Bulky Disease Research Articles

Loncastuximab in high-risk and heavily pretreated relapsed / refractory diffuse large B-cell lymphoma: a real-world analysis from 21 US centers.

Outcomes in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor. Loncastuximab-teserine (Lonca) is an antibody drug conjugate (ADC) which was FDA approved for R/R DLBCL patients who have received at least 2 prior lines of therapy based on the LOTIS-2 trial. However, there are limited data regarding its efficacy in the real-world setting (RWS). This retrospective study included 21 US centers and evaluated outcomes of patients with R/R DLBCL treated with Lonca. Our analysis includes 187 patients with notably higher risk baseline features compared to LOTIS-2 including a higher proportion of patients with bulky disease (17% vs 0%), high-grade B-cell histology (HGBL) (22% vs 8%), and increased number of prior lines of therapy (median 4 vs 3). The complete response (CR) rate was 14% and overall response rate (ORR) was 32%. Median event free (EFS) and overall survival (OS) were 2.1 and 4.6 months, respectively. Those with bulky disease and HGBL had significantly worse outcomes, and those with non-germinal center cell of origin and CR to most recent line of therapy demonstrated superior outcomes. In summary, in this largest retrospective cohort study of Lonca in the RWS, the response rates, EFS, and OS were lower than those reported in LOTIS-2, which is likely reflective of its use in higher risk and more heavily pre-treated patients within the real world compared to those enrolled on clinical study.

Clinical study of immune-targeting combined with attenuated chemotherapy in the treatment of children with classic Hodgkin lymphoma

Objective: To evaluate the efficacy and safety of brentuximab vedotin (BV) combined with rituximab and attenuated chemotherapy in the treatment of children with classic Hodgkin lymphoma (cHL). Methods: A prospective, non-randomized, risk-assigned study. Clinical data (including age, gender, B symptoms, bulky disease, CD30 and Epstein-Barr virus-encoded RNA(EBER) expression, clinical stage, risk stratification, etc.) of 28 intermediate to high-risk cHL children diagnosed and treated at Beijing Children's Hospital Affiliated to Capital Medical University from October 2022 to May 2024 were collected. Immuno-targeted combined with attenuated chemotherapy was administered based on risk stratification and early treatment response. The patients were followed up until May 1st, 2024. The infusion reactions and adverse reactions after treatment were recorded. Results: In all 28 patients, there were 22 males and 6 females, the age was 12 (5,16) years, 16 cases (57%) presented with bulky disease and 10 cases (36%) with B symptoms. The most common pathological type was nodular sclerosis (14 cases, 50%). There were 7 cases of stage Ⅱ, 14 cases of stage Ⅲ and 7 cases of stage Ⅳ according to the Ann Arbor staging system. There were 5 cases in the intermediate-risk group and 23 cases in the high-risk group. EBER was positive in 20 cases (71%) and negative in 6 cases (21%), and CD30 antigen was expressed in tumor cells of all enrolled children. Treatment duration: 5 cases (18%) received 4 courses of treatment, 21 cases (75%) received 6 courses of treatment, and 2 cases (7%) received 8 courses of treatment, 25 cases (89%) achieved complete metabolism response (CMR) through early assessment after 2 courses of chemotherapy. The CMR rates were 100% in intermediate-risk group and 87% in high-risk group, respectively. Four patients (14%) finally received residual field radiotherapy. Toxicities included grade Ⅰ-Ⅱ myelosuppression, early infusion reaction and mild peripheral neuropathy, only one case of grade 3 adverse events was recorded and did not affect sequential treatment. At the end of treatment and 3 months of follow-up, the levels of IgA, IgG and IgM were all decreased compared with the baseline before chemotherapy, and the total B cell count began to be lower than the level before chemotherapy at the early stage of treatment (after 2 courses). The total B cell count monitored during treatment was 50 (0, 101)×106/L and was 12 (0, 25)×106/L at the end of treatment. The follow-up time was 6 (3, 13) months, all 28 children had event-free survival and all achieved complete remission. At 6 and 9 months of follow-up, IgA, IgG, IgM and total B cell counts returned to pre-chemotherapy baseline levels, respectively. Conclusion: BV combined with rituximab attenuated chemotherapy has demonstrated efficacy and a tolerable safety profile in the treatment of cHL in children, and significantly reduce radiation rate.

External validation and calibration of the HoLISTIC Consortium's advanced-stage Hodgkin lymphoma international prognostic index (A-HIPI) in the Brazilian Hodgkin lymphoma registry.

