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.

Evaluating Outcome Prediction via Baseline, End-of-Treatment, and Delta Radiomics on PET-CT Images of Primary Mediastinal Large B-Cell Lymphoma.

OBJECTIVES: Accurate outcome prediction is important for making informed clinical decisions in cancer treatment. In this study, we assessed the feasibility of using changes in radiomic features over time (Delta radiomics: absolute and relative) following chemotherapy, to predict relapse/progression and time to progression (TTP) of primary mediastinal large B-cell lymphoma (PMBCL) patients. MATERIAL AND METHODS: Given the lack of standard staging PET scans until 2011, only 31 out of 103 PMBCL patients in our retrospective study had both pre-treatment and end-of-treatment (EoT) scans. Consequently, our radiomics analysis focused on these 31 patients who underwent [18F]FDG PET-CT scans before and after R-CHOP chemotherapy. Expert manual lesion segmentation was conducted on their scans for delta radiomics analysis, along with an additional 19 EoT scans, totaling 50 segmented scans for single time point analysis. Radiomics features (on PET and CT), along with maximum and mean standardized uptake values (SUVmax and SUVmean), total metabolic tumor volume (TMTV), tumor dissemination (Dmax), total lesion glycolysis (TLG), and the area under the curve of cumulative standardized uptake value-volume histogram (AUC-CSH) were calculated. We additionally applied longitudinal analysis using radial mean intensity (RIM) changes. For prediction of relapse/progression, we utilized the individual coefficient approximation for risk estimation (ICARE) and machine learning (ML) techniques (K-Nearest Neighbor (KNN), Linear Discriminant Analysis (LDA), and Random Forest (RF)) including sequential feature selection (SFS) following correlation analysis for feature selection. For TTP, ICARE and CoxNet approaches were utilized. In all models, we used nested cross-validation (CV) (with 10 outer folds and 5 repetitions, along with 5 inner folds and 20 repetitions) after balancing the dataset using Synthetic Minority Oversampling TEchnique (SMOTE). RESULTS: To predict relapse/progression using Delta radiomics between the baseline (staging) and EoT scans, the best performances in terms of accuracy and F1 score (F1 score is the harmonic mean of precision and recall, where precision is the ratio of true positives to the sum of true positives and false positives, and recall is the ratio of true positives to the sum of true positives and false negatives) were achieved with ICARE (accuracy = 0.81 ± 0.15, F1 = 0.77 ± 0.18), RF (accuracy = 0.89 ± 0.04, F1 = 0.87 ± 0.04), and LDA (accuracy = 0.89 ± 0.03, F1 = 0.89 ± 0.03), that are higher compared to the predictive power achieved by using only EoT radiomics features. For the second category of our analysis, TTP prediction, the best performer was CoxNet (LASSO feature selection) with c-index = 0.67 ± 0.06 when using baseline + Delta features (inclusion of both baseline and Delta features). The TTP results via Delta radiomics were comparable to the use of radiomics features extracted from EoT scans for TTP analysis (c-index = 0.68 ± 0.09) using CoxNet (with SFS). The performance of Deauville Score (DS) for TTP was c-index = 0.66 ± 0.09 for n = 50 and 0.67 ± 03 for n = 31 cases when using EoT scans with no significant differences compared to the radiomics signature from either EoT scans or baseline + Delta features (p-value> 0.05). CONCLUSION: This work demonstrates the potential of Delta radiomics and the importance of using EoT scans to predict progression and TTP from PMBCL [18F]FDG PET-CT scans.

