9 from treatment-related mortality caused by salvage treatment, 14 from secondary malignancies, and 11 from other diseases or reasons. There were 34 secondary malignancies in 31 patients (14.6%) in the R-CHOP arm, and 39 cases in 35 patients (16.8%) in the RW-CHOP arm. The most common secondary malignancies were lung cancer (2.6%), colon cancer (1.9%), prostate cancer (1.7%) and gastric cancer (1.9%). Three cases of acute myeloid leukemia (0.7%) and three of myelodysplastic syndromes (0.7%) were observed. The median age of patients who developed secondary malignancy was 72 years (range: 49-84) at the onset. The median time from study enrollment to the onset of secondary malignancy was 4.5 (range: 0.1-13.1) years and the incidence was time dependent. There were no unexpected adverse events, including late opportunistic infections. Conclusion: This final-follow up data demonstrated again no superiority of RW-CHOP in PFS and OS. Standard R-CHOP remains a standard of care for untreated DLBCL.

Deciphering the Clinical Benefit of Pola-R-CHP versus R-CHOP in Different Genetic Subtypes Beyond Cell of Origin in the POLARIX Study

Introduction: In the POLARIX study, polatuzumab vedotin in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) demonstrated prolonged progression-free survival (PFS) vs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL; NCT03274492; Tilly et al. N Engl J Med 2022); the PFS benefit was sustained with longer follow-up (Herrera et al. Blood 2022). Exploratory analyses demonstrated a trend towards greater PFS improvement in activated B cell-like (ABC) DLBCL with Pola-R-CHP vs R-CHOP (Tilly et al. N Engl J Med 2022). Although not yet available for daily practice, more granular molecular subtypes of DLBCL beyond cell of origin (COO) classification have demonstrated poor prognosis with R-CHOP, including EZH2 mutations/ BCL2 translocations (EZB), MYD88/ CD79B-mutated (MCD; as defined by LymphGen; Wright et al. Cancer Cell 2020), and dark zone gene expression signature (DZsig; Alduaij et al. Blood 2023). Here, in a post hoc exploratory analysis, we investigate the prevalence and clinical outcomes of molecularly defined subtypes of DLBCL in pts treated with Pola-R-CHP vs R-CHOP in POLARIX. Methods: All genetic analyses were performed on baseline tumor biopsies. Using mutations derived from whole exome sequencing (WES), pts were allocated to different genetic subtypes, as defined by the LymphGen classifier. DZsig status was determined from global gene expression patterns (GEP) as measured by RNAseq, as previously described (Ennishi et al. J Clin Oncol 2019). COO was determined by NanoString. Hazard ratios (HR) were adjusted for International Prognostic Index score (2 vs 3-5) and age (≤60 vs >60 years). Due to the exploratory nature of the subtype analyses, all statistics are descriptive. Results: WES data were available for 594 pts (Pola-R-CHP, n=292; R-CHOP, n=302), and baseline clinical characteristics were balanced between treatment arms. The observed 2-year PFS rates with EZB and MCD subtypes were numerically higher but not statistically significant in the Pola-R-CHP vs R-CHOP arm ( Table): EZB, 83% (95% confidence interval [CI]: 76-92) vs 75% (95% CI: 65-86), HR 0.61, 95% CI: 0.33-1.13; MCD, 85% (95% CI: 73-98) vs 73% (95% CI: 63-90), HR 0.64, 95% CI: 0.24-1.70. Lower 2-year PFS rates were observed in pts with the BCL6 fusions and NOTCH2 mutations (BN2) subtype treated with Pola-R-CHP vs R-CHOP (HR 1.82, 95% CI: 0.46-7.18; Table). In the subgroup of pts with an undetermined genetic subtype, 2-year PFS estimates were numerically higher with Pola-R-CHP vs R-CHOP (74% vs 62%, respectively; HR 0.70, 95% CI: 0.46-1.07). GEP data were available for 665 pts (Pola-R-CHP, n=331; R-CHOP, n=334); 108 (16.2%) were DZsig+ (Pola-R-CHP, n=52; R-CHOP, n=56). Of those who were DZsig+, 103 (95.4%) had germinal center B cell-like (GCB) DLBCL, 3 (2.8%) had ABC DLBCL, and 2 (1.9%) had an unknown COO. In pts who were DZsig+ and had FISH results, 54/86 (62.8%) had BCL2 translocations, 41/92 (44.6%) had MYC translocations, and 6/40 (15%) had BCL6 translocations (BCL6 FISH was only done in pts with a MYC translocation), resulting in 23/90 (25.6%) pts with double/triple-hit DLBCL. Pts who were DZsig+ were predominantly within the EZB genetic subtype (60.3%). In the R-CHOP arm, pts who were DZsig+ had shorter PFS vs pts who were DZsig− (2-yr PFS: 62% [95% CI: 51-77] vs 73% [95% CI: 68-79], respectively; HR 1.61, 95% CI: 1.02-2.56; Figure). In the Pola-R-CHP arm, no significant difference in PFS was observed between pts who were DZsig+ vs DZsig− (2-yr PFS: 77% [95% CI: 66-89] vs 79% [95% CI: 74-84]; HR 0.97, 95% CI: 0.54-1.75). Improved PFS was demonstrated in pts who were DZsig+ and treated with Pola-R-CHP vs R-CHOP (HR 0.47, 95% CI: 0.24-0.95). Conclusions: In this exploratory biomarker analysis, we recapitulated that pts with molecularly defined DLBCL subtypes, including EZB and MCD by LymphGen and DZsig+ by RNAseq, have poor outcomes with R-CHOP therapy. In pts with the EZB and MCD subtypes, Pola-R-CHP appeared to improve 2-year PFS compared with R-CHOP. Pts with GCB DLBCL who were DZsig+ significantly benefited from Pola-R-CHP vs R-CHOP. In summary, our data indicate that molecular analysis beyond COO leads to identification of distinct molecular subsets of DLBCL that may respond favorably to Pola-R-CHP; future prospective validation is required.

