Untreated Diffuse Large B-cell Lymphoma Research Articles

Polatuzumab Vedotin for Diffuse Large B-Cell Lymphoma: Innovation's Allure versus a Time-Honored Tradition

AbstractChemotherapy with R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, prednisolone) is the standard of care for patients with diffuse large B-cell lymphoma as the first-line therapy. The recent approval of polatuzumab as the first-line therapy after demonstration of its efficacy in the Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma (POLARIX) trial is the first significant change in this treatment regimen over two decades. This concise appraisal of trial evidence and clinical context highlights the limited potential for a clinically significant benefit with the addition of polatuzumab to the first-line therapy for this common hematologic malignancy.

FDA Approval Summary: Polatuzumab Vedotin in the First-Line Treatment of Select Large B-cell Lymphomas.

In April 2023, the U.S. Food and Drug Administration granted regular approval to polatuzumab vedotin-piiq in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (pola+R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma, not otherwise specified or high-grade B-cell lymphoma and who have an International Prognostic Index score of 2 or greater. Approval was based on POLARIX, a randomized, double-blinded, placebo-controlled trial evaluating the superiority of substituting vincristine with polatuzumab vedotin in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen as first-line therapy for patients with large B-cell lymphoma (LBCL). Efficacy was based on investigator-assessed progression-free survival (PFS) in 879 patients who were randomized to receive pola+R-CHP or R-CHOP, followed by two cycles of rituximab alone. PFS was statistically significantly longer with pola+R-CHP with a HR of 0.73 [95% CI: 0.57, 0.95] and log-rank p-value of 0.0177 (two-sided α=0.05). There was no improvement demonstrated in the key secondary endpoints of CR rate at the end of therapy or overall survival (OS). Several issues raised uncertainty about the benefit-risk of polatuzumab vedotin in this curative-intent setting including the modest PFS benefit of pola+R-CHP and lack of OS benefit. The application was therefore presented at an Oncology Drug Advisory Committee. This article summarizes key aspects of the regulatory review, including perspectives on PFS and OS results and other endpoints.

Low magnesium levels and prognosis in newly diagnosed diffuse large B-cell lymphoma.

Magnesium (Mg) is an essential element involved in cellular metabolism. We demonstrated that in patients with diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (SCT), those with a serum Mg < 2.0mg/dL at the time of transplant had worse outcomes. In this study, we aimed to learn the prognostic value of low serum Mg in patients with untreated DLBCL. We analyzed serum from 408 patients and tested 2 Mg cutpoints-low (<1.7mg/dL) and low normal (<2.0mg/dL), a range we found associated with lower survival in the SCT group. We found 3% of patients with low levels and 23% with low normal levels. Low normal serum Mg levels were associated with a higher stage at diagnosis, more extranodal involvement, higher international prognostic index score, lower overall survival (OS), and event-free survival. These data warrant testing Mg replacement to a target of >2.0mg/dL to learn if survival can be improved.

ABCL-427 Polatuzumab-R-CHP in Previously Untreated Diffuse Large B-Cell Lymphoma: A Retrospective Study

ABCL-427 Polatuzumab-R-CHP in Previously Untreated Diffuse Large B-Cell Lymphoma: A Retrospective Study

Polatuzumab-R-CHP in Previously Untreated Diffuse Large B-Cell Lymphoma: A Retrospective Study

Polatuzumab-R-CHP in Previously Untreated Diffuse Large B-Cell Lymphoma: A Retrospective Study

Comparison of R-CHOP-14 and R-mini-CHOP in older adults with diffuse large B-cell lymphoma-A retrospective multicenter cohort study.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity, and its incidence increases with age. There is a paucity of data regarding use of biweekly R-CHOP (R-CHOP-14) in patients ≥80 years of age. We performed a retrospective cohort study of patients with DLBCL aged ≥80 years treated with R-CHOP-14 and R-miniCHOP in two academic tertiary centers in Germany between 01/01/2005 and 12/30/2019. Overall, 79 patients were included. Median age was 84 years (range 80-91). Despite higher CR rates with R-CHOP-14 (71.4% vs. 52.4%), no statistically significant difference could be found between patients treated with R-CHOP-14 and R-miniCHOP regarding overall survival (OS) (p = .88, HR 0.94, 95% CI = 0.47-1.90) and progression-free survival (PFS) (p = .26, HR 0.66, 95% CI = 0.32-1.36). At a median follow-up of 40 months, the 2-year OS rates were 56% with R-CHOP-14 and 53% with R-miniCHOP. Two-year PFS rates were 46% for R-CHOP-14 and 50% for R-mini-CHOP. Relative dose intensity of chemotherapy did not correlate with OS (p = .72). With the caveat of a retrospective cohort study, we conclude that lacking a difference in OS, R-miniCHOP should be preferred for most patients with untreated DLBCL aged ≥80 years.