The Hodgkin lymphoma International Study for Individual Care (HoLISTIC) Consortium's A-HIPI model, developed in 2022 for advanced-stage classical Hodgkin lymphoma (cHL), predicts survival within 5 years amongst newly diagnosed patients. This study validates its performance in the Brazilian Hodgkin lymphoma registry. By 2022, the Brazilian HL registry included 1357 cHL patients, with a median 5-year follow-up. Probabilities for 5-year progression-free survival (PFS) and overall survival (OS) were calculated using A-HIPI-model equations. Discrimination (Harrell C-statistic/Uno C-statistic) and calibration measures assessed external validation and calibration. Lab values beyond the allowed range were excluded, mirroring the initial A-HIPI analysis. A total of 694 advanced-stage cHL patients met the original inclusion criteria (age 18-65 years, Stage IIB-IV). Median age was 31 years; 46.3% were females. Stage distribution was IIB (33.1%), III (27.4%), IV (39.5%). Bulky disease in 32.6%. Five-year PFS and OS were 68.4% and 86.0%, respectively. Harrell C-statistics were 0.60 for PFS and 0.69 for OS, and Uno C-statistics were 0.63 for PFS and 0.72 for OS. Calibration plots demonstrated well-calibrated predictions with calibration slopes of 0.91 and 1.03 for 5-year OS and PFS, respectively. Despite differing patient, clinical characteristics, and socioeconomic factors, the baseline prediction tool performed well in the Brazilian cohort, demonstrating adequate discrimination and calibration. This supports its reliability in diverse settings.

Reduced Intensity Conditioning Prior Autologous Stem Cell Transplantation in Elderly DLBCL Patients.

High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is widely used in patients with diffuse large B-cell lymphoma. HDCT/ASCT is associated with increased morbidity in elderly/unfit patients. We retrospectively evaluated the use of reduced intensity conditioning in DLBCL patients. Our study included 146 patients aged 60 years and older treated at our institution between 2005 and 2019; 86 patients received standard intensity conditioning (SI group) with BEAM or TEAM (BCNU or thiotepa, etoposide, cytarabine, melphalan). Sixty patients received reduced intensity high-dose conditioning (RI group) with BM (BCNU, melphalan, 43.3%), TM (thiotepa, melphalan, 16.7%), BCNU or busulfan thiotepa (38.4%), or bendamustine melphalan (1.7%). Median follow-up was 62.4 months. We observed comparable toxicities in the SI and RI groups. The cumulative incidence of relapse at 3 years was higher in the RI group (30.8% vs. 23.4%, p = 0.034). There was no difference in nonrelapse mortality (NRM). In univariate analyses, SI vs. RI conditioning resulted in superior progression-free survival (PFS) (HR 1.80 CI 1.11-2.92, p = 0.017) but not in superior overall survival (OS) (HR 1.48 CI 0.86-2.56, p = 0.152). On multivariate analysis, we observed no difference in PFS (HR 0.74 CI 0.40-1.38, p = 0.345) and a trend toward better OS with RI conditioning (HR 0.45 CI 0.22-0.94, p = 0.032). Age 60-69 versus ≥ 70 years and remission prior to ASCT were the only factors predicting better PFS. Factors associated with better OS were RI conditioning, age 60-69 versus ≥ 70 years, ECOG 0 versus ≥ 1 performance status, bulky disease, and prior lines 1 versus ≥ 2. In conclusion, RI conditioning prior to ASCT may be feasible in elderly patients and led to a comparable outcome when corrected for several significant confounders.

DA-R-EPOCH May Mitigate the Adverse Prognostic Implication of the Diagnosis-to-Treatment Interval (DTI) in Large B-Cell Lymphomas

BackgroundShort diagnosis-to-treatment interval (DTI) is associated with high-risk disease and poor survival in diffuse large B-cell lymphoma (DLBCL). There is a paucity of literature on DTI and survival in DLBCL treated with first-line DA-R-EPOCH. We hypothesized that rapid initiation of DA-R-EPOCH in aggressive and high-risk DLBCL mitigates the adverse prognostic implication of short DTI. Patients and MethodsWe retrospectively examined the association of DTI, categorically (short DTI ≤ 14 and long > 14 days) and continuously, with clinical features and survival outcomes in DLBCL treated with first-line DA-R-EPOCH at our institution. ResultsA total 190 patients were analyzed, 21% with high-grade DLBCL subtypes, 56% IPI ≥ 3, and median DTI of 13 days. The short DTI cohort contained more patients with IPI ≥ 3, bulky disease, and elevated LDH. When analyzed categorically and continuously, DTI was not associated with significant differences in PFS or OS. There was significant multivariable interaction between bulky disease, DTI, and PFS (P = .033), with improved PFS in patients with bulky disease in the short DTI cohort. ConclusionWe found that negative prognostic implications of DTI are mitigated in DLBCL patients treated with first-line DA-R-EPOCH, suggesting that urgent initiation of DA-R-EPOCH in high-risk DLBCL, including bulky disease, may improve survival. Our study's shorter DTI compared with DTIs reported in prospective DLBCL trials highlights DTI as a marker of external validity in clinical trial results. Future trials should implement protocols encouraging shorter, realistic DTIs to avoid selection bias against high-risk patients who are unable to delay treatment.

Oncologic and Perioperative Outcomes of Robot-Assisted Versus Conventional Laparoscopy for the Treatment of Clinically Uterine-Confined High-Grade Adenocarcinoma.

