Glofitamab is a T-cell engaging bispecific monoclonal antibody that was granted accelerated approval from the United States Food and Drug Administration for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified or large B-cell lymphoma arising from follicular lymphoma, after ≥2 lines of systemic therapy (3L+).

A budget impact model was developed for a hypothetical blended commercial/Medicare health plan with 1,000,000 members. Comparators were axicabtagene ciloleucel (Axi-cel), lisocabtagene maraleucel (Liso-cel), tisagenlecleucel (Tisa-cel), loncastuximab tesirine, polatuzumab vedotin + bendamustine + rituximab, rituximab + gemcitabine + oxaliplatin, tafasitamab + lenalidomide, and epcoritamab (Epcor). Total costs included those for drugs, wastage, administration, grade ≥3 adverse reactions, and all-grade cytokine release syndrome) and routine care. Market shares were based on internal projections and expert opinions. Total and per-member per-month (PMPM) net budget impacts over 3 years were calculated.

Approximately nine patients were projected to be eligible for 3L + DLBCL treatment in a health plan of 1,000,000 members. The introduction of glofitamab as a treatment option resulted in estimated total and PMPM cost savings of $728,697 and -$0.0202, respectively, over 3 years. Costs were reduced across all cost categories but particularly in drug costs. Among the newer therapies, total 3-year cost per treated patient was lowest for glofitamab: $226,658 versus Tisa-cel = $564,113; Axi-cel = $540,002; Liso-cel = $516,272; and Epcor = $335,293. Across all sensitivity analyses, the inclusion of glofitamab had minimal PMPM budget impact, ranging from -$0.0256 to -$0.0108.

With the lowest 3-year total cost per treated patient among the newer therapies, glofitamab being an available option in the 3L + DLBCL market is estimated to save a hypothetical 1,000,000-member health plan $728,697 in cumulative total costs and $0.0202 in PMPM costs over 3 years.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard treatment for relapsed diffuse large B cell lymphoma (DLBCL). The BEAM regimen is widely used, but the MEAM regimen is more common in Japan due to the unavailability of carmustine. This retrospective analysis evaluated the efficacy of the thiotepa and busulfan (TT/BU) regimen compared with other regimens in 27 patients with systemic DLBCL who underwent ASCT at our institution from December 2013 to March 2022. Fourteen patients received the TT/BU regimen, while 13 received alternative regimens. The TT/BU regimen demonstrated superior progression-free survival (PFS) and overall survival (OS) compared to other regimens, with a 3 year PFS of 84.4% and OS of 91.7%. The TT/BU group also had fewer severe adverse events, particularly regarding renal function. Our findings suggest that the TT/BU regimen is a well-tolerated and effective alternative for relapsed/refractory DLBCL and provide valuable insights for future treatment strategies.

Anti-CD19 CAR-T therapy has been a breakthrough in treatment of primary refractory or relapsed large B-cell lymphoma (r/r LBCL) and is poised to supplant previous second line of high dose chemotherapy and autologous stem cell transplantation (HDT/ASCT). However, in clinical practice, high risk patients with chemoimmunotherapy sensitive disease continue to receive salvage chemoimmunotherapy or cannot access CAR-T in a timely manner and thus may still proceed to HDT/ASCT. Little is known about clinical outcomes of CAR-T in patients who receive HDT/ASCT compared to those who are transplant-naïve.

We conducted a retrospective study of patients with r/r LBCL who previously underwent HDT/ASCT or were transplant-naïve (n = 97) and received axicabtagene ciloleucel after at least 2 prior therapy lines between 1/1/2018 to 12/31/2021. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), nonrelapse mortality (NRM), and cumulative incidence of relapse/progression.

82 (84.5%) patients were transplant-naïve and 15 (15.5%) previously received HDT/ASCT. No differences were found in the incidence of high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome, length of hospital admission, or incidence of cytopenia at day 30. 90-day response, PFS, OS, cumulative incidence of relapse/progression, and NRM were not different. Factors that adversely affected outcomes were prior bridging therapy, elevated LDH or thrombocytopenia at time of lymphodepleting chemotherapy, and worse ECOG performance status.

Prior treatment with HDT/ASCT does not compromise the safety and efficacy of anti-CD19 CAR-T therapy, suggesting a continued role for HDT/ASCT in treatment of select patients with r/r DLBCL.

This study aims to compare the efficacy and safety of chimeric antigen receptor T-cell (CAR-T) immunotherapy with standard treatment for B-cell lymphoma, providing evidence-based support for the more efficient use of CAR-T cell immunotherapy.

We conducted a comprehensive literature search of high-quality randomized controlled trials (RCTs) on CAR-T therapy for B-cell lymphoma in the following databases: Wanfang, Web of Science, CNKI, VIP database, and PubMed, up to February 2024. The outcome measures included objective remission rate (ORR), complete remission rate (CRR), and incidence of adverse reactions. Subgroup analysis was performed based on the differences in co-stimulatory domains. Meta-analysis was conducted using Review Manager 5.4 and Stata software.