A real-world pharmacovigilance study of polatuzumab vedotin based on the FDA adverse event reporting system (FAERS).

Polatuzumab vedotin, the first FDA-approved antibody-drug conjugate (ADC) targeting CD79b, is utilized in the treatment of previously untreated diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL), as well as relapsed or refractory (R/R) DLBCL. Despite its approval, concerns persist regarding the long-term safety profile of polatuzumab vedotin. This study aims to evaluate the adverse events (AEs) associated with polatuzumab vedotin since its approval in 2019, utilizing data mining strategies applied to the FDA Adverse Event Reporting System (FAERS). Signal detection employed four methodologies, including reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multi-item gamma poisson shrinker (MGPS), to evaluate and quantify the signals of polatuzumab vedotin-associated AEs. Additionally, subgroup analyses based on patients age, gender, and fatal cases were conducted to investigate AEs occurrences in specific subpopulations. A total of 1,521 reports listing polatuzumab vedotin as a "principal suspect (PS)" drug were collected from the FAERS database. Through concurrent compliance with four algorithms, 19 significant Standardized MedDRA Query (SMQ) AEs and 92 significant Preferred Term (PT) AEs were detected. Subgroup analyses revealed a higher incidence of PTs in male patients compared to female patients, increased likelihood of polatuzumab vedotin-associated AEs in elder patients (>65years), and AEs with a high risk of fatal cases include: blood lactate dehydrogenase increased, cytopenia, and hydronephrosis. The median time to AEs occurrence following polatuzumab vedotin initiation was 18.5 (5∼57.75) days, with 95% of AEs occurred within 162days. This study identified various AEs associated with polatuzumab vedotin, offering critical insights for clinical monitoring and risk identification in patients receiving polatuzumab vedotin therapy.

Tucidinostat plus R-CHOP in previously untreated diffuse large B-cell lymphoma with double expression of MYC and BCL2: An interim analysis from the phase III DEB study.

LBA7003 Background: Epigenetic dysregulation is commonly correlated with the pathogenesis and development in diffuse large B-cell lymphoma (DLBCL). Tucidinostat, a subtype-selective histone deacetylase (HDAC) inhibitor, has shown promising efficacy in combination with R-CHOP in DLBCL patients with double expression of MYC and BCL2 (DE) in exploratory studies. Methods: We conducted a randomized, double-blind, placebo-controlled, phase III trial (DEB) to evaluate the efficacy and safety of tucidinostat plus R-CHOP in comparison with R-CHOP in previously untreated DLBCL patients with DE. Patients were randomly assigned in a 1:1 ratio to receive six cycles of either tucidinostat plus R-CHOP (tucidinostat group) or placebo plus R-CHOP (placebo group). Patients who achieved complete response (CR) after combination therapy received either tucidinostat or placebo as maintenance treatment with a maximum duration of 24 weeks. The primary endpoint was investigator-assessed event-free survival (EFS), and the key secondary endpoint was the complete response rate (CRR) evaluated at the end of combination treatment. An interim analysis was pre-defined to be conducted when CRR was obtained and the number of EFS events reached at least 60% of the total events required for entire study. Results: Between May 21, 2020, and July 25, 2022, 423 patients were enrolled and randomly assigned, 211 to the tucidinostat group and 212 to the placebo group. At data cutoff of this interim analysis (January 10, 2023), the median follow-up time was 13.9 months (95% CI, 12.9 - 15.4). A total of 152 EFS events (68.5% of the planned total) were observed, with 64 (30.3%) in the tucidinostat group and 88 (41.5%) in the placebo group. The 24-month EFS rate was 58.9% (95% CI, 48.9-67.6) in the tucidinostat group and 46.2% (95% CI, 35.7-56.1) in the placebo group. The hazard ratio (HR) between the two groups was 0.68 (95% CI, 0.49-0.94), with a p-value of 0.018. At the completion of combination treatment, the CRR in the tucidinostat and placebo groups were 73.0% (95% CI, 66.6-78.5) and 61.8% (95% CI, 55.1-68.1), respectively. The adjusted difference in CRR was 11.1% (95% CI, 2.3-20.0; P=0.014). The safety profiles of both groups were as expected, with no new safety findings. The incidence of ≥ grade 3 hematologic adverse events was generally higher in the tucidinostat group than the placebo group, but most patients were able to tolerate and complete the planned treatment cycles. No significant cardiac toxicity, hepatotoxicity, or nephrotoxicity were observed in both groups. Conclusion: The DEB study is the first phase III trial to show that combining tucidinostat with R-CHOP regimen is a feasible and efficacious novel approach in previously untreated DLBCL patients with DE. Tucidinostat plus R-CHOP could be a new frontline treatment option in this patient population. Clinical trial information: NCT04231448 .