The aim of this study was to compare oncologic and perioperative outcomes of robot-assisted laparoscopy (RA) and conventional laparoscopy (LSC) in apparent clinically uterine-confined, high-grade adenocarcinoma. A retrospective review was conducted to identify patients with newly diagnosed high-grade uterine adenocarcinoma treated at our institution between 1 January 2009 and 30 June 2021. Exclusion criteria included bulky extrauterine disease, no lymph node assessment, or synchronous tumors. Clinicopathologic details were obtained from medical records. Postoperative complications were classified using the Memorial Sloan Kettering Cancer Center Surgical Secondary Events system, and statistical analysis was performed using appropriate tests. Of 901 patients identified, 748 (83%) underwent RA and 153 (17%) underwent LSC. Median age was 65 years (range 25-92) and median body mass index was 30 kg/m2 (range 15-60). Overall, 650 patients (72%) had 2009 International Federation of Obstetrics and Gynecology (FIGO) stage I disease. Forty-one patients (4.6%) converted to laparotomy-26 (3.5%) from RA versus 15 (9.8%) from LSC (p=0.02). Postoperative complications occurred in 81 patients (9.0%), with no significant differences in type or rate between groups. Median operative time was 192mins (range 88-936) for RA versus 168 mins (range 90-372) for LSC (p=0.002). Median follow-up was 52 months (range 1-163) for RA and 66 months (range 7-165) for LSC. Four-year progression-free survival (PFS) and disease-specific survival (DSS) were similar between groups. Multivariate analysis showed stage, histology, peritoneal cytology, and lymphovascular invasion predicated a decrease in PFS and DSS. RA demonstrated comparable oncologic outcomes to LSC in patients with high-grade endometrial carcinoma, with no significant difference in postoperative complications or long-term survival.

Contralateral submental artery island flap for oral tongue reconstruction — a retrospective study in patients with oral tongue squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is a leading cause of cancer-related death in developing countries. The oral tongue is the most common site involved by OSCC. About a third of the patients have neck nodal metastasis at presentation. Reconstruction of the oral tongue after resection for cancer is necessary for proper rehabilitation. For patients who are medically unfit for prolonged surgery like a free tissue transfer, local flaps are employed for tongue reconstruction. The submental flap is a popular option. However, when there is extensive floor of mouth involvement or bulky nodal disease in ipsilateral level 1, harvesting the submental flap based on contralateral facial vessels is possible, without compromising oncological safety. We discuss the feasibility and outcomes of contralateral submental artery island flap for reconstruction after resection of oral tongue carcinoma in a retrospective series of 34 patients followed up for a median of 8.5 months. ResultsOf the 34 oral tongue cancer patients in the study, 16 had neoadjuvant chemotherapy prior to surgery. 33 underwent bilateral neck dissection. Two patients had partial flap loss which was managed conservatively. There were five patients who had either locoregional or distant recurrence, none in the flap site. Three had pathological positive nodes at contralateral level 1b and two had pathologically positive nodes in contralateral level 1b. Tongue motility and speech intelligibility were satisfactory on follow-up. ConclusionIn the properly selected patient, the contralateral submental artery island flap offers an oncologically safe and technically simpler alternative for free flap reconstruction.

Characterization of lymphopenia and correlating the risk of cytopenias with dose and BM volume irradiated in aggressive B-cell lymphoma patients bridged with radiation therapy for CAR-T cell therapy

IntroductionThe impact of bridging radiation therapy (bRT) for CAR T-cell therapy on absolute lymphocyte count (ALC) kinetics and treatment outcome is unknown. MethodsWe retrospectively reviewed adults with relapsed/refractory aggressive large B-cell lymphoma (LBCL) who received bRT prior to CD-19 CAR-T between 11/2017-4/2023. The change in ALC (ALC Δ RT) was computed by subtracting ALC pre- and post-bRT. Percent bone marrow (%BM) irradiated was calculated by estimating skeletal BM distribution. PFS, DSS, and OS were modeled via Kaplan-Meier. ResultsFifty-one patients received bRT, of which 13 (25.5%) had bulky disease (≥7.5cm). The median bRT dose was 30Gy (range: 4-48Gy); 26 patients (51%) received ≥30Gy. Thirty-one patients (61%) received bRT comprehensively to all disease sites. The median cumulative %BM irradiated was 5.05% (range: 0-50%). At a median follow-up of 10.3 months (95% CI: 7.7-16.4), the 1-year OS, PFS, and DSS rates were 80% (95% CI: 66-99), 78% (64-87), and 82% (68-90), respectively. The incidence of ≥Grade 3 lymphopenia was 33% pre-RT and 68% post-RT, but recovered to 43% at the conditioning chemotherapy (CC) timepoint. There was no correlation between post-RT Grade ≥3 lymphopenia and the receipt of comprehensive bRT, combined modality bridging, ≥30Gy bRT, or bRT to ≥15% of BM (all p>0.2). Among patients with Grade 0-2 lymphopenia pre-RT, increased conversion to Grade ≥3 lymphopenia post-RT correlated with comprehensive or ≥30Gy bRT, but these factors did not impair ALC recovery at CC. There was no association between ALC Δ RT or post-RT ALC with 30 or 90 day response (p>0.25), DSS, PFS, or OS (p>0.3). ConclusionsLymphocyte change during bRT is not associated with CAR-T outcomes. Persistent cytopenia risk following bRT is not associated with bRT to ≥30Gy, ≥15% of BM, or comprehensive coverage. While bRT can be delivered safely, we urge careful treatment planning when incorporating into pre-CAR-T regimens.