Comparison of statistical methods for extrapolating survival in previously untreated diffuse large B-cell lymphoma: results based on the POLARIX study

Objective The ongoing Phase III randomized POLARIX study (GO39942; NCT03274492) demonstrated significantly improved progression-free survival (PFS) with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) versus rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). We compared statistical methodologies to extrapolate long-term PFS data from POLARIX.Materials and methods This analysis explored four different approaches to extrapolate the POLARIX data: standard parametric survival, mixture-cure, landmark, and spline models. The resulting extrapolation curves were validated via comparison with the corresponding Kaplan–Meier (KM) curves from POLARIX and the POLARIX-like population of the Phase III GOYA study (NCT01287741; R-CHOP arm).Results The R-CHOP PFS KM curve from the GOYA validation set was well aligned with the POLARIX KM curve. As we anticipated that PFS in POLARIX would evolve similarly to that of GOYA, the data from GOYA were used to externally validate the extrapolated modelling results. While all four statistical methods were able to fit the data to the POLARIX KM curve, the mixture-cure model was the most accurate in predicting long-term PFS in the GOYA external validation set. In the mixture-cure model, generalized gamma distribution estimated 64% (95% confidence intervals [CI]: 56–71%) of patients to have long-term remission in the R-CHOP arm of POLARIX and GOYA, and 75% (95% CI: 70–79%) in the Pola-R-CHP arm of POLARIX. A limitation of this study was the comparison of the statistical models only in the PFS KM curves, since it was not possible to determine which statistical method was more appropriate to extrapolate the overall survival KM curves.Conclusions Within this analysis, the mixture-cure model provided the best prediction of long-term outcomes from the primary PFS analysis of the POLARIX study.

Circulating tumor DNA (ctDNA) status and clinical outcomes in patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL) in the POLARIX study.

7523 Background: the POLARIX study, pts with previously untreated DLBCL were randomized to Pola-R-CHP or R-CHOP (NCT03274492; Tilly et al. 2022). We previously validated the prognostic value of ctDNA at baseline and after one cycle of therapy in POLARIX (Herrera et al. 2022); here, we evaluate the relationship between ctDNA clearance and PFS and OS. Methods: Pts were included if baseline and longitudinal ctDNA results were available. Plasma ctDNA was measured at baseline, Cycle (C) 5 Day (D) 1, and end of treatment (EOT), with the AVENIO NHL CAPP-Seq assay (Stokowski et al. 2022). ctDNA clearance was determined as previously described (Herrera et al. 2022). PFS and OS according to ctDNA status were reported as landmarked hazard ratios (HR) and 3-yr rates. HRs were adjusted for IPI score (>2), region, bulky disease (>7.5cm), age (>60 years), and cell of origin. Results: At baseline, 654 pts had ctDNA results; 494 (76%) and 519 (79%) pts were evaluable at C5D1 and EOT, respectively. Undetectable ctDNA (ctDNA−) was achieved by 57% (152/265) of Pola-R-CHP-treated pts and 59% (135/229) of R-CHOP-treated pts at C5D1 (p=0.79), and by 66% (172/262) of Pola-R-CHP-treated pts and 67% (172/257) of R-CHOP-treated pts at EOT (p=0.83). Achieving ctDNA− was prognostic for PFS and OS in each treatment arm at C5D1 and EOT (Table). Pts in the Pola-R-CHP arm who had complete response (CR) with PET-CT and ctDNA− at EOT had superior PFS and OS compared with pts with CR and detectable ctDNA (ctDNA+) at EOT (PFS HR 0.30, 95% confidence interval [CI]: 0.14–0.66; OS HR 0.20, 95% CI: 0.07–0.60). This was not observed with R-CHOP (PFS HR 0.74, 95% CI: 0.34–1.63; OS HR 1.11, 95% CI: 0.30–4.16). Among pts with CR and ctDNA− at EOT, pts treated with Pola-R-CHP had superior PFS vs R-CHOP (HR 0.41, 95% CI: 0.21–0.82); this was not observed with OS (HR 0.41, 95% CI: 0.14–1.18). There was no statistically significant difference in PFS between treatment arms in pts with CR and ctDNA+ at EOT (PFS HR 1.20, 95% CI: 0.49–2.83). Conclusions: Achieving ctDNA− at C5D1 and EOT was prognostic for longer survival. Although no difference was observed in the number of pts with ctDNA− at EOT between arms, pts achieving CR and ctDNA− at EOT had superior PFS in the Pola-R-CHP vs the R-CHOP arm, suggesting deeper molecular responses in pts treated with Pola-R-CHP beyond the detection sensitivity of the assay used in this analysis. Clinical trial information: NCT03274492 . [Table: see text]

IMMUNE CONTEXTURE ANALYSIS IN POLARIX SUGGESTS RESPONSE TO POLA‐R‐CHP TREATMENT REDUCES TUMOR MICROENVIRONMENT DEPENDENCY

IMMUNE CONTEXTURE ANALYSIS IN POLARIX SUGGESTS RESPONSE TO POLA‐R‐CHP TREATMENT REDUCES TUMOR MICROENVIRONMENT DEPENDENCY

CIRCULATING TUMOR DNA (CTDNA) STATUS AND CLINICAL OUTCOMES IN PATIENTS (PTS) WITH PREVIOUSLY UNTREATED DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL) IN THE POLARIX STUDY

CIRCULATING TUMOR DNA (CTDNA) STATUS AND CLINICAL OUTCOMES IN PATIENTS (PTS) WITH PREVIOUSLY UNTREATED DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL) IN THE POLARIX STUDY

Epidemiological Impact of Polatuzumab Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin and Prednisone (Pola-R-CHP) Use in Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL) in Terms of Second Line (2L) Treatment: An Ad Hoc Analysis from the POLARIX Study