Durable Responses With Mosunetuzumab in Relapsed/Refractory Indolent and Aggressive B-Cell Non-Hodgkin Lymphomas: Extended Follow-Up of a Phase I/II Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Mosunetuzumab is a CD20xCD3 T-cell-engaging bispecific antibody administered as an off-the-shelf, fixed-duration treatment in an outpatient setting. We report an updated analysis of the durability of response, by investigator assessment, after an overall median follow-up of 3.5 years in patients with relapsed/refractory indolent or aggressive B-cell non-Hodgkin lymphoma (iNHL/aNHL) from the dose-escalation stage of a phase I/II study of mosunetuzumab (ClinicalTrials.gov identifier: NCT02500407). Across dose levels, 65.7% of patients with iNHL and 36.4% with aNHL achieved a complete or partial response to mosunetuzumab. Median duration of response (DoR) in patients with iNHL for all responders was 23.2 months (95% CI, 13.8 to not estimable [NE]), but was not reached in complete responders (95% CI, 21.0 to NE). After a median time on study of 38.9 months, no relapses were observed beyond 26 months in complete responders. In patients with aNHL, median DoR for all responders was 7.8 months (95% CI, 4.6 to 22.8). Among 12 complete responders who progressed postmosunetuzumab treatment and were retreated with mosunetuzumab, 83.3% had an objective response and 58.3% achieved a second complete response. Our study reports the longest follow-up using bispecific antibodies in patients with B-cell non-Hodgkin lymphoma and demonstrates that mosunetuzumab can mediate durable remissions with time-limited treatment.

Semi-supervised learning towards automated segmentation of PET images with limited annotations: application to lymphoma patients.

Manual segmentation poses a time-consuming challenge for disease quantification, therapy evaluation, treatment planning, and outcome prediction. Convolutional neural networks (CNNs) hold promise in accurately identifying tumor locations and boundaries in PET scans. However, a major hurdle is the extensive amount of supervised and annotated data necessary for training. To overcome this limitation, this study explores semi-supervised approaches utilizing unlabeled data, specifically focusing on PET images of diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) obtained from two centers. We considered 2-[18F]FDG PET images of 292 patients PMBCL (n = 104) and DLBCL (n = 188) (n = 232 for training and validation, and n = 60 for external testing). We harnessed classical wisdom embedded in traditional segmentation methods, such as the fuzzy clustering loss function (FCM), to tailor the training strategy for a 3D U-Net model, incorporating both supervised and unsupervised learning approaches. Various supervision levels were explored, including fully supervised methods with labeled FCM and unified focal/Dice loss, unsupervised methods with robust FCM (RFCM) and Mumford-Shah (MS) loss, and semi-supervised methods combining FCM with supervised Dice loss (MS + Dice) or labeled FCM (RFCM + FCM). The unified loss function yielded higher Dice scores (0.73 ± 0.11; 95% CI 0.67-0.8) than Dice loss (p value < 0.01). Among the semi-supervised approaches, RFCM + αFCM (α = 0.3) showed the best performance, with Dice score of 0.68 ± 0.10 (95% CI 0.45-0.77), outperforming MS + αDice for any supervision level (any α) (p < 0.01). Another semi-supervised approach with MS + αDice (α = 0.2) achieved Dice score of 0.59 ± 0.09 (95% CI 0.44-0.76) surpassing other supervision levels (p < 0.01). Given the time-consuming nature of manual delineations and the inconsistencies they may introduce, semi-supervised approaches hold promise for automating medical imaging segmentation workflows.

TMTV-Net: fully automated total metabolic tumor volume segmentation in lymphoma PET/CT images - a multi-center generalizability analysis.