Radical neck dissection

Radical neck dissection was originally developed as an “en bloc” lymphadenectomy technique for malignancies of the head and neck and is sometimes utilized in current management for bulky disease not otherwise amenable to preservation therapy and for salvage disease. Although the majority of neck dissections are no longer radical, optimal technique is important as is the understanding of postoperative care. Historic and current literature was reviewed in order to provide the most up-to-date descriptions and considerations when performing this operating. Surgical technique is described as well as modern indications and contraindications. Common complication and options for minimizing postoperative morbidities are discussed. While the paradigm for en bloc resection of head and neck malignancy has changed, radical neck dissection remains a useful tool in the armamentarium of the contemporary head and neck surgeon for select cases.

Novel prognostic scoring systems for severe CRS and ICANS after anti-CD19 CAR T cells in large B-cell lymphoma

Autologous anti-CD19 chimeric antigen receptor (CAR) T cells are now used in routine practice for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Severe (grade ≥ 3) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are still the most concerning acute toxicities leading to frequent intensive care unit (ICU) admission, prolonging hospitalization, and adding significant cost to treatment. We report on the incidence of CRS and ICANS and the outcomes in a large cohort of 925 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in France based on patient data captured through the DESCAR-T registry. CRS of any grade occurred in 778 patients (84.1%), with 74 patients (8.0%) with grade 3 CRS or higher, while ICANS of any grade occurred in 375 patients (40.5%), with 112 patients (12.1%) with grade ≥ 3 ICANS. Based on the parameters selected by multivariable analyses, two independent prognostic scoring systems (PSS) were derived, one for grade ≥ 3 CRS and one for grade ≥ 3 ICANS. CRS-PSS included bulky disease, a platelet count < 150 G/L, a C-reactive protein (CRP) level > 30 mg/L and no bridging therapy or stable or progressive disease (SD/PD) after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 CRS. ICANS-PSS included female sex, low level of platelets (< 150 G/L), use of axi-cel and no bridging therapy or SD/PD after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 ICANS. Both scores were externally validated in international cohorts of patients treated with tisa-cel or axi-cel.

Anti-CD19 CAR-T Cell Therapy in Elderly Patients: Multicentric Real-World Experience from GETH-TC/GELTAMO

Chimeric antigen receptor (CAR)-T cell therapy is approved for the treatment of relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, elderly patients might not be candidates for this therapy due to its toxicity, and criteria for candidate selection are lacking. Our aim was to analyze efficacy and toxicity results of CAR-T cell therapy in the population of patients 70 years and older as compared to those obtained in younger patients in the real-world setting. A multicentric retrospective study was performed including patients with R/R aggressive LBCL who received commercial CAR-T cell therapy with either tisagenlecleucel or axicabtagene ciloleucel within the Spanish Group of Hematopoietic Transplant and Cell Therapy/Spanish Group of Lymphomas and Autologous Transplant (GETH-TC/GELTAMO) centers between 2019 and 2023. As of August 2023, 442 adult patients with aggressive LBCL underwent apheresis for CAR-T cell therapy as third or subsequent line and follow-up data was collected. Of 412 infused patients, 71 (17%) were 70 years or older. Baseline characteristics, product selection, and characteristics at apheresis (including disease status, Ann Arbor stage, revised international prognosis index (R-IPI), bulky disease, lactate dehydrogenase [LDH] and ECOG [Eastern Cooperative Group performance status]) were comparable between groups. Median time from both approval to infusion and apheresis to infusion did not differ. No differences were found between groups in overall and complete response rates at 1 and 3 months. With a median follow-up of 12.2 months (range 1-44), 12-month progression-free survival (PFS) and overall survival (OS) were comparable between groups (35.2% in <70 years vs. 35.9% in ≥70 years (P = .938) and 51.1% and 52.1% (P = .885), respectively). Age ≥70 years did not affect PFS (hazard ratio (HR) 0.98, P = .941) and OS (HR 0.97, P = .890) in the univariate and multivariate analysis. Cytokine release syndrome (CRS) was observed in 82% of patients <70 years old and 84.5% in ≥ 70 years old (P = .408). Grade ≥3 CRS was more frequent in the older group (5% vs. 15%, P = .002). In the multivariate analysis, age ≥70 years was associated with an increased risk of grade ≥3 CRS (OR 3.7, P = .013). No differences were observed in terms of overall neurotoxicity (35% vs. 42%, P = .281) or grade ≥3 (12% vs. 17%, P = .33). The proportion of patients with infections, admission to the intensive care unit within the first month, and non-relapse mortality were similar between both groups. CAR-T cell therapy in patients older than 70 years showed similar efficacy to that observed in younger patients in the real-world setting. However, age ≥70 years was an independent risk factor for grades 3-4 CRS. The need for additional strategies to reduce toxicity in this population should be addressed in future studies.