Patients’ voices matter: Translating pretreatment patient-reported outcomes into high and low health-related quality of life provides a new clinical aspect on prognosis and survival in patients with previously untreated diffuse large B‐cell lymphoma.

e23165 Background: Patient-reported health-related quality of life (HRQoL) measures collected prior to treatment initiation have been shown to be prognostic of disease outcomes and survival in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), including progression-free survival (PFS) and overall survival (OS), However, these HRQoL measures are usually expressed as numbers from a scale (e.g. from 0 to 100), which limit their ease of clinical utility compared to binary scales (i.e. high vs. low). Using HRQoL measures collected from the phase 3 study GOYA, we aim to convert these measures into binary scales by identifying optimal cutoffs and demonstrate their clinical utility in differentiating patient risks in DLBCL. Methods: HRQoL data from the physical functioning (PF2), global health status (QL2), and fatigue (FA) scales from the EORTC QLQ-C30 questionnaire and the lymphoma subscale (LYMS) from the FACT-LYM questionnaire were used in this analysis. The optimal cutoff points were identified using statistical metrics that evaluate the prognostic value and goodness-of-fit for each assessed cutoff point. The top performing binary HRQoL scale was further assessed in its clinical utility as an addition to the Internal Prognostic Index (IPI), a standard risk classification tool in DLBCL based on 5 binary measures of patient baseline characteristics, to evaluate whether adding the HRQoL scale would potentially improve the risk classification. Results: As shown in the table, while all binary scales can clearly differentiate patient overall survival (demonstrated by the hazard ratios), PF2 numerically exhibited the best performance, and was further assessed as an addition to IPI. After adding PF2 to the base OS model containing only IPI, we observed improvements in model performance metrics, including the concordance index and the goodness-of-fit. In addition, among patients classified as high risk by IPI (n = 185, 3-yr OS: 65% [95% CI 68-72%]), those with low HRQoL (n = 102, 3-yr OS: 56% [95% CI 47-67%]) had a substantially worse OS, suggesting that further refinement of patient-risk defined by IPI may be feasible with HRQoL measures. Conclusions: Our work highlights the potential of the binary HRQoL scales to provide additional prognostic value to IPI, and suggests that patient reported outcomes may be useful in further refining patient risk classification in addition to IPI in untreated DLBCL. [Table: see text]

Phase 3 trial evaluating efficacy and safety of odronextamab plus CHOP vs rituximab plus CHOP in previously untreated diffuse large B-cell lymphoma (DLBCL; OLYMPIA-3).

TPS7086 Background: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains a standard of care first-line (1L) treatment for patients (pts) with DLBCL. However, poor outcomes persist for certain DLBCL pt subgroups, including those with high-risk features: activated B-cell-like (ABC) cell of origin (5-yr progression-free survival [PFS]/overall survival [OS] 48%/56%), MYC and BCL2 rearrangements (median OS 15 months), or International Prognostic Index [IPI] score 4–5 (5-yr PFS/OS 46%/54%). Improving outcomes through effective 1L treatment continues to be important, highlighted by the dismal prognosis in pts who are primary refractory (2-yr OS 24%) or who relapse early after 1L treatment (4-yr OS 30%). Odronextamab, a CD20×CD3 bispecific antibody, showed encouraging efficacy (objective response rate 52%; complete response [CR] rate 31%; 47% maintained CR at 2 years) and generally manageable safety as a monotherapy in pts with heavily pretreated relapsed/refractory DLBCL, including in pts who were anti-CD20 antibody refractory (Ph 2 ELM-2 study; Ayyappan, et al. ASH 2023). These data provide the rationale to evaluate the efficacy and safety of odronextamab plus CHOP (O-CHOP) vs R-CHOP in pts with previously untreated DLBCL. Methods: OLYMPIA-3 (NCT06091865) is a Ph 3, randomized, open-label, multicenter study of O-CHOP vs R-CHOP in pts with previously untreated DLBCL and intermediate- or high-risk features. The study consists of Part 1A (dose escalation), Part 1B (dose optimization), and Part 2 (randomized controlled). Part 1A will assess the safety of O-CHOP. In Part 1B, pts will be randomized 1:1 to one of two O-CHOP regimens, selected based on Part 1A results. In Part 2, pts will be randomized 1:1 to O-CHOP or R-CHOP, with odronextamab dosing dependent on Part 1 results, and R-CHOP given per standard practice. Intravenous odronextamab will be administered weekly from Cycle (C) 1 Day (D) 8 until C5D8, with step-up dosing during C1 and C2, then every 2 weeks until the end of C6. CHOP will be administered in six 21-day cycles, starting on C1D1. Key inclusion criteria: aged ≥18 years; untreated CD20+ DLBCL; ECOG PS ≤2; and IPI score ≥2. Pts with central nervous system lymphoma, Grade ≥3 peripheral neuropathy, or an active infection are excluded. The primary endpoints are the incidence of dose-limiting toxicities, and incidence and severity of treatment-emergent adverse events (Part 1), and PFS by independent central review (Part 2). Part 2 key secondary endpoints are event-free survival and CR rate (both by independent central review), as well as OS. Other secondary endpoints are minimal residual disease (by ctDNA) and patient-reported outcomes (EORTC QLQ-C30, FACT-LymS, PGIS, PGIC, and EQ-5D-5L). The trial is currently recruiting and is expected to enroll up to 64 pts in Part 1 and ~840 pts in Part 2 at ~200 global sites. Clinical trial information: NCT06091865 .