Background: In the POLARIX study (NCT03274492), Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) vs previous standard of care rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP; stratified hazard ratio [HR], 0.73; 95% confidence interval [CI]: 0.57-0.95; p=0.02), with a similar safety profile in patients (pts) with previously untreated DLBCL (Tilly H, et al. N Engl J Med 2022). Here we report an ad hoc analysis to evaluate the potential impact of Pola-R-CHP on 2L treatment, using results of the POLARIX study projected to the real-world DLBCL population. Methods: Data from pts across six countries were derived from POLARIX (data cut-off: June 28, 2021). 2L treatment was defined as the first treatment after progression, or treatment change due to toxicity or other reasons, whichever occurred first. 2L treatments were grouped into six categories: autologous stem cell transplant (ASCT), chemotherapy only (chemo), rituximab plus chemotherapy (R-chemo), radiotherapy (RT), clinical trials, and other therapy. Cumulative incidence of 2L treatment as a function of time was estimated using Fine-Grey methodology, with death as a competing risk; long-term extrapolation outcome was estimated using the mixture cure rate models fitted on PFS and overall survival data. A dynamic multi-cohort partition survival model was constructed to estimate population-level impact of first line (1L) DLBCL treatment with Pola-R-CHP on the incidence of 2L treatment, over a 10-year period (2023-2033). DLBCL population incidence (2018-2032) was based on age-specific rates taken from country-specific registries and applied to population counts for each age group using United Nations population data (United Nations. World Population Prospects 2019). The population distribution of International Prognostic Index (IPI) score 2-5 was assessed from literature and reflected 70% of diagnosed pts (Harrysson S, et al. Blood Cancer J 2021; Tuominen S, et al. Future Oncol 2022). DLBCL population incidence counts for IPI 2-5 were imputed into the dynamic model to parse the effects between treatment with Pola-R-CHP and R-CHOP. Results: Among pts who received 2L treatment in POLARIX (Pola-R-CHP, n=78; R-CHOP, n=109), the majority (84%) in both arms required subsequent treatment due to disease progression. In line with the previously reported PFS benefit, pts in the Pola-R-CHP arm received fewer 2L treatments than pts in the R-CHOP arm, with a 34% risk reduction (subdistribution HR, 0.66; 95% CI: 0.49-0.88); cumulative incidence of 2L treatment at 24 months was 17.1% (95% CI: 13.5-20.6) vs 24.4% (95% CI: 20.4-28.5), respectively (Figure A). At baseline, risk factors for requiring 2L treatment, after adjustment for treatment effect, were: Ann Arbor Stage III-IV, bulky disease, and double expressor lymphoma (DEL). Mortality as a competing risk to 2L was similar across both treatment arms. As expected, the types of 2L therapies used were similar between the Pola-R-CHP and R-CHOP arms of POLARIX (Pola-R-CHP vs R-CHOP, n [%]: ASCT, 16 [20.5] vs 25 [22.9]; R-chemo, 39 [50.0] vs 53 [48.6]; chemo, 5 [6.4] vs 7 [6.4]; RT, 10 [12.8] vs 12 [11.0]; clinical trials, 3 [3.8] vs 8 [7.3] [including chimeric antigen receptor T-cell therapy, n=2 vs n=1, respectively], and other therapy, 5 [6.4] vs 4 [3.7], respectively), suggesting that the use of Pola-R-CHP instead of R-CHOP in 1L DLBCL does not impact choice of 2L treatment strategy. In the real-world setting, replacing R-CHOP with Pola-R-CHP as 1L treatment in pts with IPI 2-5 would translate to a 27% cumulative reduction of 2L treatments during the 10-year period analyzed (Figure B). For the six countries studied, this would result in a total of 27,741 additional pts avoiding the burden of later-line therapies. Conclusions: Results demonstrate that 2L therapies used were similar between pts who received Pola-R-CHP vs R-CHOP, suggesting 1L use of Pola-R-CHP does not alter subsequent therapy selection. Moreover, analysis of the potential impact on 2L treatment in the next 10 years showed that Pola-R-CHP reduced the risk of undergoing 2L treatment compared with R-CHOP by 27%, including pts with high-risk tumor subsets such as DEL, translating to 27,741 pts across the countries studied. Further study with longer follow up is needed to determine the number of treatments that would have been avoided by these pts in the third-line setting and beyond. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Five-Year Survival Results from the Remodl-B Trial (ISRCTN 51837425) Show Improved Outcomes in Diffuse Large B-Cell Lymphoma Molecular Subgroups from the Addition of Bortezomib to R-CHOP Chemoimmunotherapy

Introduction: The REMoDL-B trial compared R-CHOP versus R-CHOP + bortezomib (RB-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL) stratified by cell of origin (COO) determined by gene expression profile (GEP). The primary analysis of the trial at a median follow-up of 30 months found no overall difference in progression free (PFS) or overall survival (OS) by treatment arm. Retrospective analysis using a gene expression based classifier identified a molecular high grade group (MHG) with distinct molecular features. We present an update of this analysis and the trial final results for patients with lymphomas of activated B-cell (ABC), germinal-centre B-cell (GCB) or MHG type. Methods: REMoDL-B was an open label randomised phase 3 adaptive trial with patients recruited from UK and Switzerland. Eligible patients had untreated, histologically confirmed DLBCL stage I-IV, were >18 year old, ECOG performance status≤2, and had cardiac, lung, renal, and liver function sufficient to tolerate full dose chemotherapy. Patients with sufficient material from initial biopsies for GEP were randomised between R-CHOP or RB-CHOP from cycle 2, stratified by international prognostic index (IPI) and COO. COO classification was performed in the trial with the DLBCL automatic classifier in time for randomisation and reassessed retrospectively adding in the MHG classifier. Time to event analyses were performed using the Kaplan-Meier method and cox regression modelling. REMoDL-B was coordinated by the Southampton Clinical Trials Unit and funded by a grant from Janssen-Cilag and endorsed by Cancer Research UK after independent peer review (C328/A12128). Results: 801 of the 1,077 patients registered were identified as ABC, GCB or MHG type in the final analysis. 128 were unclassified and in 148 the diagnostic biopsy sample was insufficient. Median age was 65 (range 20-86) and 67% were stage III/IV, 48% had abnormal LDH, 29% had bulk, 17% had high IPI and 30% high intermediate IPI, 31% ABC, 59% GCB and 10% MHG. At a median follow up of 64 months in those still alive, there was no overall benefit of bortezomib on PFS or OS (5-year PFS of 64% in R-CHOP and 70% in RB-CHOP HR, 0.81 p=0.085, 5-year OS of 76% vs 79% HR, 0.86; p=0.32). Improved PFS and OS with RB-CHOP was however seen in ABC patients; 5-year PFS of 54% with R-CHOP vs 69% with RB-CHOP (Figure 1); 5-year OS of 67% in the R-CHOP arm vs 80% in the RB-CHOP arm: OS HR 0.58; (95% CI, 0.35 to 0.95) p=0.032. PFS was significantly improved in MHG patients: 5-year PFS 29% with R-CHOP vs 55% with RB-CHOP: HR 0.46 (95% CI 0.26-0.84) p=0.011 (Figure 2). 5-year OS was 48% vs 60% HR, 0.62; 95% (CI, 0.32 to 1.20) p=0.156. Outcomes by LymphGen classification will be presented. Adverse events were similar to those reported previously, with the most common grade 3 or worse being haematological toxicity, reported in 38% R-CHOP patients and 42% RB-CHOP patients. Conclusions: Gene expression profiling can identify subtypes of DLBCL which may benefit from the addition of bortezomib to R-CHOP in initial therapy, specifically, ABC and MHG types. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Final Analysis of JCOG0203 for Advanced-Stage Indolent B-Cell Lymphoma 15 Years after the End of Enrollment: Pooled Analysis of Arms a and B for Follicular Lymphoma