A total of five RCTs involving 1670 patients were included in this meta-analysis. The results showed that the CAR-T treatment group had significantly higher ORR (RR: 1.47, 95% CI 1.23-1.76, I2 = 80%, p < 0.0001), CRR (RR: 2.19, 95% CI 2.16-3.79, I2 = 93%, p = 0.005), cytokine release syndrome (CRS) incidence (RR: 34.51, 95% CI 2.27-523.78, I2 = 98%, p = 0.01), neurotoxicity (NT) incidence (RR: 6.00, 95% CI 1.82-19.75, I2 = 80%, p = 0.003), neutropenia incidence (RR: 1.39, 95% CI 1.02-1.88, I2 = 93%, p = 0.03), leukopenia incidence (RR: 1.39, 95% CI 1.04-1.87, I2 = 61%, p = 0.03), and headache incidence (RR: 1.56, 95% CI 1.25-1.95, I2 = 34%, p < 0.0001) compared to the standard treatment group. Subgroup analysis based on co-stimulatory domains revealed that the 4-1BB subgroup had higher incidences of CRR, CRS, NT and leukopenia than the CD28 subgroup; however, the CD28 subgroup exhibited higher ORR and neutropenia than the 4-1BB subgroup.

CAR-T cell immunotherapy demonstrates superior efficacy compared to standard therapy in treating B-cell lymphoma. However, CAR-T treatment can lead to adverse reactions such as CRS and NT. Infusion of an appropriate dose of CAR-T cells (e.g., 100 × 106) may be a strategy to mitigate the risk of CRS and NT.

Older adults (OA) with DLBCL are a heterogenous population with suboptimal outcomes. In this review, we identify and address the unique challenges encountered in the care of OA with DLBCL. We elaborate on the role and limitations of current geriatric assessment (GA) tools and ways to incorporate fitness in therapeutic decision making. We suggest best practices to implement GA in routine practice and clinical trials. The most widely used tool is simplified GA (sGA) which categorizes patients into fit, unfit and frail groups. Patients who are fit benefit from full dose/curative approach, whereas consideration should be made to reduce the intensity of chemotherapy for unfit patients. Frail patients with DLBCL are a major unmet need without any satisfactory treatment options. Ongoing investigations combining novel therapies into chemotherapy-free regimens are underway with promising early results. In the relapsed/refractory (R/R) setting, anti-CD19 CAR-T cell therapy (CART) is now the standard of care for primary refractory disease or relapse within 12 months of completing therapy. Autologous stem cell transplant is still a consideration for fit OA with relapse >12 months after completing therapy. The recent approval of bispecific antibodies is a welcome advance that will greatly benefit OA not eligible for CART. Other regimens available for patients ineligible for CART or for those who experience progression post-CART include polatuzumab-rituximab±bendamustine, tafasitamab-lenalidomide, loncastuximab or chemotherapy-based approaches such as rituximab-gemcitabine-oxaliplatin. We discuss the changing paradigm in R/R DLBCL and spotlight emerging data from recent congresses that can improve outcomes in this vulnerable population.

Immune cells within the lymphoma tumor microenvironment promote immune evasion and are rational therapeutic targets. Alemtuzumab targets CD52 expressed on malignant B-cells and infiltrating nonmalignant T-cells. We evaluated the safety and efficacy of alemtuzumab with DA-EPOCH-R in 48 patients with relapsed/refractory aggressive B-cell lymphoma. Febrile neutropenia occurred in 18% of cycles and serious infections in 21% of patients. Responses were observed in 30 (62%) patients, including 12 (80%) patients with classical HL and 3 (75%) patients with T-cell/histiocyte-rich large B-cell lymphoma (THRLCL). Seventeen (35%) patients achieved complete responses, and 12 (25%) were bridged to consolidation. The 2-year progression-free survival (PFS) and overall survival were 22.1% (95% CI, 11.5-34.7%) and 45.2% (95% CI, 34.3-58.9%), respectively. The 2-year PFS for HL and THRLCL patients was 35% and 50%, respectively. Alemtuzumab can be safely combined with DA-EPOCH-R in relapsed/refractory aggressive B-cell lymphomas and can induce durable responses in patients with T-cell-rich microenvironments.

Time to progression is the strongest predictor of outcome in relapsed diffuse large B-cell lymphoma. Second-line treatment with chimeric antigen receptor (CAR) T-cell therapy is recommended for patients with progression within 12 months of first-line chemoimmunotherapy. In patients with late relapse, platinum-based chemotherapy followed by high-dose chemotherapy with autologous stem cell rescue is recommended. In second relapse, CAR T-cell or CD3xCD20 bispecific antibody therapy is recommended in eligible patients. Other treatment options are available for less fit patients. Specific recommendations are made on diagnostic immunohistochemistry, bendamustine use and bridging to CAR T-cell therapy.

Primary mediastinal B-cell lymphoma (PMBCL) is a distinct subtype of large B-cell lymphoma with unique clinical, histopathological, and molecular characteristics. Despite its aggressive nature, PMBCL has a high cure rate when managed appropriately. Advances in the understanding of PMBCL biological characteristics, coupled with improvements in diagnostic tools and therapeutic approaches, have significantly improved patient outcomes in recent years. In this article, we present a set of pragmatic guidelines developed by the Lymphoma Study Association (LYSA) for the management of PMBCL. These guidelines address key aspects of diagnosis, staging, response evaluation, and treatment, integrating the latest evidence from clinical trials, expert consensus, and real-world practice. The aim of the guidelines is to provide clinicians with a clear, practical framework to optimize care for patients with PMBCL, ensuring that the best available evidence is translated into clinical practice.