Palmitic acid reduces the methylation of the FOXO1 promoter to suppress the development of diffuse large B-cell lymphoma via modulating the miR-429/DNMT3A axis

Diffuse large B-cell lymphoma (DLBCL) is characterized by significant treatment resistance. Palmitic acid (PA) has shown promising antitumor properties. This study aims to elucidate the molecular mechanisms by which PA influences DLBCL progression. We quantified the expression levels of microRNAs (miRNAs), Forkhead box protein O1 (FOXO1), and DNA methyltransferase 3A (DNMT3A) in both untreated and PA-treated DLBCL tumors and cell lines. Assessments were made of cell viability, apoptosis, and autophagy-related protein expression following PA administration. Interaction analyses among miR-429, DNMT3A, and FOXO1 were conducted using luciferase reporter assays and methylation-specific (MSP) Polymerase chain reaction (PCR). After transfecting the miR-429 inhibitor, negative control (NC) inhibitor, shRNA against DNMT3A (sh-DNMT3A), shRNA negative control (sh-NC), overexpression vector for DNMT3A (oe-DNMT3A), or overexpression negative control (oe-NC), we evaluated the effects of miR-429 and DNMT3A on cell viability, mortality, and autophagy-related protein expression in PA-treated DLBCL cell lines. The efficacy of PA was also tested in vivo using DLBCL tumor-bearing mouse models. MiR-429 and FOXO1 expression levels were downregulated, whereas DNMT3A was upregulated in DLBCL compared to the control group. PA treatment was associated with enhanced autophagy, mediated by the upregulation of miR-429 and downregulation of DNMT3A. The luciferase reporter assay and MSP confirmed that miR-429 directly inhibits DNMT3A, thereby reducing FOXO1 methylation. Subsequent experiments demonstrated that PA promotes autophagy and inhibits DLBCL progression by upregulating miR-429 and modulating the DNMT3A/FOXO1 axis. In vivo PA significantly reduced the growth of xenografted tumors through its regulatory impact on the miR-429/DNMT3A/FOXO1 axis. Palmitic acid may modulate autophagy and inhibit DLBCL progression by targeting the miR-429/DNMT3A/FOXO1 signaling pathway, suggesting a novel therapeutic target for DLBCL management.

Genomic profiling in a subgroup analysis of patients (pts) with diffuse large B-cell lymphoma (DLBCL) and extranodal (EN) sites of involvement in the phase 3 Pola-R-CHP versus R-CHOP (POLARIX) study.

7061 Background: The prognosis and survival outcomes of pts with EN involvement remain a challenge for DLBCL management. In the Phase 3 POLARIX study (NCT03274492), Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) compared with R-CHOP in previously untreated DLBCL (Tilly et al. 2022). This retrospective analysis assessed clinical outcomes and genomic patterns of pts with DLBCL and EN disease. Methods: POLARIX methods were previously described (Tilly et al. 2022). Using a data cutoff of June 15, 2022, this analysis assessed pts with EN involvement as determined by investigators. Additional outcomes and genomics analyses were performed on pts whose EN status was confirmed from documented radiographic lesions or bone marrow biopsy with denotation of EN disease sites. Hazard ratios (HRs) for investigator-assessed PFS were adjusted for age (≤60 vs &gt;60) and sex. Cell of origin (COO) by NanoString, mutation analysis by whole exome sequencing, and global gene expression profiling by RNAseq were performed centrally. Results: In POLARIX, 616/879 pts (70%) had identified EN involvement. After a median follow-up of 39.7 months, pts showed improved PFS with Pola-R-CHP vs R-CHOP (HR 0.72, 95% confidence interval [CI]: 0.55–0.96), with a 2-year PFS of 75% vs 66%. A total of 556 pts (Pola-R-CHP, n=279; R-CHOP, n=277) had confirmed sites of EN involvement, defined as pts with EN radiographic lesions or bone marrow disease. In these pts, PFS favored Pola-R-CHP vs R-CHOP but the difference was not statistically significant (HR 0.84, 95% CI: 0.63–1.13). Of pts with confirmed EN disease, 429 had COO results (activated B-cell, 145 [34%]; germinal center B-cell, 223 [52%]; unclassified DLBCL, 61 [14%]). Mutation data and frequencies of select clinically relevant mutations (Ptashkin, 2023) across EN sites were available for 364 pts (Table). Gene expression data were available for 418 pts; genes involved in proliferation (E2F or PI3K signaling targets and checkpoint genes) and regulated by IRF4, OCT2 and XBP1, were commonly upregulated in pts with EN disease. Conclusions: Results in pts with DLBCL with EN involvement suggest superior PFS with Pola-R-CHP vs R-CHOP. Ongoing analyses will further assess the independent impact of EN status on outcome. POLARIX represents the largest cohort of pts with annotated EN disease and systematic genomic analysis, providing new insights into the genomics of these pts. Clinical trial information: NCT03274492 . [Table: see text]