PURPOSE: Total metabolic tumor volume (TMTV) segmentation has significant value enabling quantitative imaging biomarkers for lymphoma management. In this work, we tackle the challenging task of automated tumor delineation in lymphoma from PET/CT scans using a cascaded approach. METHODS: Our study included 1418 2-[18F]FDG PET/CT scans from four different centers. The dataset was divided into 900 scans for development/validation/testing phases and 518 for multi-center external testing. The former consisted of 450 lymphoma, lung cancer, and melanoma scans, along with 450 negative scans, while the latter consisted of lymphoma patients from different centers with diffuse large B cell, primary mediastinal large B cell, and classic Hodgkin lymphoma cases. Our approach involves resampling PET/CT images into different voxel sizes in the first step, followed by training multi-resolution 3D U-Nets on each resampled dataset using a fivefold cross-validation scheme. The models trained on different data splits were ensemble. After applying soft voting to the predicted masks, in the second step, we input the probability-averaged predictions, along with the input imaging data, into another 3D U-Net. Models were trained with semi-supervised loss. We additionally considered the effectiveness of using test time augmentation (TTA) to improve the segmentation performance after training. In addition to quantitative analysis including Dice score (DSC) and TMTV comparisons, the qualitative evaluation was also conducted by nuclear medicine physicians. RESULTS: Our cascaded soft-voting guided approach resulted in performance with an average DSC of 0.68 ± 0.12 for the internal test data from developmental dataset, and an average DSC of 0.66 ± 0.18 on the multi-site external data (n = 518), significantly outperforming (p < 0.001) state-of-the-art (SOTA) approaches including nnU-Net and SWIN UNETR. While TTA yielded enhanced performance gains for some of the comparator methods, its impact on our cascaded approach was found to be negligible (DSC: 0.66 ± 0.16). Our approach reliably quantified TMTV, with a correlation of 0.89 with the ground truth (p < 0.001). Furthermore, in terms of visual assessment, concordance between quantitative evaluations and clinician feedback was observed in the majority of cases. The average relative error (ARE) and the absolute error (AE) in TMTV prediction on external multi-centric dataset were ARE = 0.43 ± 0.54 and AE = 157.32 ± 378.12 (mL) for all the external test data (n = 518), and ARE = 0.30 ± 0.22 and AE = 82.05 ± 99.78 (mL) when the 10% outliers (n = 53) were excluded. CONCLUSION: TMTV-Net demonstrates strong performance and generalizability in TMTV segmentation across multi-site external datasets, encompassing various lymphoma subtypes. A negligible reduction of 2% in overall performance during testing on external data highlights robust model generalizability across different centers and cancer types, likely attributable to its training with resampled inputs. Our model is publicly available, allowing easy multi-site evaluation and generalizability analysis on datasets from different institutions.

The influence of immunodeficiency, disease features, and patient characteristics on survival in plasmablastic lymphoma.

ABSTRACT: Plasmablastic lymphoma (PBL) is a rare and aggressive non-Hodgkin lymphoma associated with immunodeficiency, characterized by uncertain treatment approaches and an unfavorable prognosis. We conducted a multicenter, international, retrospective cohort study, aiming to characterize the clinical features, risk factors, and outcomes of patients with PBL. Data were collected from 22 institutions across 4 countries regarding patients diagnosed with PBL between 1 January 1999 and 31 December 2020. Survival risk factors were analyzed using both univariate and multivariate regression models. Overall survival (OS) was calculated using Kaplan-Meier statistics. First-line treatment regimens were stratified into standard- and higher-intensity regimens, and based on whether they incorporated a proteasome inhibitor (PI). A total of 281 patients (median age, 55 years) were included. Immunodeficiency of any kind was identified in 144 patients (51%), and 99 patients (35%) had HIV-positive results. The 5-year OS for the entire cohort was 36% (95% confidence interval, 30%-42%). In multivariate analysis, inferior OS was associated with Epstein-Barr virus-negative lymphoma, poor performance status, advanced stage, and bone marrow involvement. In an independent univariate analysis, the international prognostic index was associated with OS outcomes. Neither immunosuppression nor HIV infection, specifically, influenced OS. Among patients treated with curative intent (n = 234), the overall response rate was 72%. Neither the intensity of the treatment regimen nor the inclusion of PIs in first-line therapy was associated with OS. In this large retrospective study of patients with PBL, we identified novel risk factors for survival. PBL remains a challenging disease with poor long-term outcomes.

Frontline therapy with bendamustine rituximab (BR) and rituximab cyclophosphamide vincristine prednisone (RCVP) confers similar long-term outcomes in patients with treatment naïve Waldenström macroglobulinemia in a real-world setting: a population-based analysis.