Diffuse large B cell lymphoma (DLBCL) presents a great challenge in the clinic due to its poor prognosis. Prior research has identified c-Myc as a promising therapeutic target in DLBCL; however, direct targeting of c-Myc protein has proven challenging. The bromodomain and extraterminal (BET) protein family, which acts as transcriptional and epigenetic regulators, plays a crucial role in super-enhancer organization and transcriptional regulation of oncogenic drivers like c-Myc, offering an alternative approach. Recently developed BET proteolysis targeting chimera (PROTAC) compounds can rapidly and effectively degrade BET proteins and potentially offer a more durable effect than traditional BET inhibitors. In this work, we compared the anti-tumor activity of a BET PROTAC, ARV-825, with a BET inhibitor, JQ1, in DLBCL. Cell proliferation was assessed by CCK-8 assay, apoptosis was evaluated by Annexin V/PI staining, and the cell cycle was analyzed by staining DNA with propidium iodide (PI). Western blotting was used to determine the expression levels of BET family proteins and its downstream regulatory gene c-Myc, and the in vivo SCID mouse model implanted with SU-DHL-4 cells was used to analyze the in vivo drug efficacy. Our results showed that ARV-825 was superior to JQ1 in inhibiting DLBCL cell proliferation, inducing apoptosis, promoting cell cycle arrest, and prolonging survival. Notably, ARV-825 was more effective at downregulating c-Myc and BET protein levels than JQ1 in both in vitro and in vivo experiments. These evidences suggest that BET-PROTACs may offer a promising novel strategy for the clinical treatment of DLBCL.

Histone deacetylase inhibitors (HDACi) and combination chemotherapy are independently used to treat relapsed/refractory (R/R) lymphoma. In vitro studies suggest that the addition of HDACi to platinum-based chemotherapy is synergistic.

We conducted a phase I study of romidepsin, gemcitabine, oxaliplatin and dexamethasone (Romi-GemOxD) in R/R aggressive lymphomas with an expansion cohort in T-cell lymphomas. A total of 24 patients were enrolled with median age 70; 6 patients had diffuse large B-cell lymphoma (DLBCL) and 18 patients had peripheral T-cell lymphomas (PTCL-NOS: 10; angioimmunoblastic T-cell lymphoma [AITL]: 7; ALK-negative anaplastic large cell lymphoma: 1). Patients had received a median of 2 prior lines of therapy and 10 patients were refractory to last line of therapy.

Using a standard 3 + 3 dose escalation design, the maximum tolerated dose of romidepsin was determined to be 10 mg/m2 in combination with GemOxD. There were no unexpected toxicities. The most common grade ≥ 3 treatment-emergent adverse events were thrombocytopenia (79%) and lymphopenia (46%). The overall response rate for Romi-GemOxD was 52% (12/23) with complete response (CR) rate of 43% (10/23). All 6 patients with AITL evaluable for efficacy achieved CR. Durable responses were seen in patients with AITL, PTCL-NOS and DLBCL. Without additional therapy, 4 patients remained in remission for more than 2 years, with 3 patients progressing at 46.5, 30.8, and 32.6 months and 1 remission ongoing at 83 months. A total of 4 patients proceeded to consolidative stem cell transplant following induction.

Romi-GemOxD represents a well-tolerated, time-limited, effective option for patients, particularly for those with AITL in which durable responses were seen. NCT02181218.

While chimeric antigen receptor (CAR-T) targeting CD19 as second-line therapy for diffuse large B cell lymphoma (DLBCL) is a promising strategy, the high costs and limited access to CAR-T pose significant challenges. When assessing the cost-effectiveness of CAR-T, we need to consider not only individual outcomes but also how to effectively integrate CAR-T into the overall treatment approach for relapsed DLBCL. We conducted a cost-effective analysis for patients with DLBCL in early relapse or primary refractory, to compare "immediate CAR-T," which proceeds directly to CAR-T, and "late CAR-T," which initially aims at ASCT and quickly switches to third-line CAR-T if non-responsive. The primary analysis used a patient age of 60 years, and it also examined variations from 40 to 70 years. The analysis was performed for both Japanese and US settings using a Markov model incorporating life expectancy in both countries, with extensive sensitivity analysis including factors such as age, the choice of CAR-T (lisocabtagene maraleucel or axicabtagene ciloleucel), and the opportunity to receive third-line CAR-T, to reflect real-world situations. The length of a Markov cycle was defined to be 1 month, and patients in the model were assumed to age 1 year every 12 Markov cycles. The analysis was made over a lifetime horizon, and the outcome was measured based on incremental cost-effectiveness ratio (ICER), with willingness-to-pay (WTP) thresholds of ¥7,500,000 and $150,000 per quality-adjusted life years (QALY) in Japan and the US, respectively, with an annual discount rate of 3%. Compared with "late CAR-T," the "immediate CAR-T" strategy gained QALYs of 0.97 and 0.89 with an incremental cost of ¥5,998,354 and $88,440 in Japan and the US, respectively. The ICERs were ¥6,170,058/QALY in Japan and $99,596/QALY in the US. In the probabilistic sensitivity analysis for patients aged 60, "immediate CAR-T" was cost-effective in 54.8% and 61.7% of the 10,000 Monte Carlo iterations in Japan and the US, respectively. Sensitivity analyses showed that "immediate CAR-T" was not cost-effective when patients were over 68.4 in Japan, when the standardized mortality ratio of CAR-T and ASCT survivors was close, and when utility during treatment-free remission was low. Incorporating various clinical factors, the analysis showed that "immediate CAR-T" is more cost-effective than "late CAR-T." However, this conclusion should be interpreted with caution, as the ICERs were very close to the WTP thresholds, and the results were highly sensitive to parameter changes.