Population pharmacokinetics and exposure-response analyses of polatuzumab vedotin in patients with previously untreated DLBCL from the POLARIX study.

Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure-response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody-conjugated (acMMAE)/unconjugated MMAE area under the concentration-time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression-free and event-free survival (both p = 0.01). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.

Results from the Epcore NHL-2 Trial Arm 8: Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP

Results from the Epcore NHL-2 Trial Arm 8: Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP

Real-world efficacy of chidamide plus R-CHOP in newly diagnosed double-expressor diffuse large B-cell lymphoma

Background: Approximately 20%–30% of diffuse large B-cell lymphoma (DLBCL) cases are classified as double-expressor lymphoma (DEL), characterized by the co-expression of the MYC and BCL2 proteins. However, the most effective therapeutic strategy for DEL remains unidentified. Objectives: To evaluate the efficacy of a novel histone deacetylase inhibitor, chidamide, in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (CR-CHOP) in the treatment of DEL. Design: This was a retrospective study. Methods: This study included 62 DEL patients from December 2016 to December 2020. All patients were administered a first-line treatment with CR-CHOP. The short-term efficacy, survival status, and adverse reactions in this population were observed, and the prognostic factors were analyzed. Results: The median age was 53.9 years (range, 19–77). All patients received a median of six cycles (range, 1–8) of treatment, with 79.0% achieving complete response (CR) and an overall response rate of 88.7%. With a median follow-up of 45.5 months (range, 1–82), the median progression-free survival (PFS) and median overall survival (OS) had not yet been reached. However, the 3-year PFS rate was 71% (95% CI: 61–83), the 3-year OS rate was 87% (95% CI: 79–96), the 5-year PFS rate was 67% (95% CI: 55–80), and the 5-year OS rate was 85% (95% CI: 77–95). Age and autologous stem cell transplantation after CR or partial response were independent prognostic factors for PFS, while various clinical factors were not associated with OS outcomes. The most common grades 3–4 hematologic and nonhematologic toxicity were leukopenia (46.7%) and infection (21%), respectively. Conclusion: This long-term follow-up study indicates that CR-CHOP in untreated DLBCL with the DEL phenotype demonstrates high short-term efficacy and safety as well as promising survival outcomes.

EE701 Cost-Effectiveness Analysis of Polatuzumab Vedotin Combined with Chemoimmunotherapy in Untreated Diffuse Large B-Cell Lymphoma (DLBCL) in China

EE701 Cost-Effectiveness Analysis of Polatuzumab Vedotin Combined with Chemoimmunotherapy in Untreated Diffuse Large B-Cell Lymphoma (DLBCL) in China

Zanubrutinib Combined with R-CHOP in Previously Untreated Non-Germinal Center B-Cell (GCB) Diffuse Large B-Cell Lymphoma (DLBCL) Patients with BCL2 and MYC Protein Co-Expression: A Multicenter, Phase II Study