Optimal immunochemotherapy as first-line treatment for patients with follicular lymphoma (FL) remains undetermined. FL frequently relapses after frontline treatment; thus, fatal secondary malignancies (SMs) and treatment-related death, including death due to infection, which will be accumulated by subsequent treatments, should be avoided. To evaluate the cumulative incidence of SMs as well as histologic transformation (HT), a follow-up of more than 15 years is necessary. However, such data are available only in the pre-rituximab era by retrospective and single-institute studies. In addition, the real incidence of HT was probably underestimated in the studies that estimated only biopsy-proven cases. In JCOG0203, previously untreated patients with stage III/IV indolent B-cell lymphoma were randomly assigned to receive six cycles of R-CHOP (Arm A) or R-CHOP-14 (every 2 weeks with G-CSF, Arm B) without rituximab maintenance. All histopathological specimens were centrally reviewed by three hematopathologists. To evaluate long term follow-up data, analyses for overall survival (OS), progression-free survival (PFS), HT, SMs, and progression of disease within 24 months after treatment initiation (POD24) were performed. OS and PFS were calculated using Kaplan-Meier method. Hazard ratios (HRs) were estimated by proportional hazards model. Cumulative incidence function of HT and SM were estimated. Exploration of risk factors for frequency of HT and POD24 were conducted by logistic regression model. Between Sep 1, 2002 and Feb 28, 2007, 300 patients, including 248 with grade (G)1-3A FL, were enrolled from 44 centers. Nineteen (6.3%) patients were lost to follow-up. The 10- and 15-year OS of patients with FL in Arm A vs. Arm B was 83.8% vs. 85.3% and 76.4% vs. 75.9%, respectively. No protocol treatment-related death or fatal late infection was reported. Multivariable analysis for the 299 patients eligible for OS revealed that significant adverse prognostic factors were age ≥61 (HR=2.54, p<0.0001), male sex (HR=2.06, p=0.002), and ECOG PS ≥1 (HR=1.71, p=0.044). As both arms revealed similar outcomes, pooled analyses of Arms A and B were performed for FL. The incidence of HT, including biopsy-proven and clinically diagnosed HT, was 9.8% and 14.4% at 10 and 15 years after enrollment, respectively, and increased thereafter. Seventy-seven of 245 (31.4%) patients, excluding two who died and one lost to follow-up patients without POD24, experienced POD24. HT occurred in 19 of 76 (25.0%) patients. Multivariable analysis for POD24 identified high Follicular Lymphoma International Prognostic Index (FLIPI) score (Odds ratio (OR)=4.40) and G3A histology (OR=2.63) as risk factors for HT and intermediate (OR=2.53) and high (OR=2.24) FLIPI score, B symptoms (OR=2.09), and G3A (OR=1.83) as risk factors for POD24. Additional analysis suggested that, restricted to within a 10-year period, high FLIPI (OR=3.24, p=0.046) and G3A (OR=3.30, p=0.054) were more related to HT than in the whole study period in univariable analysis. The cumulative incidence of SMs increased after the 10-year follow-up. The incidence of solid tumors was 12.8% {10.6% (fatal [f], n=3/17 events) in Arm A vs. 15.0% (f, n=10/23 events) in Arm B} at 15 years, whereas that of hematologic malignancies was 3.7% {4.1% (f, n=2/5) in Arm A vs. 3.3% (f, n= 1/4) in Arm B}. These results are the longest follow-up data of more than 200 patients with FL homogeneously treated in a multicenter prospective trial. R-CHOP was safe and efficacious, reducing HT, without increasing fatal hematologic malignancies in the long-term and may, therefore, be a reasonable option as frontline therapy for advanced-stage FL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ABCL-101 Cost-Effectiveness of Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma

Polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly increased progression-free survival (PFS) (HR, 0.73; 95% CI: 0.57-0.95) vs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the POLARIX clinical trial (NCT03274492). The objective of this analysis was to evaluate the cost-effectiveness of Pola-R-CHP vs R-CHOP in frontline diffuse large B-Cell lymphoma (DLBCL). In our cost-effectiveness model, we derived PFS, overall survival (OS), drug utilization, adverse events (AE), and subsequent treatment from POLARIX, including higher utilization of chimeric antigen receptor-modified T-cell therapy (CAR-T) and stem-cell transplantation in the R-CHOP arm compared with Pola-R-CHP arm. Costs included drug acquisition, AE management, routine medical care, subsequent treatments, end-of-life care, and work productivity. A scenario analysis was conducted to assess the future impact of increased second-line CAR-T utilization. We estimated the life years, quality-adjusted life years (QALY), cost impacts, and incremental cost-effectiveness ratio (ICER) of Pola-R-CHP vs R-CHOP. Probabilistic sensitivity analyses (PSA) were performed to assess the impact of uncertainty on cost per QALY-gained outcomes. The ICER of Pola-R-CHP vs R-CHOP was $80,920/QALY gained from a societal perspective and $96,014/QALY gained from a payer perspective. From a societal perspective, the total cost of Pola-R-CHP was $41,159 higher than R-CHOP, primarily due to higher drug costs ($125,623 vs $34,034, respectively). Drug cost offsets for Pola-R-CHP included subsequent treatment costs (-$42,269), routine care (-$1,195), end-of-life care (-$393), and work productivity (-$7,677). AE management costs were $1,069 higher with Pola-R-CHP vs. R-CHOP. Pola-R-CHP resulted in an increase of 0.50 life years and 0.51 QALYs vs R-CHOP. PSA results demonstrated that Pola-R-CHP was cost-effective in 63.0% of simulations at a willingness-to-pay of $150,000/QALY gained from a societal perspective, and 60.8% of simulations from a payer perspective. In the increased CAR-T use scenario, the ICER was $61,220/QALY gained. Pola-R-CHP was projected to be cost-effective vs R-CHOP in previously untreated DLBCL. Our economic model demonstrates an improvement in QALYs with Pola-R-CHP vs R-CHOP and savings in costs relating to DLBCL progression. These cost-effectiveness results reinforce the clinical findings from POLARIX suggesting that Pola-R-CHP should be considered as a frontline standard of care.

Improving outcomes for high-risk DLBCL: a pilot study looking at the role of fractionated cyclophosphamide with RCHOP chemo-immunotherapy (SCUBA-1 trial).

The outcomes for patients with high-risk DLBCL are suboptimal, especially in Low-middle income countries in comparison to published data from the western world. Most newer therapies aimed at improving outcomes are either unavailable or out of reach for the majority of patients in low-middle income countries. Cyclophosphamide is an easily available and accessible drug that forms the backbone for therapy for DLBCL. We conducted a single-center, open-label randomized pilot study comparing standard RCHOP to RCHOP with fractionated cyclophosphamide (RfCHOP) in patients with newly diagnosed, high-risk DLBCL. Fifty-five patients were randomized- 28 to RfCHOP and 27 to the RCHOP arm. RfCHOP was associated with a higher complete response rate than RCHOP at the end of 6 cycles of therapy (81.2% vs. 59.3%; p-0.062). Grade III/IV adverse events were comparable in both arms with the use of prophylactic GCSF in the RfCHOP arm. At a median follow-up of 22 months, the Median EFS and OS was not reached in either arm. RfCHOP may represent a therapeutic option for patients with newly-diagnosed, high-risk DLBCL, especially in Low-middle income countries. Larger studies are required to confirm these findings.