We report on outcomes of 111 patients with treatment naïve Waldenström macroglobulinemia (TN WM) treated with frontline bendamustine-rituximab (BR) (n = 57) or rituximab-cyclophosphamide-vincristine-prednisone (RCVP) (n = 54). Median follow-up was 60.7 months (range 1.9-231.6). Median progression-free survival (PFS) was 60.5 months (95% CI 47.6-73.4) for BR and 79.0 months (95% CI 31.3-126.8) for RCVP (p = .96). Median overall survival (OS) was not reached for BR and 153.4 months (95% CI 114.5-192.4) for RCVP (p = .37). While overall and major response rates did not differ between treatment groups, BR had numerically higher rate of very good partial response or better response (51% vs. 37%, p = .30) and complete response (26% vs. 13%, p = .13). RCVP confers comparable outcomes to BR in a real-world population of TN WM patients and remains an effective regimen, particularly when tolerance or frailty is an issue, or in resource-limited settings.

A comparison of the prognostic performance of the Lugano 2014 and RECIL 2017 response criteria in patients with NHL from the phase III GOYA and GALLIUM trials.

The Lugano 2014 criteria are the standard for response assessment in lymphoma. We compared the prognostic performance of Lugano 2014 and the more recently developed response evaluation criteria in lymphoma (RECIL 2017), which relies primarily on computed tomography and uses unidimensional measurements, in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) from the phase III GOYA and GALLIUM trials, respectively. Concordance between responses according to the Lugano 2014 and RECIL 2017 criteria was analyzed. Landmark analyses of progression-free survival (PFS) and overall survival (OS) by end of treatment (EOT) and end of induction (EOI) response status according to RECIL 2017 and Lugano 2014 criteria, and prognostic value of response at EOT/EOI were also compared. Overall, 1333 patients were included from GOYA and 502 from GALLIUM. Complete response (CR) status according to RECIL 2017 criteria showed high concordance with complete metabolic response (CMR) status by Lugano 2014 criteria in both GOYA (92.5%) and GALLIUM (92.4%). EOT and EOI CR/CMR status by both criteria was highly prognostic for PFS in GOYA (RECIL 2017 [CR]: hazard ratio [HR], 0.35 [95% confidence interval [CI] 0.26-0.46]; Lugano 2014 [CMR]: HR, 0.35 [95% CI 0.26-0.48]; both p < .0001) and GALLIUM (RECIL 2017 [CR]: HR, 0.35 [95% CI 0.23-0.53]; Lugano 2014 [CMR]: HR, 0.21 [95% CI 0.14-0.31]; both p < .0001). In conclusion, response categorization by RECIL 2017 is similar to that by Lugano 2014 criteria, with high concordance observed. Both were prognostic for PFS and OS.

Polatuzumab vedotin plus bendamustine and rituximab or obinutuzumab in relapsed/refractory follicular lymphoma: a phase Ib/II study.

Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. Despite treatment advances that have improved outcomes for patients with relapsed or refractory (R/R) FL, many patients still die from progressive disease or treatment-related toxicities. In the phase Ib/II GO29365 study (NCT02257567), the safety and efficacy of polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) versus BR alone, and polatuzumab vedotin plus bendamustine and obinutuzumab (Pola-BG) as a single-arm cohort were evaluated in patients with R/R FL. Following the phase Ib safety run-in, patients were randomized 1:1 to receive Pola-BR or BR alone in the phase II stage; a separate non-randomized Pola-BG cohort was examined in the phase Ib/II expansion stage. Primary endpoints included safety and tolerability (phase Ib) and positron emission tomography complete response (PET-CR) rate by independent review committee (phase II). Overall, 112 patients were enrolled (phase Ib safety run-in: Pola-BR, n=6; phase II randomized cohort: Pola-BR, n=39; BR, n=41; phase Ib/II expansion cohort: Pola-BG, n=26). PET-CR rates were 66.7% (phase Ib safety run in, Pola-BR); 69.2% (phase II randomized, Pola-BR); 63.4% (phase II randomized, BR); and 65.4% (phase Ib/II expansion Pola-BG). There was a higher occurrence of cytopenias with Pola-BR and Pola-BG than with BR; serious adverse events were more frequent with Pola-BR (61.4%) and Pola-BG (46.2%) than with BR (29.3%). Overall, this analysis does not demonstrate a benefit of adding Pola to BR or BG regimens for patients with R/R FL.

Diffuse large B-cell lymphoma.