Introduction DLBCL is the most common subtype of lymphoma, accounting for up to 40% of lymphoma cases worldwide and can be classified into GCB and non-GCB by immunohistochemistry (IHC). Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy is the standard first-line treatment of DLBCL. Patients with non-GCB DLBCL or co-expression of BCL2 and MYC have a worse outcome with R-CHOP treatment. Previous study has showed that ibrutinib combined with R-CHOP had improved event free survival (EFS) compared with placebo plus R-CHOP in non-GCB DLBCL patients with BCL2 and MYC co-expression (Johnson et al., Blood 2019). This study aimed to investigate the efficacy and safety of the new-generation BTKi zanubrutinib combined with R-CHOP in previously untreated non-GCB DLBCL patients with BCL2 and MYC protein co-expression. Here, we report the preliminary results of this study. Methods Eligible patients were previously untreated non-GCB DLBCL confirmed by Hans' algorithm age 18 years or older, MYC positive (defined as ≥40% of tumor cells showed any level of MYC nuclear staining above background) and BCL-2 positive (defined as ≥50% of tumor cells showed a cytoplasmic intensity score of 2+ or 3+) determined by IHC, and Eastern Cooperative Oncology Group performance status of 0-2.Patients were treated with R-CHOP combined with zanubrutinib (160 mg oral BID per day) of each 21-day cycle for six cycles. After 4 cycles, response was assessed by CT per Lugano 2014 criteria. Patients who were progression disease (PD) would discontinue the treatment. After completion of 6 cycles treatment, patients who were assessed with complete response (CR) (by PET-CT) would proceed to zanubrutinib (160 mg oral BID) maintenance treatment for one year, or until PD, intolerance of toxicity, loss of follow-up, withdrawal of informed consent, or death. Patients who were not CR would receive subsequent anti-tumor therapies determined by investigator. The primary endpoint was 3-year EFS rate assessed by investigator, Secondary endpoints included overall response rate (ORR), CR rate, 3-year progression free survival rate, 3-year overall survival rate and safety. Results From Jan 2022 to Jun 2023, 27 patients were enrolled with a median age of 58, and 40.7% (11/27) were with IPI ≥3. At the data cut-off date of 30 Jun 2023, all 27 patients received at least one cycle of R-CHOP plus zanubrutinib and included in safety evaluation. Seventeen patients have received 4 cycles treatment and were assessed by CT with CR (n=1) or partial response (n=16); 2 patients withdrew the study before the first assessment. Among the 17 patients, 11 patients completed 6 cycles of treatment and achieved a response (11/11), with a CR (CR and complete metabolic response) of 10/11 ( Table). Two patients discontinued after 4 cycles treatment (1 due to outbreak of COVID 19 and 1 due to AE, infectious pneumonia). Ten patients with CR are in the zanubrutinib maintenance treatment, while 1 patient with PR had received salvage therapy decided by the investigator. The most common hematologic TEAEs were neutropenia (33.3% in Grade 1-2, 18.5% in Grade ≥3) and thrombocytopenia (7.4% in Grade 1-2, 11.1% in Grade ≥3), and non-hematologic TEAE includes alanine aminotransferase increased, aspartate aminotransferase increased, rash, hypokalemia, anemia, diarrhea, infectious pneumonia and hemorrhage (Figure). Hypertension and atrial fibrillation/flutter were not observed during the treatment. Four patients experienced SAE of infectious pneumonia (n=1), neutropenia (n=1), and thrombocytopenia (n=2, Grade 3), and were recovered. Conclusions At the time of data cut-off 30 Jun 2023, 6 cycles of zanubrutinib combined with R-CHOP regimen was well tolerated and showed a promising response result in untreated non-GCB double-expression DLBCL patients. The study is ongoing and further results will be continuously released.

Selinexor in Combination with R-EPOCH for Patients with Previously Untreated HIV-Associated Diffuse Large B Cell Lymphoma(DLBCL)