P1190: OUTCOMES BY BCL2 AND MYC EXPRESSION AND REARRANGEMENTS IN UNTREATED DIFFUSE LARGE B-CELL LYMPHOMA FROM THE POLARIX TRIAL

Background: Overexpression of BCL2 and MYC, and translocation of MYC, BCL2, and BCL6, are associated with poorer outcomes in patients with diffuse large B-cell lymphoma (DLBCL; Horn et al. Blood 2013). We previously reported progression-free survival (PFS) from POLARIX in subgroups of patients with DLBCL receiving Pola-R-CHP or R-CHOP, including patients with double expressor lymphoma (DEL; favoring Pola-R-CHP: hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.42–0.97), and double- or triple-hit lymphoma (DHL/THL; favoring R-CHOP: HR 3.81, 95% CI 0.82–17.64) (Tilly et al. NEJM 2022). Aims: This is a prespecified exploratory analysis, to further analyze immunohistochemistry (IHC) expression status of BCL2 and MYC, and rearrangements (R) of BCL2, BCL6 and MYC as independent prognostic markers. The prognostic impact of DEL, and BCL2 and MYC overexpression within treatment arms was also explored. Methods: BCL2 and MYC protein expression were assessed by IHC and identified as IHC+ (≥50% [BCL2]/≥40% [MYC]) or IHC−; MYC-R, BCL2-R, and BCL6-R were detected by fluorescence in situ hybridization (Tilly et al. NEJM 2022). All patients provided informed consent. Pola-R-CHP is an investigational combination. Exploratory multivariate Cox regression models were adjusted for treatment, stratification factors (International Prognostic Index, bulky disease, geographic region), age >60 years, cell of origin, and biomarker evaluated, as appropriate. Results: The prevalence, univariate HR, and 2-year PFS estimates of BCL2+/MYC+ and BCL2-R/MYC-R/BCL6-R subgroups are presented (Table) except for BCL6-R, because all four PFS events in this subgroup were with Pola-R-CHP. Multivariate analyses results for Pola-R-CHP vs R-CHOP in patients with BCL2+ (HR 0.60, 95% CI 0.43–0.86) and those with MYC+ (HR 0.63, 95% CI 0.45–0.89) were similar to results of univariate analyses. Multivariate analyses of other subgroups were not performed due to the low patient number with BCL2-R/MYC-R/BCL6-R. While patients with DEL treated with Pola-R-CHP had improved PFS vs patients treated with R-CHOP (HR 0.64, 95% CI 0.42–0.97), the prognostic impact of DEL vs non-DEL was identified in the R-CHOP arm (univariate HR 1.53, 95% CI 1.06–2.21; multivariate HR 1.29, 95% CI 0.88–1.91) vs the Pola-R-CHP arm (univariate HR 1.10, 95% CI 0.72–1.69; multivariate HR 1.42, 95% CI 0.89–2.28). Similarly, patients with BCL2+ had inferior PFS vs patients with BCL2– in the R-CHOP arm (univariate HR 1.96, 95% CI 1.31–2.93; multivariate HR 1.74, 95% CI 1.14–2.66); however, no prognostic difference was detected in the Pola-R-CHP arm (univariate HR 1.30, 95% CI 0.85–2.01; multivariate HR 1.56, 95% CI 0.99–2.47). No prognostic impact of MYC+ vs MYC– was detected in either arm (R-CHOP: univariate HR 1.17, 95% CI 0.77–1.77; multivariate HR 1.00, 95% CI 0.65–1.55; Pola-R-CHP: univariate HR 0.83, 95% CI 0.54–1.27; multivariate HR 0.91, 95% CI 0.58–1.42). Image:Summary/Conclusion: Multivariate analyses support the benefit of Pola-R-CHP in patients with BCL2+ and MYC+ DLBCL. The poor prognostic impact associated with DEL, which was mainly driven by BCL2+, appears reduced in Pola-R-CHP- vs R-CHOP-treated patients.

PB2085: UPFRONT TREATMENT OF MANTLE CELL LYMPHOMA (MCL) WITH R-HDAC (RITUXIMAB-HIGH DOSE CYTARABINE + DEXAMETHASONE) IN YOUNG, HIGH RISK PATIENTS IS WELL TOLERATED AND LEADS TO DURABLE RESPONSES.

Background: MCL commonly presents as aggressive disease with a low cure rate and multiply relapsing/remitting course. Treatment of classical MCL with upfront intensive chemoimmunotherapy (CIT) consolidated with an autologous stem cell transplant (ASCT) is considered best practice in younger patients. There is no gold standard intensive CIT regimen. Common approaches include alternating RCHOP/RDHAP (Nordic) and R-Hyper-CVAD.(1) The addition of high dose Cytarabine (HDAC) has been shown to improve time to treatment failure (TTF), complete response (CR) rates and progression free survival (PFS). Aims: There is little published on the efficacy of R-HDAC in treatment-naive MCL, however a 2013 case series (Forbes et al) reported good early efficacy (CR in 16/18), with no detriment to harvest success. We describe tolerability and efficacy of upfront R-HDAC in a high risk cohort of younger patients with MCL. Methods: We identified 28 patients who received upfront R-HDAC in 3 UK centres from 2010–2021. Data were collected, anonymized and transferred centrally for analysis using Kaplan-Meier survival curves. Results: For baseline characteristics see Table 1. Treatment regimen: Dexamethasone 40mg d1-d4, Rituximab 500mg d1, Cytarabine 3000mg/m2 BD d2-d3 in 21day cycles. 22/28 (79%) completed their planned quota of 4-6cycles; 6/28 (21%) did not. Of these n=5 had progressive disease (PD), n=1 ceased with toxicity. 4/28 incurred cycle delays. 1 patient developed PD after completing R-HDAC. Haematological toxicity ≥ Grade 3 CTCAE: Anaemia 71%; Thrombocytopenia 93%; Neutropenia 93%. Fatigue (57%), Nausea 25%, Vomiting 7%, Constipation 21%, Diarrhoea 11%, Cardiac toxicity 11%, Pulmonary toxicity 18%, Rash 11%. 20/28 (71%) underwent stem cell transplant consolidation of which 19 had an ASCT. The median CD34+ stem cell harvest was 8.3x109^L/Kg (2.56-40.9) with no harvest failures. One patient underwent an allogeneic SCT. Of those who didn’t undergo transplant: 1/8 declined; 1/8 was ineligible; 6/8 had PD and switched to 2nd line therapy. Overall Response Rate (ORR) (RECIST) was 78%, CR 41%; PR (Partial response) 37%; and PD 22%. The median PFS was 3.39years (95% CI 0-7.937). 5y OS was 64.3% (95% CI 44.9-83.7%), median OS 8.7years (95% CI 2.634 – 14.894). Image:Summary/Conclusion: Our cohort showed higher rates of haematological toxicity, but lower gastrointestinal toxicity than those reported with the Nordic approach.(1) There were no incidents of treatment related mortality (TRM). More intensive regimens e.g. R-Hyper-CVAD have documented TRM rates of up to 8%. Only 1 patient in our cohort ceased treatment because of toxicity. Whilst our ORR is lower than those published in trial data on commonly used regimens (78% vs MCL Younger trial ORR: RCHOP arm 90%/Cytarabine arm 94%) our cohort’s baseline demographics are comparably much higher risk: MIPIb High 53% vs 25/20%; Blastoid disease 25% vs 9/8%. Of those with PD in our cohort, 4/6 had high MIPIb and blastoid disease. Despite this disparity, R-HDAC retains a comparable CR rate (41% vs 38%) and 5y OS (64.3% vs 65%). Whilst this observational retrospective study has limitations, it has shown that R-HDAC is an option for younger patients with high risk MCL. Using fewer CIT drugs could reduce toxicity and reserve more agents for use in future relapse.