Histone deacetylase (HDAC) inhibitors demonstrated a synergistic anti-tumor effect with rituximab and chemotherapy in preclinical studies on diffuse large B-cell lymphoma (DLBCL). This phase 2 trial aimed to evaluate the efficacy and safety of chidamide, an orally active HDAC inhibitor, plus the R-GemOx regimen for relapsed/refractory (R/R) DLBCL.

Patients with transplantation-ineligible R/R DLBCL received chidamide (20 mg, oral, days 1, 4, 8, 11, 15, and 18), rituximab (375 mg/m2, day 1), gemcitabine (1000 mg/m2, day 2), and oxaliplatin (100 mg/m2, day 2) in a 21-day cycle for 6 cycles (induction phase), followed by chidamide (20 mg, oral, twice weekly on Mondays and Thursdays) until disease progression or intolerable toxicity (maintenance phase). The primary endpoint was overall response rate (ORR).

Between June 19, 2019 and July 5, 2022, 54 patients were enrolled. The ORR was 59.3% (95% CI: 45.0-72.4). With a median follow-up of 38.1 months (interquartile range: 19.5-48.2), the median progression-free survival and overall survival were 7.4 (95% CI: 5.2-14.2) and 23.9 (95% CI: 15.2-not reached) months, respectively. The most common grade 3/4 treatment-emergent adverse events (TEAEs) were neutropenia (40.7%), thrombocytopenia (33.3%), and leukopenia (27.8%). Whole-exome sequencing showed that CREBBP mutations and BTG2 mutations were associated with poor response and survival.

Chidamide plus R-GemOx demonstrated promising anti-tumor activity with acceptable toxicities in transplantation-ineligible R/R DLBCL patients. Patients with CREBBP mutations and BTG2 mutations had inferior response and survival.

ClinicalTrials.gov identifier: NCT04022005.

Diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) is the most common aggressive lymphoma and can be cured with CHOP-R immunochemotherapy in 60% of cases. The second-line therapy includes salvage regimens followed by autologous stem cell transplantation (ASCT), which offers a cure to a minority of patients due to limitations in efficacy and eligibility. These data present the unmet need in the field, and this review article focuses on how second-generation chimeric antigen receptor T (CAR T) cell therapy targeting CD19 antigen may improve the outcomes with relapsed/refractory DLBCL. In heavily pretreated patients, who have dismal outcomes with conventional therapy, all three approved products-tisangenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), and lisocabtagene maraleucel (liso-cel) have shown durable, unprecedented complete responses with the potential for cure. When compared to salvage regimens and ASCT as the standard of care, axi-cel and liso-cel, unlike tisa-cel, have demonstrated superiority in long-term control. In ASCT-ineligible r/r DLBCL, liso-cel has shown a favourable benefit-risk ratio. Regarding safety, two adverse events of interest have emerged: cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, both of which are manageable. Real-world evidence reflects the results of pivotal trials while favouring axi-cel in heavily pretreated patients, albeit with higher toxicity. The main barrier to the implementation of this treatment modality is the cost associated with the process of CAR T therapy, along with complications and reimbursement issues. However, the barriers can be overcome, and CAR T therapy has the potential to become the standard of care in relapsed/refractory DLBCL. Furthermore, with advances in the scientific engineering of CAR products and the understanding of novel treatment modalities currently being tested in clinical trials, we believe that targeted cellular therapy will become the future of relapsed/refractory DLBCL treatment.

Diffuse large B-cell lymphoma (DLBCL) presents considerable clinical challenges due to its aggressive nature and diverse clinical progression. New molecular biomarkers are urgently needed for outcome prediction. We analyzed blood samples from DLBCL patients and healthy individuals using short, non-coding RNA sequencing. A classifier based on six tsRNAs was developed through random forest and primary component analysis. This classifier, established using Cox proportional hazards modeling with repeated 10-fold cross-validation on an internal cohort of 100 samples analyzed using RT-qPCR, effectively identified high-risk patients with significantly lower overall survival compared to low-risk patients (Hazard ratio: 6.657, 95%CI 2.827-15.68, P = 0.0006). Validation in an external cohort of 160 samples using RT-qPCR confirmed the classifier's robust performance. High-risk status was strongly associated with disease histological subtype, stage, and International Prognostic Index scores. Integration of the classifier into the IPI model enhanced the precision and consistency of prognostic predictions. A dynamic study revealed that patients experiencing a 1.06-fold decrease after one therapy cycle (early molecular response) exhibited better treatment outcomes and prognosis. Furthermore, the 6-tsRNA signature accurately differentiated healthy individuals from DLBCL (AUC 0.882, 95%CI 0.826-0.939). These findings underscore the potential of the identified 6-tsRNA profile as a biomarker for monitoring treatment effectiveness and predicting DLBCL outcomes.