Large B-cell lymphoma, the prototype of aggressive non-Hodgkin lymphomas, is both the most common lymphoma and accounts for the highest global burden of lymphoma-related deaths. For nearly 4 decades, the goal of treatment has been "cure", first based on CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), and subsequently with rituximab plus CHOP. However, there is significant clinical, pathologic, and biologic heterogeneity, and not all patients are cured. Understanding and incorporating this biologic heterogeneity into treatment decisions unfortunately is not yet standard of care. Despite this gap, we now have significant advances in frontline, relapsed, and refractory settings. The POLARIX trial shows, for the first time, improved progression-free survival in a prospective randomized phase 3 setting. In the relapsed and refractory settings, there are now many approved agents/regimens, and several bispecific antibodies poised to join the arsenal of options. While chimeric antigen receptor T-cell therapy is discussed in detail elsewhere, it has quickly become an excellent option in the second-line setting and beyond. Unfortunately, special populations such as older adults continue to have poor outcomes and be underrepresented in trials, although a new generation of trials aim to address this disparity. This brief review will highlight the key issues and advances that offer improved outcomes to an increasing portion of patients.

Relapse Timing Is Associated With Distinct Evolutionary Dynamics in Diffuse Large B-Cell Lymphoma.

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship. PATIENTS AND METHODS: Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients. RESULTS: Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse. CONCLUSION: These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.

Population-level impact of ibrutinib for chronic lymphocytic leukemia in British Columbia, Canada.

Ibrutinib has dramatically changed the treatment landscape for chronic lymphocytic leukemia (CLL) since its availability in British Columbia (BC), Canada in 2014. We analyzed patterns of use and real-world survival outcomes in 370 patients who received ibrutinib for first-line (1 L, n = 35) and relapsed/refractory (R/R, n = 335) CLL between 2014-2018 in BC. Dose reductions and interruptions were frequent in 32% and 27%, respectively. With a median follow-up of 27.6 months, 35% of patients discontinued ibrutinib, primarily for adverse events (AEs) rather than progressive disease. Over the course of treatment, 87% of patients experienced at least one adverse event. The 2-year overall survival (OS) and event-free survival (EFS) were excellent at 83.9% and 76.1%, respectively, with medians not reached. However, patients who discontinued ibrutinib had a median OS of 32.5 months and median EFS of only 3.8 months from time of discontinuation, highlighting the need to minimize toxicity in the real-world.

Mosunetuzumab monotherapy is active and tolerable in patients with relapsed/refractory diffuse large B-cell lymphoma.

As part of a phase 1 or 2 study, this single-arm expansion cohort established the efficacy and safety of mosunetuzumab monotherapy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (received ≥2 previous lines of therapy). Intravenous mosunetuzumab was administered with cycle (C) 1 step-up dosing for cytokine release syndrome (CRS) mitigation: C1 day (D) 1: 1 mg; C1D8 2 mg; C1D15 and C2D1: 60 mg; C3 + D1: 30 mg. Hospitalization was not mandatory. Patients with complete response (CR) completed treatment after C8; those with partial response or stable disease continued treatment for a total of 17 cycles. The primary end point was CR rate (best response), assessed against a historical control CR rate (20%) by independent review facility. Eighty-eight patients (73.9% de novo DLBCL; 26.1% transformed follicular lymphoma) were enrolled; all had received previous anthracycline and anti-CD20 therapy. Overall response and CR rates were 42.0% (95% confidence interval [CI], 31.6-53.1) and 23.9% (95% CI, 15.4-34.1), respectively; CR rate did not reach statistical significance vs the historical control (P = .36). Median time to first response was 1.4 months. Median progression-free survival was 3.2 months (95% CI, 2.2-5.3). The CR rate in 26 patients who received previous chimeric antigen receptor T-cell (CAR-T) therapy was 12%. CRS was one of the most common adverse events (26.1% of patients); predominantly grade 1 to 2 and primarily in C1. Four patients (4.5%) discontinued mosunetuzumab owing to adverse events. Mosunetuzumab demonstrated notable efficacy and a manageable safety profile in patients with R/R DLBCL, including those previously treated with CAR-Ts. This trial was registered at www.clinicaltrials.gov as #NCT02500407.