Impact of Maintenance Arm on Prognostic Value of MRD after Induction Treatment in MCL R2 Elderly Trial, a Mantle Cell Lymphoma Network Study

Impact of Maintenance Arm on Prognostic Value of MRD after Induction Treatment in MCL R2 Elderly Trial, a Mantle Cell Lymphoma Network Study

Assessment of Circulating Tumor DNA in Newly Diagnosed DLBCL Patients Randomly Treated By R-CHOP or R-High Dose Chemotherapy Plus Autologous Stem Cell Support

PurposeDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. The association of rituximab to CHOP chemotherapy is nowadays the standard of care for de novo DLBCL patients; however 40% of these patients relapse or are refractory to treatment within 2 years. Before rituximab, patients treated by high dose chemotherapy plus autologous stem-cell support (HDT) had a significantly better outcome than by CHOP alone 1. Between 2005 and 2008, the GOELAMS 075 French multicentric clinical trial (NCT00561379) enrolled 323 de novo DLBCL patients randomly treated by R-CHOP or R-HDT, and showed that rituximab erases the survival difference between the two arms of frontline treatment 2.The main objective of this study was to evaluate circulating tumor DNA (ctDNA) concentration measured by an easy-to-collect and cost-effective method in the GOELAMS 075 de novo DLBCL patients, in regards of the two frontline treatments.MethodsPlasma samples were collected at inclusion for 123 patients and 6 months after the end-of-treatment (EOT) for 50 patients in complete remission (CR) at EOT. The 123 patients were representative of the 323 eligible patients. Among the 123 patients, 68 were assigned to the R-CHOP arm and 55 to the R-HDT arm, of which, respectively, 59 and 51 achieved CR at EOT. Baseline characteristics, overall (OS) and progression free survivals were not different between randomization arms for the 123 patients. No difference in baseline characteristics was found between both studied cohorts.ctDNA concentration in ng per ml of plasma was measured as the enrichment of DNA fragments between 100 and 300 base pairs. For survival analysis, the ctDNA threshold was defined as equal to 10 times the maximum cell-free DNA concentration measured in healthy subjects. For paired samples, mutation profiles at baseline and 6 months after EOT were assessed by capture-based targeted DNA sequencing using a panel of 43 genes known to be associated to DLBCL in the literature. Intention-to-treat (ITT) analysis was performed, unless otherwise mentioned.ResultsElevated ctDNA at diagnosis was found significantly associated with adverse clinical factors (R-IPI ≥3 ; number of extranodal sites ≥2), as well as intake of salvage therapy. Patients with ctDNA ≥ 54.9 ng/ml had significantly worse OS (HR=2.4, 95 th CI : 1.1-5.2 ; Pvalue=0.029). Patients with elevated ctDNA were more likely to require a salvage therapy, regardless of the randomisation arm. Only for ITT R-CHOP patients, elevated ctDNA was associated with a significantly shorter OS (HR=4.4, 95th CI : 1.6-12.3 ; Pvalue=0.004; Figure 1). Patients with elevated ctDNA who received the initially planned 8 R-CHOP cures (no salvage therapy) had a significantly worse OS than any other patients (67% deaths ; 5-years OS : 33% ; Pvalue=0.0002).Focusing on the cohort of 50 patients in CR at the EOT, we found a significant decrease of ctDNA 6 months after EOT compared to baseline only for ITT R-HDT patients (Pvalue=0.006). Noticeably, out of the 7 patients with higher ctDNA 6 months after EOT, six had been assigned to the R-CHOP arm, and five of those did not benefit salvage therapy. Mutation profiling was performed for 46 CR patients (ITT, R-CHOP, n=23 ; R-HDT, n=23) at baseline and 6 months after EOT. Mutations were detected in 48% of R-CHOP patients and 61% of R-HDT patients. The tumor mutational burden, defined as the number of gene mutations found on the total of 164 Kb sequenced, was significantly decreased 6 months after EOT only for R-HDT patients (Pvalue=0.005). The number of mutations, especially the number of new variants, and the number of deleterious and likely oncogenic variants, increased significantly in the R-CHOP arm 6 months after EOT while decreasing in the R-HDT arm (Pvalue<0.001; Figure 2). All 46 patients in CR at EOT remained in CR 5 to 10 years after treatment, except for 3 patients, who did not receive salvage therapy and relapsed more than 5 years after EOT. All 3 patients belonged to the R-CHOP arm patients with higher ctDNA 6 months after EOT compared to baseline.ConclusionUsing an easy-to-measure and low-cost method, ctDNA concentration at diagnosis was shown, in an intention-to-treat analysis, to be an adverse prognostic factor only for de novo DLBCL patients treated by standard R-CHOP. Furthermore ctDNA was not significantly cleared in plasma at CR only for ITT R-CHOP patients, with the number of mutations increased 6 months after EOT compared to baseline. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Addition of High-Dose Cytarabine to Immunochemotherapy before Autologous Stem-Cell Transplantation in Patients Aged 65 Years or Younger with Mantle Cell Lymphoma (MCL Younger): A Long-Term Follow-up of the Randomized, Open-Label, Phase 3 Trial of the European Mantle Cell Lymphoma Network