While the advent of chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of relapsed or refractory DLBCL, it is unclear how survival has changed at the population level following its approval. Herein, we performed a population-based cohort study using the SEER-17 database. The primary exposure was a period of diagnosis (2014-2017 vs. 2018-2021), and these periods were selected based on the first FDA-approval of CAR-T in 2017. Study outcomes were relative survival (RS), overall survival (OS), lymphoma-specific survival (LSS), and the cumulative incidence of death from lymphoma (CIF). A total of 51,584 patients with DLBCL were included in the study with 24,861 patients diagnosed in time period-1 (2014-2017) and 26,723 patients diagnosed in time period-2 (2018-2021). The median age at diagnosis was 68 years (interquartile range, 57-77) and most patients were White (n = 42,190, 82%) with advanced stage at diagnosis (n = 28,203, 55%). In unadjusted analysis, the 5-year RS (95% CI) increased from 64% from 2014 to 2017 to 66% from 2018 to 2021, while 5-year OS increased from 54 to 55%, and 5-year LSS increased from 64 to 66%. On competing risks analysis, the 5-year probability of death from lymphoma decreased from 34 to 31%. The improvements in survival were observed across age, disease stage, and racial groups, and remained significant when adjusting for age, sex, race, stage, B symptoms and documented receipt of chemotherapy in multivariable survival models (adjusted OS HR = 0.97, 95%CI = 0.94-1.00, p = 0.04; adjusted LSS HR = 0.93, 95%CI = 0.90-0.96, p < 0.001). We found improved survival for patients with DLBCL diagnosed between 2018 and 2021 when compared to those diagnosed between 2014 and 2017. These findings will serve as the benchmark for future studies evaluating the impact of CAR-T administered earlier in their disease course.

Interim 18F-FDG PET/CT (iPET/CT) imaging demonstrates potential in assessing the early therapeutic response in lymphoma. Nevertheless, the prognostic significance of interim PET-CT in diffuse large B-cell lymphoma (DLBCL) remains controversial. This study aimed to evaluate whether semi-quantitative PET/CT metabolic parameters and other metrics could enhance the prognostic value of interim PET/CT in DLBCL patients exhibiting partial metabolic remission (PMR).

A retrospective analysis was performed from January 2018 to December 2023, focusing on patients with DLBCL who achieved PMR on interim PET-CT. Patient demographics, clinical characteristics, and semi-quantitative PET/CT metabolic parameters were extracted from the medical records. Multivariate analyses were conducted to identify the risk factors associated with failure to achieve complete metabolic remission (CMR) at the end of treatment (EOT). Receiver operating characteristic (ROC) curve analysis was employed to determine the optimal cut-off values for continuous predictive variables. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods, and risk factors were evaluated using Cox regression models.

In a cohort consisting of 80 newly diagnosed DLBCL cases that exhibited PMR on interim PET scans, 50 cases ultimately achieved CMR, while the remaining 30 cases still had positive PET findings at EOT. Analysis revealed that the interim lesion-to-liver maximum standardized uptake value ratio (RLL) and bone marrow involvement were independent prognostic factors for positive PET-CT outcomes at EOT. Notably, an interim RLL threshold greater than 1.66 emerged as a reliable predictor with a sensitivity of 73.3% and a specificity of 72.0%. Additionally, the International Prognostic Index (IPI) and interim RLL were identified as independent prognostic indicators for both progression-free survival (PFS) and overall survival (OS).

Our study revealed that within the cohort of DLBCL patients exhibiting PMR on interim PET scans, an interim RLL greater than 1.66 and bone marrow involvement emerged as independent risk factors for positive PET results at the end of treatment. Additionally, the IPI and interim RLL were identified as independent prognostic markers for both progression-free survival and overall survival. The integration of clinical characteristics with semi-quantitative PET/CT parameters has the potential to enhance the prognostic role of interim PET/CT exhibiting PMR in DLBCL cases.

Secondary ion mass spectrometry (SIMS) using a gas cluster ion beam (GCIB), in this case 40 keV (CO2)7k+, was used to map the intact lipid signals across 14 lymph node samples representing diffuse large B-cell lymphoma (DLBCL), a common and aggressive form of lymphoma, and nonmalignant controls. The analysis allowed the samples to be classified as malignant or nonmalignant and also highlighted additional aggressive cancer signature in a DLBCL sample with an unusually high proliferation index. A complementary, combined k-means/image PCA approach was used to interrogate the data, highlighting the pros and cons of the different approaches and potential sources for misclassification/diagnoses resulting from the heterogeneity of the DLBCL samples. Compared to other cancer types, lymphoma results in a reduction of non-neoplastic inflammatory cells and their characteristic signals that are often classed as cancer-related, highlighting the need to consider disease heterogeneity when examining MS data. While delivering new information regarding the chemistry of lymphoma, the results also highlight the need for cellular precision with high chemical specificity and sensitivity, and the challenges associated with spectral/spatial classification of such complex samples and data where differently aggressive cancer samples show different signatures and pockets of different cell types, in this case histiocytes, can show intermediate cancer/healthy lipid profiles.