Introduction : The incidence of HIV-positive lymphoma remains significantly higher than HIV-negative patients in the era of combined antiretroviral therapy(cART). DLBCL is the most common histological type of HIV-positive non-Hodgkin's lymphoma(NHL). Exportin 1 protein(XPO1) inhibitor has demonstrated preliminary anti-HIV activity and synergy with anti-lymphoma drug(e.g. etoposide, doxorubicin, prednisone). Methods: The study was designed to evaluate safety and efficacy of selinexor (60mg Days 1, 8, 15) combined with R-EPOCH(rituximab 375 mg/m2d1, etoposide 50 mg/m2 d1-d4, doxorubicin 10mg/m2 d1-d4, vinblastine 0.4mg/m2 d1-d4, prednisone 60mg/m2 d1-d5 and cyclophosphamide 750mg/m2 d5) every 3 weeks (4-6 cycles), followed by selinexor maintenance (60 mg weekly) or transplantation as per physician's choice in patients with untreated HIV-positive DLBCL. All patients received cART concomitantly during chemotherapy. This study was registered at Chictr.org.cn(ChiCTR2300069941). Results: From Feb 24, 2023 to July 17, 2023, 6 patients were enrolled and received at least one cycles of study treatment. Median age was 55 years (range 43-67) with four patients(66.7%) was male. All six patients were in advanced stage according to Ann Arbor staging system, with aaIPI intermediate to high risk or IPI low to intermediate risk. Four patients(66.7%) were germinal center B-cell-like lymphoma (GCB) subtype and three patients(50%) had an Elevated lactate dehydrogenase level. Median HIV RNA load was 74450(10000-100000) copies/mL and Median CD4 cell count was 233 cells/μL (233 cells/mm3) with one patient having a CD4 cell count less than 200 cells/μL (200 cells/mm3). Two patients were HBV-positive and one was EB virus(EBV) coinfection at baseline. Three patients achieved PR after two treatment cycles, one patient of which had completed five treatment cycles and achieved complete response at the end of the fourth cycle (Figure 1). One patients after interim evaluation with PR stopped treatment because of loss to follow-up. The EBV DNA load of the patient with EBV coinfection at baseline turned to normal level after one treatment cycle. Similar result was observed in two HBV-positive patients, the one achieved HBV-negative after two cycles and the other's HBV DNA load level declined from 7.96×10^4 IU/mL to 1.12×10^3 after completing first cycle. HIV RNA load of the patient with CR had declined to &amp;lt;20 copies/mL from 58300 copies/mL after the fourth cycle, another patient likewise became HIV-negative before the initiation of the third cycle. The change of CD4+T cell count during treatment was presented in Figure 2. All patients experienced at least one treatment-emergent adverse event (TEAE), 3 (50%) patients with at least one Grade≥3 TEAE. The most common grade 3 or 4 adverse events were hematological toxicities including lymphopenia(83.3%), neutropenia (50%), leukopenia(33.3%), thrombocytopenia (33.3%). Two patients experienced Febrile neutropenia. The non-hematological toxicities were grade 1 or 2, including nausea(66.7%), vomit(50%), constipation(33.3%), cough(33%). One patient stopped treatment for one month due to pulmonary infection. All toxicities were manageable by supportive care. Conclusion: Selinexor plus R-EPOCH regimen demonstrated a favorable Interim efficacy and manageable safety profile in patients with HIV-associated DLBCL. The change of HIV RNA load and CD4+ cell count still requires further evaluation.

Primary Pulmonary Diffuse Large B-Cell Lymphoma - a Rare Case Report

Background: Diffuse large B cell lymphoma (DLBCL) is an aggressive hematological malignancy, and a common histological form of non-Hodgkin's lymphoma. However, its extra-nodal presentation is seen in 30-40% of cases with involvement of gastrointestinal tract, skin, testes, adrenals and bone. ( Lugogo NL et al., 2006) A pulmonary manifestation is an extremely rare entity. We present an atypical case of DLBCL presenting as pleuritic chest pain with imaging consistent with bilateral pulmonary nodules suggestive of metastasis. Case description: A healthy 87 year old male former smoker with a history of type 2 diabetes mellitus, hypertension presented to the emergency department with pleuritic chest pain. There was no associated cough, shortness of breath, palpitations, nausea, dizziness or diaphoresis. No recent infections or B symptoms. He had a good appetite. He had prostate cancer 20 years ago and had a radical prostatectomy. Upon presentation, work up showed mild anemia (Hb 11.1 g/dL). Cardiac work up for chest pain was unremarkable. Chest X-Ray revealed mass like opacities in each lung with largest in left mid lung measuring up to 6 cm. CT chest with IV contrast revealed multiple lung nodules bilaterally with 2 largest in left upper lobe measuring 5.6 x 3.7 cm and 5.7 x 3.3 cm. Multiple other small nodules are present in both lung fields consistent with diffuse lung metastasis. No lymphadenopathy was noted. (Image 1) PET CT scan was significant for bilateral FDG avid lung lesions. No evidence of other FDG avid disease. CT guided biopsy of the left lung mass surprisingly revealed diffuse large B cell non-Hodgkin's lymphoma, non-germinal center type. (Image 1) Immuno-histochemistry showed atypical lymphocytes positively stained with CD20, BCL6, BCL2, PAX5 and MUM1. C-myc had 50% positivity. Ki67 had 90% proliferative index. FISH analysis was negative for MYC, BCL2 and BCL6; hence there was no double hit lymphoma detected. According to Lunago classification, patient had advanced stage disease with IPI (prognosis index) of 2. His ECOG PS score was 0. He was initiated on R-Pola-CHP. Given his age, Cyclophosphamide and Adriamycin doses were reduced as done with R-mini CHOP. Vincristine was avoided given neurotoxicity. Discussion: Primary pulmonary B-cell lymphomas (PP-BCLs) represent less than 3-4% of all extra-nodal NHL. They primarily affect the lung without evidence of extrapulmonary disease at the time of diagnosis. PP-DLBCL accounts for only 10% cases of PP-BCLs. ( Sanguedolce et al., 2021) Most cases have atypical presentation. Likewise, in our patient, he manifested with atypical chest pain without any B symptoms. Radiographic imaging can show variable findings of consolidation, single/multiple nodules, reticular interstitial infiltrate or bilateral ground glass opacities. In view of the insidious onset and lack of specificity in clinical symptoms, primary pulmonary lymphomas are frequently misdiagnosed as refractory pneumonia, lung abscess, asthma, primary lung cancer, or lung metastasis. ( Liu et al., 2020) Patients with DLBCL are typically treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). However, with this regimen, only 60% of patients are cured and the rest might relapse. In the POLARIX phase 3 trial, polatuzumab vedotin (a monoclonal antibody to CD79b ubiquitously expressed on B cells) combined with R-CHP significantly improved 2 year progression-free survival compared to the routine R-CHOP therapy in previously untreated DLBCL patients. ( Tilly et al., 2022) Given our patient's advanced stage disease, he was initiated on the Pola-R-CHP regimen. Doses of cyclophosphamide and doxorubicin were reduced as per the R-mini CHOP dose-reduced regimen for a physically fit elderly individual. Patient continues on therapy at the time of this abstract. In conclusion, primary pulmonary DLBCL is a rare entity with only a few case reports in literature. It should be considered in patients presenting with large pulmonary masses, mimicking metastatic disease.