Addition of High-Dose Cytarabine to Immunochemotherapy before Autologous Stem-Cell Transplantation in Patients Aged 65 Years or Younger with Mantle Cell Lymphoma (MCL Younger): A Long-Term Follow-up of the Randomized, Open-Label, Phase 3 Trial of the European Mantle Cell Lymphoma Network

Ten-Year Follow-up of Newly Diagnosed Follicular Lymphoma Patients Treated with Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) As First-Line Therapy in JCOG0203 Trial

[Purpose]Rituximab combined with chemotherapy has been established as a standard of care for patients with newly diagnosed advanced stage follicular lymphoma (FL), especially with high tumor burden. However, the best chemotherapy partner of rituximab remains unclear. Owing to inevitable relapse and succumbing to histologic transformation (HT), there are prerequisites for first-line treatment to improve the outcome of FL patients. To elucidate the long-term outcome of FL patients more than 10 years after treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line therapy in a prospective clinical trial, we report the 10-year follow-up results of the patients allocated to either R-CHOP arm in a randomized phase II/III trial (JCOG0203, NCT00147121), in which both arms of R-CHOP-21 and R-CHOP-14 showed almost equal survival.[Patients and Methods]Patients with untreated indolent B-cell lymphoma in advanced stages were assigned to the potential standard arm; six cycles of R-CHOP-21 or the experimental arm; R-CHOP-14 with G-CSF. Rituximab maintenance was not allowed (JCOG0203 Trial; Watanabe T, et al, J Clin Oncol 2011;29:3990). Histopathologic specimens from all 300 patients were reviewed by 3 hematopathologists. The primary endpoint of the study was progression-free survival (PFS). According to the planned analysis after 10 years following enrollment of the last patient, clinical event information was updated. PFS and overall survival (OS) were estimated by using the Kaplan-Meier method, and Hazard ratio (HR) and its confidence interval were estimated through the Cox proportional hazards model. The incidences of HT and secondary malignancies were analyzed by cumulative incidence function.[Results]From September 1st, 2002 to February 28, 2007, 300 patients were enrolled. The number of patients lost to follow-up within 10 years from randomization was 19 in all eligible patients. Ten-year PFS were 32.8% (R-CHOP-21) vs . 38.8% (R-CHOP-14), and 10-year OS were 80.9% vs . 84.7%, respectively in 299 eligible patients; namely, there were no differences. According to the Follicular Lymphoma International Prognostic Index, there were no differences found for either PFS or OS in any of the three risk groups.We identified only male sex (HR: 1.57, 95% CI: 1.16-2.12) as a significant, unfavorable PFS factor, and age (>60) (HR: 2.03, 95% CI: 1.19-3.45) and increased LDH (>ULN) (HR: 2.38, 95% CI: 1.27-4.43) as significant, unfavorable factors of OS.The proportion of FL was comparable between the arms (133 and 132 patients), and therefore, the combined analyses of the two arms were performed. In a total of 265 FL patients, 5, 8, and 10-year PFS were 46.2, 39.6, and 36.8%, respectively. Five, 8, and 10-year OS were 93.6, 86.7, and 84.4%, respectively (Figure 1).HT was diagnosed in 27 of the 248 FL G1-3a patients (10.9% [95% CI: 7.3-15.5]), including 10 HT diagnosed clinically by the data including steep elevation of LDH levels or high accumulation of FDG (defined by SUVmax) in PET imaging (63.0% of HT was proved by biopsy). The pattern of the HT accumulation slope was similar to those reported previously but slightly different from that of PRIMA Trial, which showed more than half of them occurred within the first one year of follow-up; the cumulative incidence of HT at 3, 5, 8, and 10 years after enrollment were 2.4% (95% CI: 1.0-4.9), 3.2% (95% CI: 1.5-6.0), 8.5% (95% CI: 5.4-12.4), and 9.3 % (95% CI: 6.1-13.4), respectively (Figure 2).The incidence of secondary malignancies in the 248 FL G1-3a patients at 10 years was 8.1% (95% CI: 5.1-12.0) [hematologic malignancies; 2.9%].[Conclusions]R-CHOP may reduce the incidence of HT compared with previous reports in the pre-rituximab era and did not increase a 10-year cumulative incidence of secondary malignancies in previously untreated FL patients, compared with published data. Although 10-year OS of advanced FL patients treated with R-CHOP without rituximab maintenance in the first-line setting was favorable, 10-year PFS was unsatisfactory. Dose-dense immunochemotherapy did not improve either PFS or OS in patients with indolent B-cell lymphoma. Therefore, the new treatments to deepen remissions and to prolong time to progression of FL patients are needed. [Display omitted] DisclosuresTobinai:Chugai/Roche: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria. Kinoshita:Chugai: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Jannsen: Honoraria; Kyowa Kirin: Honoraria; Bristol: Honoraria; Eisai: Honoraria; Takeda: Research Funding; Solasia: Research Funding; MSD: Research Funding. Yamaguchi:Eisai: Honoraria; Takeda Phamaceuticals: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharma: Honoraria; Nippon Shinyaku: Honoraria. Ando:Kyowa Hakko Kirin: Research Funding; Takeda Pharmaceutical: Research Funding. Ogura:Astrazeneca: Honoraria; Takeda: Consultancy, Honoraria; Mundipharma: Consultancy; Celltrion, Inc: Consultancy, Honoraria; SymBio: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; MeijiSeika Pharma: Consultancy. Tsukasaki:Chugai/Roche: Honoraria; Zenyaku Kogyo: Honoraria; Mundypharma: Research Funding; HUYA: Honoraria; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Kyowa-Kirin: Honoraria.