Treatment of relapsed or refractory aggressive B-cell lymphoma (aNHL) is still an unmet medical need. Platinum-containing salvage immunotherapies achieve remission rates of 40-60%. The phase I/II DSHNHL-R6 trial sought to investigate feasibility, safety and efficacy of R-DHAP plus lenalidomide in patients with first or subsequent relapse of aNHL. 33 patients were enrolled in the trial and could be analyzed (ITT). Lenalidomide dose was stepwise increased if no dose-limiting toxicities were observed. Maximum tolerated dose (MTD) for lenalidomide in combination with R-DHAP was 15 mg administered on days 1-7 of each cycle. The overall response rates (ORR; defined as complete, unconfirmed complete or partial remission; using the revised response criteria by CT) and complete response rates (CR) rates were 60.6% and 27.3% for the ITT-population and 81.3% and 50.0% in the patients treated as per protocol (PP). With a median follow-up of 13.9 months, the median OS was 21.2 months and PFS for the ITT and PP-population were 10.7 and 18.9 months respectively. No treatment related deaths were observed. Haematologic adverse events (77% grade 3-4) were common. Combining Lenalidomide with R-DHAP is an effective salvage therapy for patients with aNHL. Prolonged use of lenalidomide lead to more toxicities. (registered at www.clinicaltrialsregister.eu ; EudraCT number: 2009-010824-25; Start Date: 2010-04-12).

Clinical trials provide meaningful data regarding the safety and efficacy of novel therapies but there is often a lag between the time of new drug approval and information on posttreatment clinical outcomes in real-world practice. This study evaluated clinical outcomes in a large real-world population of patients with relapsed and/or refractory large B-cell lymphoma (r/r LBCL) treated with chemoimmunotherapy or novel therapies in second or later lines of therapy (2L+).

Data from the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real-World Evidence (CReWE) cohort (1/1/2015-2/15/2023) were analyzed. Patients' demographic and clinical characteristics were described and response rates, duration of response, progression-free survival, and overall survival were evaluated. Multivariable Cox proportional hazards regression models were used to assess associations between patient clinical characteristics and outcomes.

The 2L+ cohort included patients treated with chemoimmunotherapy (N = 593), lenalidomide-based therapy (n = 60), polatuzumab vedotin-based therapy (N = 116), tafasitamab-based therapy (N = 55), and loncastuximab tesirine (N = 42). Most patients who received prior chimeric antigen receptor T-cell therapy (CAR-T) were refractory to the treatment. Across all patients, overall response rates were <50%, with one-quarter achieving complete response and median duration of response and overall survival were short (<6 and <10 months, respectively) among patients treated with chemoimmunotherapy or novel therapies. The prognosis was worse for patients who had previously received CAR-T. Primary refractory status, high-risk disease, and failing 3 or more lines of therapy were significantly associated with worse outcomes.

Patients with r/r LBCL have unfavorable outcomes and need more effective treatment alternatives.

Allogeneic stem cell transplantation (alloSCT) represents a curative option for patients with relapsed/refractory (r/r) aggressive lymphomas. We compared outcomes of alloSCT in r/r PTCL and r/r DLBCL pts (n = 150) who underwent identical myeloablative conditioning chemotherapy, GvHD prophylaxis, and relapse management. 5-year PFS and OS were significantly superior in PTCL compared to DLBCL (56% vs. 24%; 56% vs. 28%; p ≤ 0.005). A landmark analysis (day≥ +100 post-alloSCT) markedly favored outcomes in PTCL vs. DLBCL: 5-year PFS and OS of 76% vs. 30% and 76% and 35%, respectively (p ≤ 0.003). Non-relapse mortality was comparable (35% PTCL vs. 34% DLBCL, p = 0.894), whereas post-alloSCT relapse mortality was significantly higher in DLBCL (36% vs. 10%, p = 0.0007). The occurence of limited chronic GvHD did not improve outcomes in DLBCL, whereas extensive chronic GvHD was a negative risk factor for both (HR 2.09 and 2.80, p ≤ 0.006). In conclusion, we gained evidence for strong graft-versus-lymphoma activity against PTCL but not DLBCL.

Since the 1990s, the standard of care for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) had been salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) in patients with a chemotherapy-sensitive remission. However, promising results from the recent TRANSFORM and ZUMA-7 trials evaluating the efficacy of CAR T-cell therapy versus HDT-ASCT for second line relapsed/refractory DLBCL have sought to challenge this standard of care. While these studies have established a new standard for the treatment of early relapsed and primary refractory DLBCL, significant differences in the trial design between these studies and limitations with the timing of randomization during the disease course warrant a thoughtful interpretation of the results. Additionally, the financial burden and logistic challenges of CAR T-cell administration and limited access to these therapies continue to be ongoing issues. Despite the encouraging results from these trials, HDT-ASCT continues to have a role in the treatment of DLBCL, especially in disease relapsing ≥12 months after initial therapy, and in chemo sensitive disease with a good response to salvage chemotherapy. Ongoing studies evaluating novel salvage regimens for use prior to HDT-ASCT, and future studies evaluating the role of CAR T-cell therapy in chemo sensitive disease will help determine the continued role of HDT-ASCT for relapsed/refractory DLBCL.

CD19-targeted chimeric antigen receptor (CAR) T cells have provided a breakthrough in the treatment of patients with relapsed and/or refractory large B cell lymphoma (LBCL). Currently, three CD19-targeted CAR T cell products are approved by the FDA and various other regulators for the treatment of patients with LBCL: axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel. Response rates following infusion of these CD19-targeted CAR T cells have been promising; however, approximately half of treated patients show relapse within 2 years. Furthermore, receiving these agents can be associated with serious toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. In this Review, we summarize the factors associated with the efficacy, including response and survival outcomes, and toxicity of CD19-targeted CAR T cells in pivotal clinical trials and large real-world datasets describing the outcomes of patients with LBCL who received treatment with these products.