Phase II Clinical Trial of R-CHOP Combined with Lenalidomide in the First-Line Treatment for Patients with High Risk Diffuse Large B Cell Lymphoma

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). Currently, R-CHOP (Rituximab-Cyclophosphamide, Epirubicin, Vincristine and Prednisone) is world-widely used in the first-line treatment for DLBCL, producing a long-term survival rate of approximately 60%. The unmet need is focused on high-risk DLBCL patients, having high International Prognostic Index (IPI) scores, non-germinal center-like B cell (non-GCB) origin, double expression of MYC and BCL2 protein, or TP53 aberrations. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of DLBCL by increasing interferon-stimulated gene transcription and activation of immunomodulatory mechanisms. At present, it has been approved for the treatment of multiple myeloma with good efficacy and safety. This is a prospective single arm, multi-center, phase II clinical trial and the goal of our trial is to assess the efficacy and safety of R-CHOP combined with lenalidomide in the first-line treatment for patients with high risk diffuse large B cell lymphoma. Methods: We did an investigator-initiated, open-label, phase 2 trial at the Affiliated Cancer Hospital of Zhengzhou University in China. Patients were eligible if they were aged over 18 years, had histologically confirmed DLBCL. The key inclusion criteria included untreated and medium to high /high risk DLBCL (International Prognostic Index (IPI) score 3-5, aaIPI score 2-3 or NCCN-IPI score≥ 4/ Immunohistochemical staining of double expression (BCL2 ≥ 50% and C-MYC ≥ 40%) or P53 protein mutation positive ≥ 50%). Participants in RL-CHOP cohort were given Lenalidomide orally 25 mg per day on days 1 through 10 of each cycle and delivered concomitantly with standard dose R-CHOP-21 chemotherapy. We also set another group treated with conventional R-CHOP-21 used as a matched contemporary cohort. The primary clinical endpoint was 2-year progression-free survival (PFS). The secondary efficacy endpoints were objective response rate (ORR), 2-year overall survival (OS) and safety. This trial is registered with ClinicalTrials.gov, number NCT04214626. Results: Between December 2019 and January 2023, 63 patients with untreated DLBCL enrolled and were evaluable in the investigator-initiated phase II study. The median age was 59 years (range: 25-76 years); 49.2% of patients were older than age 60 years. 46 of 63 patients (73.02%) had a ECOG score of 0-1; 43 of 63 patients (68.25%) had stage III-IV disease, and 33 of 63 patients (52.38%) had ≥2 extranodal localizations. The IPI score was high-intermediate and high in 73.02% (46/63) of patients. 51 of 63 patients (80.95%) were non-GCB subtype; 25 of 63 patients (39.68%) were double expressor. The TP53 protein was positive in 34.55% (19/55) of patients. In RL-CHOP cohort, the complete response rate was 80.95%, with overall response rate achieving 100%. The median follow-up time was 18.25 (3.73-42) months, median PFS and OS were not reached, and 2-year PFS and OS was 71.1% (+-6.7) and 87.4% (+-4.5), respectively. Comparing with historical matched contemporary cohort, the 2-year PFS and OS rates were improved for medium to high /high risk DLBCL. The most common adverse events of treatment were hematologic toxicities. Grade 3/4 AEs occurred in ≥20% patients were neutropenia, leukopenia, anemia, thrombocytopenia and decreased serum potassium, without bleeding complications. No grade 4 non-hematological adverse event was reported. Conclusion: RL-CHOP is effective and safe in patients with newly diagnosed DLBCL with high risk. Relevance of molecular biomarkers on RL-CHOP response warrants further investigation in DLBCL.