A Randomized, Double-Blind, Phase III Study Comparing Proposed Biosimilar Rituximab (RTXM83) Versus Reference Rituximab, Both in Combination with CHOP, in the First Line Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Methods: RTXM83 is a proposed biosimilar developed by mAbxience S.A. to the reference medicine product rituximab (MabThera®/ Rituxan®). A prospective, multicenter, double-blind, randomized trial compared the efficacy in terms of non-inferiority, pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity of RTXM83 vs rituximab (Mabthera®/Rituxan®), both in combination with CHOP chemotherapy (RTXM83-CHOP vs R-CHOP), as first-line treatment in patients with previously untreated CD20+ Diffuse Large B Cell Lymphoma (DLBCL). Adults aged ≥18 and ≤65 years, with a disease stage of I (only with bulky disease) to IV according to the Cotswolds modification of the Ann Arbor classification, and ECOG performance status ≤2 were included, and randomized (1:1) to receive up to a total of six cycles of either RTXM83-CHOP or R-CHOP. Patients were stratified according to study center and age-adjusted IPI scores (0 versus 1), which are based on: disease stage, ECOG, and lactate dehydrogenase (LDH) levels.The primary endpoint was to assess the response rate (RR) (complete response + partial response) achieved after cycle 6 of treatment by the International Working Group (IWG) criteria. PK, PD, safety and immunogenicity were assessed as secondary study endpoints. For PK, the systemic exposure (AUC and Cmax) were assessed at Cycle 1 and steady-state at Cycle 6 using a population PK (Pop PK) model approach. The serum levels of CD20+/CD19+ cells for PD profile, and of anti-drug antibodies (ADA) for immunogenicity assessment were analysed at different time points: start of treatment (Cycle 1 Day 1, pre-dose), at Cycle 5 Day 1 (pre-dose), at Cycle 6 Day 21 and during the follow-up period: FU 1 (3 months after last dose of treatment) and follow-up 3 if available (9 months after last dose of treatment).Results: A total of 241 patients, 123 in the RTXM83-CHOP arm and 118 R-CHOP arm, from 58 sites in 12 countries were eligible. Demographic and baseline characteristics were well balanced between arms. A difference of 3.9% in the RR in favour of the RTXM83-CHOP arm was achieved in the per protocol population (RR: 84.7% vs 80.8% in RTXM83-CHOP and the R-CHOP arm, respectively). The lower bound of the 95% CI of this difference (-6.20% to 14.03%) was above the non-inferiority margin of -13% that was set for the study.The Pop PK comprised a total of 5341 samples from 251 patients. Geometric least square means ratios (GLSMR) with the 90% CI of RXTM83/rituximab were 99.2% (93.6-105) for AUC and 99.6% (93.9-105) for Cmax,sd at Cycle 1 whereas, at steady-state the GLSMR were 103% (98.5-107) for AUC and 104% (99.5-109) for Cmax,ss. RXTM83 and rituximab exhibited a comparable serum concentration-time profile and the GLSMR were within the predefined margins of 80-125%. PD profile in terms of time of onset, magnitude and duration of response was similar between RTXM83 and rituximab.Safety assessment shows no obvious differential safety profile of RXTM83 and rituximab in terms of nature, frequency and severity of the adverse events (AE); being infections and blood and lymphatic system disorders the most common SAEs reported.A low and similar ADA incidence was observed in both treatment arms, with no relationship with efficacy, safety or PK/PD data was observed.Conclusion: These results demonstrate that RTXM83 has comparable efficacy to rituximab in terms of tumour response, and displays a similar PK profile, PD activity, safety profile and immunogenicity in the first line treatment of patients with newly diagnosed DLBCL, which supports the claim that RTXM83 is highly similar to the reference medicine rituximab (MabThera® / Rituxan®). DisclosuresGonzalez:Lab Eticos: Other: Principal Investigator. Radhakrishnan:Cancer Institute Adyar Chennai India: Employment. Schusterschitz:Libbs: Research Funding. Perez:Mabxience SA: Employment.

GENETIC SUBTYPE GUIDED RITUXIMAB‐BASED IMMUNOCHEMOTHERAPY IMPROVES OUTCOME IN NEWLY DIAGNOSED DIFFUSE LARGE B‐CELL LYMPHOMA: FIRST REPORT OF A RANDOMIZED PHASE 2 STUDY

Introduction: Genetic subtypes of diffuse large B-cell lymphoma (DLBCL) have distinct oncogenic pathway feature, gene expression phenotype, and variable clinical outcome. We aimed to investigate whether adding novel targeted agents to R-CHOP (R-CHOP-X) based on genetic subtypes could improve clinical efficacy in newly diagnosed DLBCL. Methods: This was a randomized phase II study comparing R-CHOP-X with R-CHOP in newly diagnosed DLBCL (NCT04025593). Eligible patients were aged 18-80 years, and IPI risk of intermediate or high (IPI≥2). All patients were treated with standard R-CHOP for the first cycle, and were randomized 1:1 to R-CHOP-X or R-CHOP for the remaining 5 cycles. Targeted sequencing was performed on formalin-fixed paraffin-embedded tumor samples at diagnosis. We used a simplified method to classify patients into six genetic subtypes MCD, BN2, N1, EZB, TP53 and NOS, using mutations in 18 genes, BCL2 translocation, and BCL6 fusion. MCD and BN2 patients were treated with BTK inhibitor ibrutinib 420 mg/d, N1 and NOS patients with immunomodulatory agent lenalidomide 25mg d1-10, EZB patients with histone deacetylase inhibitor tucidinostat 20mg d1, 4, 8, 11, and TP53 patients with intravenous demethylating agent decitabine 10 mg/m2 d1-5 followed by standard R-CHOP. The primary endpoint was complete response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate, and safety. Results: A total of 128 patients were enrolled (n = 64 per arm) between July 17th, 2019 to December 29th, 2020. Baseline clinical characteristics were similar between arms, with a median age of 64 (range 25-74), 52% male, 83% ECOG 0-1, 77% stage III/IV, and 65% IPI≥3 for all patients. According to Hans algorithm, 62% patients were categorized as non-germinal B-cell subtype and 36% as MYC/BCL2 double expression. Regarding genetic subtypes, 20%, 18%, 4%, 2%, 16% and 39% patients were classified into MCD, BN2, N1, EZB, TP53, and NOS subtype, respectively. Until March 1st, 2021, all patients received at least 3 cycles of immunochemotherapy and 107 patients were available for response evaluation. The complete and overall response rates were 85% and 91% in R-CHOP-X arm, and 65% and 72% in R-CHOP arm, respectively. With a median follow-up of 14.1 months, 1-year PFS and OS rates were 96% and 98% in R-CHOP-X arm, and 79% and 94% in R-CHOP arm, respectively (PFS: HR 0.22, 95%CI 0.09-0.61; OS: HR 0.28, 95%CI 0.05-1.60). The most common grade 3/4 adverse events (AEs) for R-CHOP-X vs R-CHOP were neutropenia (81% vs 75%), thrombocytopenia (31% vs 11%), anemia (25% vs 20%), and febrile neutropenia (20% vs 11%). For non-hematological AEs, grade 3 infection occurred in 3% vs 2%, grade 3 gastrointestinal bleeding in 2% vs 3% in R-CHOP-X vs R-CHOP arm, respectively. No grade 4 non-hematological AEs were observed. Conclusion: Genetic subtype guided R-CHOP-X showed encouraging response and outcome in DLBCL. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.