Relapsed/refractory non-Hodgkin lymphoma (r/r/NHL) is an aggressive disease with overall poor response rates to chemo-immunotherapy and autologous stem-cell transplant, especially in patients with diffuse large B-cell lymphoma. Major improvements in this disease space have come through the incorporation of novel immune therapies, including CD19/CD20 directed CAR-T cells and bispecific antibodies. These exciting new therapies continue to change the landscape of treatment for r/r NHL and have been incorporated in earlier lines of therapy with demonstrated efficacy and patient safety. In this review, the role of these treatments in the management of relapsed/refractory NHL is discussed in detail along with future directions of research.

Treatment patterns and all-cause and diffuse large B-cell lymphoma (DLBCL)-related healthcare resource use (monthly incidence) and costs (per patient per month [PPPM]) were estimated among patients with incident DLBCL in US Optum's de-identified Clinformatics® Data Mart Database (October 2015-December 2020). Among 3664 patients, 2279 (62%) had ≥1 line (1 L), 409 (18%) had 2 L, and 99 (4%) had 3 L treatment. Rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, and prednisone were most common in 1 L (75%) and 2 L (23%), although multiple regimens were used in 2 L and 3 L. With increasing lines of therapy, treatment duration decreased while hospitalization rates increased. Mean DLBCL-related hospitalization costs PPPM increased with each line (1 L: $6028; 2 L: $10,708; 3 L+: $20,483), accounting for increasing proportions of total all-cause costs (1 L: 30%; 2 L: 38%; 3 L+: 56%). Thus, DLBCL poses a substantial economic burden with fewer therapeutic alternatives, especially during later lines, highlighting the need for more effective treatment options.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in humans, and it is a highly heterogeneous malignancy with a 40% to 50% risk of relapsed or refractory (R/R), leading to a poor prognosis. So early prediction of R/R risk is of great significance for adjusting treatments and improving the prognosis of patients.

We collected clinical information and H&E images of 227 patients diagnosed with DLBCL in Xuzhou Medical University Affiliated Hospital from 2015 to 2018. Patients were then divided into R/R group and non-relapsed & non-refractory group based on clinical diagnosis, and the two groups were randomly assigned to the training set, validation set and test set in a ratio of 7:1:2. We developed a model to predict the R/R risk of patients based on clinical features utilizing the random forest algorithm. Additionally, a prediction model based on histopathological images was constructed using CLAM, a weakly supervised learning method after extracting image features with convolutional networks. To improve the prediction performance, we further integrated image features and clinical information for fusion modeling.

The average area under the ROC curve value of the fusion model was 0.71±0.07 in the validation dataset and 0.70±0.04 in the test dataset. This study proposed a novel method for predicting the R/R risk of DLBCL based on H&E images and clinical features.

For patients predicted to have high risk, follow-up monitoring can be intensified, and treatment plans can be adjusted promptly.

Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) represent the two major subtypes of mature B cell lymphoma. A deeper understanding of tumor biology, as well as molecular classification characterized by targetable gene alterations, and the introduction of novel treatment options, including targeted drugs (e.g., antibody-drug conjugates and small molecules [e.g., Bruton tyrosine kinase inhibitor]) and immune therapies (e.g., chimeric antigen receptor [CAR] T cell therapy and bispecific antibody [BsAb]), has changed the treatment paradigms for DLBCL and FL. In clinical practice, however, treatment regimens are determined mainly based on prior treatment history, duration of response after previous treatment, patient age, and patient frailty because there have been few randomized trials to inform treatment selection for patients with relapsed or refractory disease and because there is no single prognostic index that guides suitable treatment for each patient. In this review, we summarize the treatment options for DLBCL and FL and discuss the treatment strategies for these two subtypes. We also discuss future perspectives for the treatment of these subtypes.

Despite advances in treatment, approximately 15% of patients with diffuse large B-cell lymphoma (DLBCL) who achieve complete remission (CR) after first-line therapy will experience a relapse. However, there is no consensus on the optimal follow-up strategies for detecting relapse after achieving CR. This population-based study, based on the Danish Lymphoma Registry (LYFO), identified a total of 1634 patients diagnosed with DLBCL between 2010 and 2017, including 105 patients who achieved CR following first-line R-CHOP-like therapy and subsequently relapsed. The median follow-up time was 6 years (range 3-8 years). Most cases of relapse were symptomatic (83%), with B symptoms and peripheral lymphadenopathy being the most common. Asymptomatic relapses were identified through physical examination (1%), blood tests (3%), or imaging findings (13%). The proportion of relapses identified outside routine visits was 70%. Only 5% of scheduled routine visits led to a relapse diagnosis, whereas 74% of unscheduled visits initiated by the patient outside routine follow-up resulted in relapse detection. Our findings highlight that systematic, scheduled monitoring of patients in remission after first-line treatment contributes only modestly to the early detection of disease recurrence. Future studies should explore alternative methods of relapse surveillance rather than relying solely on pre-scheduled clinical follow-up.

CAR-T cell therapy has significantly improved outcomes for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but challenges such as limited resources, manufacturing timelines, and notable toxicities persist. Bispecific antibodies (BsAbs), including glofitamab and epcoritamab, have demonstrated promising efficacy and represent a new treatment option in patients who are unsuitable for or have relapsed following CAR-T therapy. Bispecific antibodies have a manageable safety profile and are generally more widely accessible than CAR-T cell therapy. Case discussions in this paper illustrate the potential real-world application of BsAbs, highlighting their role in treating patients who have relapsed after or are unable to undergo CAR-T cell therapy. Overall, glofitamab and epcoritamab represent valuable treatment options in the evolving landscape of R/R DLBCL.