Response-Based Approach for Pediatric Hodgkin Lymphoma in Nations with Restricted Resources.

Background: Hodgkin lymphoma (HL) management varies throughout developing nations. This observational study aims to present the results of children having HL who received various combinations of chemotherapy treatment. The response-based method was used regardless of the risk classification. Materials and Methods: We recruited patients≤ 18 years of age diagnosed with HL in an Iraqi cancer center between January 2014 and December 2021. By stratifying patients, three risk categories were identified. Every patient initially received two cycles of ABVD as induction chemotherapy. Following induction chemotherapy, patients showing a full radiological response continued on ABVD chemotherapy for 4-6 cycles without receiving radiotherapy. Patients showing a modest initial response received three additional courses of COPDac next to the third cycle of ABVD, followed by radiotherapy. Results: This study included fifty-nine patients with a median age of 7 years. Stage III patients accounted for 33.9% (n=20), then stage II (32.2%). B symptoms were present in 25 patients. Eleven children had initial splenic involvement. Fifty-two individuals (n = 19; 32.2%) had bulky disease. Mixed cellularity was the most prevalent histology (n=44). The median duration of follow-up was 2.7 years. EFS was 78% ±10%, and survival was 92% at 5-year estimation. Bulky disease was the only factor with a substantial unfavorable impact on the result. Conclusion: Response-based approach is a valuable strategy in nations with limited resources to prevent long-term sequelae from unnecessary radiotherapy.

Baseline 18F-FDG PET/CT may contribute to the determination of initial treatment strategy for newly diagnosed follicular lymphoma

Background“Watch-and-wait” approach is an important management option in asymptomatic follicular lymphoma (FL) patients with low tumor burden. Since most FL lesions are FDG-avid, we wonder if 18F-FDG PET/CT at baseline can help to better choose the patients who can benefit from early chemotherapy. This study aimed to investigate the prognostic value of baseline 18F-FDG PET/CT in newly diagnosed FL patients treated with either watch-and-wait approach or chemotherapy. ResultsPatients received chemotherapy as initial treatment had higher Ann Arbor stage, higher incidence of extranodal involvement and bulky disease, more involved lymph nodes larger than 3 cm, and higher SUVmax, MTV, and TLG than those managed with watch-and-wait approach (p < 0.05). The median PFS and TTNT in patients received chemotherapy and under watch-and-wait did not show significant difference, however patients with MTV<111.66 mL or TLG<141.50 SUVbw*mL had significantly longer PFS and TTNT than those patients with MTV≥111.66 mL or TLG≥141.50 SUVbw*mL (p < 0.05). Further analysis revealed that for patients with TLG≥141.50 SUVbw*mL or MTV≥111.66 mL, those who received chemotherapy as initial treatment had a significantly longer PFS and TTNT than those managed with initial watch-and-wait approach (p < 0.05). However, for patients with MTV<111.66 mL or TLG<141.50 SUVbw*mL in baseline PET/CT, there was no significant difference in PFS or TTNT between patients who received chemotherapy and those under watch-and-wait. ConclusionBaseline 18F-FDG PET/CT may provide prognostic value and help to improve the decision-making of initial treatment plans for newly diagnosed FL patients.

Prognosis Prediction of Diffuse Large B-Cell Lymphoma in 18F-FDG PET Images Based on Multi-Deep-Learning Models.

Diffuse large B-cell lymphoma (DLBCL), a cancer of B cells, has been one of the most challenging and complicated diseases because of its considerable variation in clinical behavior, response to therapy, and prognosis. Radiomic features from medical images, such as PET images, have become one of the most valuable features for disease classification or prognosis prediction using learning-based methods. In this paper, a new flexible ensemble deep learning model is proposed for the prognosis prediction of the DLBCL in 18F-FDG PET images. This study proposes the multi-R-signature construction through selected pre-trained deep learning models for predicting progression-free survival (PFS) and overall survival (OS). The proposed method is trained and validated on two datasets from different imaging centers. Through analyzing and comparing the results, the prediction models, including Age, Ann abor stage, Bulky disease, SUVmax, TMTV, and multi-R-signature, achieve the almost best PFS prediction performance (C-index: 0.770, 95% CI: 0.705-0.834, with feature adding fusion method and C-index: 0.764, 95% CI: 0.695-0.832, with feature concatenate fusion method) and OS prediction (C-index: 0.770 (0.692-0.848) and 0.771 (0.694-0.849)) on the validation dataset. The developed multiparametric model could achieve accurate survival risk stratification of DLBCL patients. The outcomes of this study will be helpful for the early identification of high-risk DLBCL patients with refractory relapses and for guiding individualized treatment strategies.