Relapse timing is associated with distinct evolutionary dynamics in DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is cured in over 60% of patients, but outcomes are poor for patients with relapsed or refractory disease (rrDLBCL). Here, we performed whole genome/exome sequencing (WGS/WES) on tumors from 73 serially-biopsied patients with rrDLBCL. Based on the observation that outcomes to salvage therapy/autologous stem cell transplantation are related to time-to-relapse, we stratified patients into groups according to relapse timing to explore the relationship to genetic divergence and sensitivity to salvage immunochemotherapy. The degree of mutational divergence increased with time between biopsies, yet tumor pairs were mostly concordant for cell-of-origin, oncogene rearrangement status and genetics-based subgroup. In patients with highly divergent tumors, several genes acquired exclusive mutations independently in each tumor, which, along with concordance of genetics-based subgroups, suggests that the earliest mutations in a shared precursor cell constrain tumor evolution. These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease.

Clinical impact of ibrutinib plus R-CHOP in untreated DLBCL coexpressing BCL2 and MYC in the phase 3 PHOENIX trial.

Diffuse large B-cell lymphoma (DLBCL), with high coexpression of BCL2 and MYC proteins (DE lymphoma), is considered an adverse prognostic indicator associated mostly with non-germinal center B-cell-like (non-GCB) DLBCL. BCL2/MYC overexpression is associated with B-cell receptor (BCR) pathway activation; consequently, DE DLBCL may be sensitive to BCR inhibitors. We assessed whether high BCL2/MYC coexpression by RNA sequencing could identify a patient subset responsive to ibrutinib using baseline biopsies from the PHOENIX trial, which evaluated the addition of ibrutinib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-GCB DLBCL. BCL2/MYC RNA expression was correlated with lower event-free survival (EFS) and overall survival (OS) using Kaplan-Meier estimates with Cox regression and log-rank testing. In total, 234 of 766 (30.5%) patients had high BCL2/MYC coexpression: 123 of 386 (31.9%) received ibrutinib plus R-CHOP and 111 of 380 (29.2%) received R-CHOP. EFS was superior with ibrutinib plus R-CHOP compared with R-CHOP alone in patients with high BCL2/MYC coexpression, but there was no significant impact on OS. However, EFS and OS showed clinically meaningful improvement with ibrutinib plus R-CHOP over R-CHOP alone in patients aged <60 years with high BCL2/MYC coexpression. We observed a significant association between high BCL2/MYC coexpression and activated B-cell-like and MYD88L265P/CD79B-mutated subtypes of DLBCL. Consequently, high BCL2/MYC coexpression identified a subset of non-GCB DLBCL that may be preferentially responsive to ibrutinib and warrants further investigation. This trial was registered at www.clinicaltrials.gov as #NCT01855750.

Polatuzumab vedotin in previously untreated DLBCL: an Asia subpopulation analysis from the phase 3 POLARIX trial.

In the phase 3 POLARIX study in previously untreated diffuse large B-cell lymphoma, polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with similar safety. Patients were randomized 1:1 to 6 cycles of Pola-R-CHP or R-CHOP plus 2 cycles of rituximab alone. For registration of POLARIX in China, consistency of PFS in an Asia subpopulation (defined as ≥50% of the risk reduction in PFS expected in the global population) was evaluated. Overall, 281 patients were analyzed: 160 patients from Asia in the intention-to-treat (ITT) population of the global study and 121 from an ITT China extension cohort. Of these, 141 were randomized to Pola-R-CHP and 140 to R-CHOP. At data cutoff (28 June 2021; median follow-up 24.2 months), PFS met the consistency definition with the global population, and was superior with Pola-R-CHP vs R-CHOP (hazard ratio, 0.64; 95% confidence interval [CI], 0.40-1.03). Two-year PFS was 74.2% (95% CI, 65.7-82.7) and 66.5% (95% CI, 57.3-75.6) with Pola-R-CHP and R-CHOP, respectively. Safety was comparable between Pola-R-CHP and R-CHOP, including rates of grade 3 to 4 adverse events (AEs; 72.9% vs 66.2%, respectively), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to study treatment discontinuation (5.0% vs 7.2%), and any-grade peripheral neuropathy (44.3% vs 50.4%). These findings demonstrate consistent efficacy and safety of Pola-R-CHP vs R-CHOP in the Asia and global populations in POLARIX. This trial was registered at https://clinicaltrials.gov/ct2/home as # NCT03274492.