Secondary central nervous system lymphoma (SCNSL) is a rare manifestation of diffuse large B-cell lymphoma (DLBCL) with a poor prognosis. We present updated data from a nationwide study on the incidence and clinical characteristics of SCNSL. The incidence of SCNSL was calculated considering death or relapse without SCNSL as competing risks. Risk factors associated with SCNSL were identified using a cause-specific Cox proportional hazards model. A total of 1972 patients with DLBCL were included, of which 68 (3.4%) experienced SCNSL at the first relapse. The crude 1- and 2-year cumulative incidence of SCNSL was 2.0% (95% confidence interval [CI], 1.5-2.7) and 2.6% (95% CI, 2.0-3.4), respectively. For patients with a high-risk central nervous system international prognostic index (CNS-IPI) score, the 1- and 2-year cumulative incidence was 6.4% and 7.5%, respectively. The number and location of extranodal (EN) sites were the most significant predictors of SCNSL. Specific EN sites associated with an increased risk were the bone marrow, heart, kidneys/adrenal glands, ovaries, testes, and uterus. The median overall survival (OS) after SCNSL was 3.2 months. SCNSL within 6 months after the end of treatment (EOT) was associated with a higher baseline CNS-IPI score and worse OS than SCNSL >6 months after EOT. Patients with a combination of low-risk CNS-IPI and late-onset SCNSL had the most favorable prognosis. In conclusion, updated real-world population-based data on SCNSL at first relapse, adjusted for competing risks, demonstrated a lower incidence of SCNSL than previously reported, with the number and location of EN sites being the most significant predictors of SCNSL.

Relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy remains a major challenge in B-cell acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma (B-NHL). One of the main strategies to avoid CD19-negative relapse has been the development of dual CAR T cells targeting CD19 and an additional target, such as CD22 or CD20. Different methods have been used to achieve this, including coadministration of 2 products targeting 1 single antigen, cotransduction of autologous T cells, use of a bicistronic vector, or the development of bivalent CARs. Phase 1 and 2 trials across all manufacturing strategies have shown this to be a safe approach with equivalent remission rates and initial product expansion. CAR T-cell persistence remains a significant issue, with the majority of relapses being antigen-positive after CAR T-cell infusion. Further, despite adding a second antigen, antigen-negative relapses have not yet been eliminated. This review summarizes the state of the art with dual-targeting CAR T cells for B-cell ALL and B-NHL, the challenges encountered, and possible next steps to overcome them.

Monitoring quality of healthcare is vital to ensure that changes made to clinical practice achieve the intended goals. Assessing temporal trends due to the accumulated effect of all changes in clinical practice in a given period is essential in quality monitoring. However, this assesment is compplicated by the fact that numerous of changes might occour over time unrelated to the clinical practice. Furthermore, the methods used to assess temporal trends in patient outcomes in the medical literature are heterogeneous, making it difficult to compare results between studies. In this paper, we describe methods that enable researchers to investigate temporal trends in survival data and we discuss their pros and cons. Numerous unrelated changes may occur over time which must be taken into account and disentangled when assessing the improvement in clinical management. The methods and interpretation thereof are exemplified on patients with diffuse large B-cell lymphoma from the Danish lymphoma registry.

Over the past decade, drug shortages have become increasingly more problematic for clinicians, with over 300 drug shortages reported in the first quarter of 2023. Shortages of chemotherapy drugs can have a negative impact on patient care, as omission or delay of treatment can lead to worse outcomes. Although many articles have been published on this topic, currently no review articles discuss strategies for using alternative regimens or substitutions in the event of severe chemotherapy drug shortages.

In this article, we review the literature on antineoplastic agents used to treat hematologic malignancies that experienced a drug shortage from 2010 through 2023, providing recommendations for substitutions and alternative regimens in the event of a critical shortage. In particular, we discuss how shortages of fludarabine, cytarabine, daunorubicin, methotrexate, and platinum agents may be addressed, including supporting clinical evidence.

Further publications assessing possible alternatives and substitutions for chemotherapy agents and examining the efficacy of previous strategies are needed to mitigate potentially devastating interruptions to care for patients with cancer during severe drug shortages.

Primary mediastinal large B-cell lymphoma (PMLBCL) is a rare, aggressive B-cell lymphoma, sharing common features with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). PMLBCL is usually cured with single-hit immunochemotherapy in the first-line setting. Relapses tend to be aggressive and may be unresponsive to conventional chemotherapy. Autologous stem cell transplant (ASCT) remains a viable option for chemosensitive patients; nevertheless, targeted therapies appear to be highly promising. Checkpoint inhibitors (CPIs) have already transformed the course of relapse/refractory disease, while CD-19-directed Chimeric Antigen Receptor (CAR) T-cell therapy may produce remarkably favorable outcomes. The exact position of CAR T-cells and CPIs in the treatment algorithm, along with the role of radiotherapy and ASCT, remains to be precisely determined. In the current review, we aim to present the recent research on targeted agents in PMLBCL and define their sequencing within the treatment algorithm, mainly in the relapse/refractory setting.