Anti-CD19 chimeric antigen receptor T-cell therapy in older patients with relapsed or refractory large B-cell lymphoma: A multicenter study.

Chimeric antigen receptor T-cell (CAR-T) therapy, despite being a potentially curative therapy in relapsed or refractory (RR) large B-cell lymphoma (LBCL), remains underutilized in older patients due to limited clinical data. We therefore studied the safety and efficacy of CAR-T therapy in older patients with RR LBCL in the real-world setting. Patients aged ≥65 years with RR LBCL, treated with anti-CD19 CAR-T therapy at 7 US institutions were included in this multicenter, retrospective, observational study. In total, 226 patients were included. Median age at infusion was 71 years (range 65-89). Best objective and complete response rates were 86% and 62%, respectively. Median follow-up after infusion was 18.3 months. The median progression-free survival (PFS) was 6.9 months, with 6- and 12-month PFS estimates of 54% and 44%, respectively. The nonrelapse mortality (NRM) rate was 10.9% at day 180, primarily due to infections, and not impacted by the age groups. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 7% and 26%, respectively. In univariate analysis, no significant difference in PFS was seen regardless of the age groups or CAR-T type, whereas ECOG PS ≥2, elevated LDH, bulky disease, advanced stage, extranodal involvement, the need for bridging therapy, and prior bendamustine exposure were associated with shorter PFS. These findings support the use of CAR-T in older patients, including those aged ≥80 years. The age at CAR-T therapy did not influence safety, survival, and NRM outcomes. Older patients should not be excluded from receiving CAR-T therapy solely based on their chronological age.

Revisiting beta-2 microglobulin as a prognostic marker in diffuse large B-cell lymphoma.

Several clinical prognostic models for diffuse large B-cell lymphoma (DLBCL) have been proposed, including the most commonly used International Prognostic Index (IPI), the National Comprehensive Cancer Network IPI (NCCN-IPI), and models incorporating beta-2 microglobulin (β2M). However, the role of β2M in DLBCL patients is not fully understood. We identified 6075 patients with newly diagnosed DLBCL treated with immunochemotherapy registered in the Danish Lymphoma Registry. A total of 3232 patients had data available to calculate risk scores from each of the nine considered risk models for DLBCL, including a model developed from our population. Three of four models with β2M and NCCN-IPI performed better than the International Prognostic Indexes (IPI, age-adjusted IPI, and revised IPI). Five-year overall survival for high- and low-risk patients were 43.6% and 86.4% for IPI and 34.9% and 96.2% for NCCN-IPI. In univariate analysis, higher levels of β2M were associated with inferior survival, higher tumor burden (advanced clinical stage and bulky disease), previous malignancy and increased age, and creatinine levels. Furthermore, we developed a model (β2M-NCCN-IPI) by adding β2M to NCCN-IPI (c-index 0.708) with improved discriminatory ability compared to NCCN-IPI (c-index 0.698, p < 0.05) and 5-year OS of 33.1%, 56.2%, 82.4%, and 96.4% in the high, high-intermediate, low-intermediate and low-risk group, respectively. International Prognostic Indices, except for NCCN-IPI, fail to accurately discriminate risk groups in the rituximab era. β2M, a readily available marker, could improve the discriminatory performance of NCCN-IPI and should be re-evaluated in the development setting of future models for DLBCL.

A study of a new mechanism: Intracellular retention allo-CART safety and efficacy for extranodal bulky B-NHL.