Utilization of real-world data in assessing treatment effectiveness for diffuse large B-cell lymphoma.

Direct comparisons of the effectiveness of the numerous novel therapies in the diffuse large B-cell lymphoma (DLBCL) treatment landscape in a range of head-to-head randomized phase 3 trials would be time-consuming and costly. Comparative effectiveness studies using real-world data (RWD) represent a complementary approach. Recently, several studies of relapsed/refractory (R/R) DLBCL have used RWD to create observational cohorts to compare patient outcomes with cohorts derived from single-arm phase 2 trials. Using propensity score methods to balance clinically and prognostically relevant baseline covariates, closely matched patient-level cohorts can be generated. By incorporating appropriate measures to assess covariate balance and address potential bias in comparative effectiveness study designs, robust comparative analyses can be performed. Results from such studies have been used to supplement regulatory approval of therapies assessed in single-arm trials. While RWD studies have a greater susceptibility to bias compared to randomized controlled trials, well-designed and appropriately analyzed studies can provide complementary real-world evidence on treatment effectiveness.

Molecular determinants of clinical outcomes in a real-world diffuse large B-cell lymphoma population.

Molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) underlies the variable outcomes achieved with immunochemotherapy. However, outcomes of gene expression profiling (GEP)-defined molecular subgroups in a real-world DLBCL population remain unknown. Here we examined the prevalence and outcomes of molecular subgroups in an unselected population of 1149 patients with de novo DLBCL in British Columbia, Canada. Evaluable biopsies were profiled by fluorescence in situ hybridization (FISH), immunohistochemistry, and digital GEP to assign cell-of-origin and the so-called "double-hit signature" (DHITsig)-a signature originally described as being characteristic for high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). DHITsig was expressed in 21% of 431 germinal center B-cell-like (GCB)-DLBCL and all 55 Burkitt lymphomas examined. Reflecting this latter finding, DHITsig has been renamed the "dark zone signature" (DZsig). DZsigpos-DLBCL, non-DZsigpos GCB-DLBCL and activated B-cell-like (ABC)-DLBCL were associated with a 2 year overall survival of 57%, 89%, and 71%, respectively. 62% of DZsigpos tumors were negative for HGBCL-DH-BCL2 by FISH, but were associated with outcomes similar to HGBCL-DH-BCL2. A small group of HGBCL-DH-BCL2 that lacked DZsig expression had different molecular features compared with DZsig-expressing HGBCL-DH-BCL2 and were associated with favorable outcomes comparable to DLBCL, not otherwise specified. DZsigpos and ABC-DLBCL had a shorter diagnosis-to-treatment interval (DTI) than GCB-DLBCL, with this metric being associated with outcome. In conclusion, DZsig expression extends beyond HGBCL-DH-BCL2 and captures a poor-prognosis DLBCL subgroup with short DTI, including patients unidentifiable by routine FISH testing, that should be considered for treatment intensification or novel therapies in prospective trials.

Looking to achieve cure the first time around for DLBCL patients who are older and/or with co-morbidities.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive but often curable malignancy. Older patients, especially those 80 years and older, have poor outcomes compared to those < 60, likely due to a number of reasons including disease biology, comorbidities, and treatment intolerance. Prospective data informing the treatment of older patients and those with multiple co-morbidities is limited. Here, we intend to review available data for regimens other than standard R-CHOP (rituximab, cyclophosphamide, adriamycin, prednisone) or R-pola-CHP (rituximab, polatuzumab vedotin [pola], cyclophosphamide, adriamycin, prednisone), tools available that may aid in treatment selection, and future directions, including the incorporation of newer treatment modalities into therapy for more vulnerable patients.