e19007 Background: Extranodal bulky lesions, a significant adverse prognostic factor in lymphoma, commonly denote a more aggressive disease course, mandating prompt and intensified treatment strategies. In response, we developed ThisCART19A, a non-genetic editing and off-the-shelf anti-CD19 CAR T-cell therapy incorporating intracellular retention of membrane proteins, representing a novel approach that downregulates surface expression of TCRαβ/CD3 complexes. ThisCART19 has exhibited a favorable safety profile and promising efficacy in patients with relapsed/refractory bulky B-cell Non-Hodgkin Lymphoma. Methods: This is an investigator-initiated trial employing an open-label, dose escalation, and expansion design to evaluate the safety and efficacy of ThisCART19A in patients with relapsed or refractory bulky B-cell non-Hodgkin lymphoma (B-NHL). Bulky disease was defined as the longest diameter of the mass &gt;5 cm at baseline. Results: Between June, 2021, and June, 2023, 13 extranodal bulky disease were enrolled in the studies and successfully received ThisCART19A. The median age was 56 (range, 37~67) years. All 13 patients had 3 median prior lines of therapy (range, 2-5). All patients received anti-CD20 and multi- agent chemotherapy. 8 (61.54%) patients had prior auto CART. mSPD was 48 (range, 16~162) cm². mTMTV was 114.9 (range, 14~483) ml. As of February 2024, The most common adverse events were CRS (100%) , infections (30.77%), ICANS (23.08%) and cytopenias(100%); This is no grade 3 or higher CRS occurred;only 1(7.69%)patient experienced grade 4 ICANS and relieved after intravenous dexamethasone treatment. This is no treatment-related deaths occurred. Among the 13 patients, 10 were evaluable, with an ORR and CR of 90% and 80%, respectively, at 28 days post-infusion. mPFS was 62 days (range, 28~227). The patient who achieved a PR received chemotherapy and radiotherapy as consolidation, As of February 5th, 2024, the patient has survived for 263 days and is still under follow-up. Additionally, two patients progressed after CR received sequential chemotherapy and BCL-2 Inhibitor, with an average OS of 326.5 days, still being under follow-up. In 13 evaluable patients, the mean C-max was 1043.13 cells/μL(range, 0.59~10045.4), and the mean AUC0-28d was 1542.23 cells/μL × day(range, 0.91~11724).In this cohort, two patients received low-dose infusions at 1×106 cells/kg and still achieved excellent expansion, the respective C-max were 726.432 cells/μL and 336.67 cells/μL. Conclusions: This CART19A exhibited favorable safety, remarkable expansion potential, and efficacy profiles in the treatment of r/r bulky lymphoma. Notably, it achieved a high ORR of 90%, providing a favorable window of opportunity for subsequent consolidation and intensification treatments. Moreover, this transition from a bulky to a non-bulky disease state reduces the intricacy of follow-up treatments. Clinical trial information: NCT04384393 .

Subcutaneous epcoritamab + GemOx in patients with relapsed or refractory DLBCL: Updated results from EPCORE NHL-2.

7037 Background: Gemcitabine + oxaliplatin (GemOx) is commonly used with rituximab to treat relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL); however, outcomes are suboptimal: 33% complete response (CR) rate; 5 mo median progression-free survival (PFS); 10 mo median overall survival (OS; Cazelles et al, Leuk Lymphoma 2021). We report additional efficacy and safety results of epcoritamab + GemOx in difficult-to-treat R/R DLBCL (EPCORE™ NHL-2 phase 1/2 trial, NCT04663347). Methods: Adults with R/R CD20+ DLBCL who failed or were ineligible for autologous stem cell transplant (ASCT) enrolled to receive subcutaneous (SC) epcoritamab (2 step-up doses followed by 48-mg full doses) in 28-d cycles (C): QW, C1–3; Q2W, C4–9; Q4W, C≥10 until unacceptable toxicity or disease progression. GemOx was given Q2W in C1–4. The primary endpoint was overall response rate (ORR) per Lugano criteria. Subgroup analyses by prior treatment (tx) and response were performed. Results: As of Sept 1, 2023, 97 pts with ≥6 mo of follow-up had received epcoritamab 48 mg + GemOx (median follow-up, 9.7 mo). Pts had a median of 2 prior lines of tx (pLOT; range, 1–6); 55% had primary refractory disease, 38% had bulky disease (&gt;6 cm), 30% had prior CAR T, and 9% had prior ASCT. Median age was 72 y, with 34% of pts ≥75 y. A median of 7 cycles of epcoritamab and 4 cycles of GemOx were initiated. At data cutoff, tx was ongoing in 46% of pts. ORR was 78% and CR rate was 55%. Median time to CR was 1.7 mo; median duration of CR was 13.3 mo. Additional efficacy outcomes are shown in the Table. Safety was consistent with previous reports. The most common tx-emergent AEs (TEAEs) of any grade (G) were hematologic AEs (68% thrombocytopenia; 59% neutropenia [6% febrile neutropenia]; 51% anemia) and CRS (51%). CRS was primarily low grade (27% G1, 23% G2), with only 1 pt experiencing G3 CRS; all events resolved and none led to tx discontinuation. ICANS was reported in 3 pts (G1, n=2; G3, n=1); all events resolved, but 1 pt discontinued tx. There were 13 fatal TEAEs; in 3 cases, the contribution of epcoritamab + GemOx could not be ruled out: COVID-19, multiple organ dysfunction syndrome, and small intestinal perforation. Conclusions: These long-term results continue to demonstrate that SC epcoritamab in combination with GemOx leads to deep, durable responses, which translate to high rates of PFS and OS in challenging-to-treat, high-risk pts with R/R DLBCL. CR rates were consistently high across prespecified subgroups. Higher CR rates in pts with 1 vs ≥2 pLOT indicate that earlier use may further improve outcomes. No new safety signals were identified. The benefit-risk profile of this combination supports the combinability of epcoritamab in R/R DLBCL. Clinical trial information: NCT04663347 . [Table: see text]

Efficacy and safety of lurbinectedin (LUR) with irinotecan (IRI) in patients (Pts) with relapsed small cell lung cancer (SCLC): Results from a phase 2 expansion cohort.

8094 Background: LUR has been approved in the US and elsewhere for treatment of adult pts with metastatic SCLC and disease progression on or after platinum-based chemotherapy. Preclinical studies found synergy for LUR with IRI (Galmarini C. Cancer Res 2013; 73: Abst 5499). The phase 1b/2 study PM1183-A-014-15 (NCT02611024) evaluated the LUR/IRI combination in pretreated pts with advanced solid tumors. The phase 1b part defined the recommended dose at LUR 2.0 mg/m2 on Day (D)1 + IRI 75 mg/m2 on D1,D8 every three weeks with primary G-CSF prophylaxis, and found promising results for the combination in SCLC pts after first-line therapy (Ponce Aix S. Ann Oncol 2019; 30: Abst 471P). Methods: Eligibility criteria for this cohort of the phase 2 part of this study included: confirmed SCLC, progression after one platinum-containing regimen, controlled brain metastases and ECOG PS ≤ 1. The primary endpoint was overall response rate (ORR). Results: 101 evaluable pts were enrolled. Baseline characteristics included: median age 63 (range, 45-77 y), 60.4% males, 76.2% ECOG PS 1, 28.7% CNS involvement, 39.6% bulky disease and 41.6% pretreated with immunotherapy. Chemotherapy-free interval (CTFI) was &lt;90 d in 51.4% of pts (26.7% had CTFI&lt;30 d. Median CTFI was 85 d (range, 0-323 d). Median number of cycles per pt was 6 (range, 1-34); 25.7% received &gt;10 cycles. Efficacy results by independent review committee are summarized in the table. Treatment-related adverse events (AEs) were observed in 99.0% of pts (grade ≥3 in 69.3%). Most relevant grade ≥3 events/abnormalities were neutropenia (52.5%), anemia (27.7%), diarrhea (19.8%), fatigue (18.8%), and febrile neutropenia (9.9%). Treatment-related SAEs occurred in 25.0% of pts and 5.0% discontinued due to treatment-related AEs. No treatment-related deaths occurred. Conclusions: The LUR/IRI combination showed promising antitumor activity and a manageable safety profile in these pts with poor prognosis, particularly those with CTFI&gt;30 d. These encouraging results reinforce the rationale for including this combination as an experimental arm in the ongoing pivotal phase 3 LAGOON trial (NCT05153239) in relapsed SCLC with CTFI&gt;30 d. Clinical trial information: NCT02611024 . [Table: see text]

Efficacy and safety of RP1 combined with nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial.

9517 Background: Patients (pts) with melanoma who progress on anti–PD-1 therapy (anti–PD-1–failed) have limited treatment options. RP1 is an HSV-1–based oncolytic immunotherapy expressing human GM-CSF and a fusogenic protein (GALV-GP-R−). Here, we present data from pts with anti–PD-1–failed melanoma, including the initial cohort and updated data from a registration-directed (R-D) cohort, from the phase 1/2 IGNYTE study (NCT03767348). Methods: Pts had locally advanced or metastatic cutaneous melanoma with ≥1 measurable and injectable tumor (≥1 cm) and confirmed progressive disease (PD) while on therapy and received anti–PD-1 ± anti–CTLA-4 therapy for ≥8 consecutive weeks, with anti–PD-1 being the last treatment received. Pts on prior adjuvant anti–PD-1 therapy had confirmed PD while on adjuvant therapy. RP1 was initially given intratumorally at 1×106 plaque-forming units (PFU)/mL and then every 2 weeks (Q2W) at 1×107 PFU/mL for up to 8 total cycles (≤10 mL/cycle) combined with nivolumab (nivo; cycles 2–8, 240 mg IV); pts then received nivo alone (240 mg Q2W or 480 mg Q4W IV) for up to 2 years, with the option to receive additional courses of RP1 if specified criteria were met. Results: Overall, 156 pts were enrolled (initial melanoma cohort, n = 16; R-D cohort, n = 140); 46.2% of pts had been treated with prior anti–PD-1 combined with anti–CTLA-4, and 51.3% of patients had stage IVM1b-d disease. The overall objective response rate (ORR) was 31.4%, and 12.2% of pts achieved complete response (CR; Table). Responses were observed irrespective of prior anti–PD-1 therapy setting and disease stage (Table). Responses were seen in uninjected lesions and in bulky and visceral disease. The ORR for pts with primary anti–PD-1 resistance was 34.1%. In pts who failed prior ipilimumab + nivo, the ORR was 26.4% (Table). The median duration of response (time from baseline to end of response for responders) was &gt; 24 months, with 100% of responses lasting &gt; 6 months from baseline; 78% of responses were ongoing. Treatment-related adverse events (TRAEs) associated with RP1 + nivo were predominantly grade 1–2; there was 1 grade 5 TRAE (immune-mediated myocarditis attributed to nivo). Conclusions: The updated data from this expanded cohort show that RP1 + nivo provides durable and clinically meaningful antitumor activity in pts with anti–PD-1–failed melanoma. Responses were observed in both injected and uninjected lesions, including visceral lesions. The combination continues to be well tolerated. Clinical trial information: NCT03767348 . [Table: see text]