Advanced-stage Diffuse Large B-cell Lymphoma Research Articles

Matched control analysis suggests that R-CHOP followed by (R)-ICE may improve outcome in non-GCB DLBCL compared with R-CHOP

AbstractRituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score–matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score–matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582.

Loncastuximab Tesirine Demonstrated Substantial Single-Agent Efficacy and Manageable Safety Profile in Heavily Pretreated Chinese Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Introduction: Patients with R/R DLBCL who failed multi-agent chemoimmunotherapies usually have a poor prognosis, leaving a significant unmet medical need. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate, composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin that showed clinical efficacy and manageable safety in heavily pretreated DLBCL patients in a global phase 2 study of Lonca monotherapy (NCT03075696). Here we present results from a phase 2 study (ChiCTR2300072058) of Lonca monotherapy in Chinese patients with R/R DLBCL for the first time, including analyses of responses in high-risk DLBCL subgroups. Methods: This open-label, single-arm, phase 2 study was designed to confirm the safety, efficacy and PK profiles of Lonca monotherapy in Chinese patients with R/R DLBCL who had failed ≥ 2 lines of systemic therapies. The primary endpoint was overall response rate (ORR) as assessed by IRC according to the Lugano 2014 criteria. Secondary efficacy endpoints include complete response rate (CRR), DOR, RFS, PFS, and OS. Treatment-emergent adverse events (TEAEs) were reported by CTCAE v4.0. Results: As of data cutoff (11-Jan-2023), 64 Chinese patients with DLBCL were enrolled and received at least one dose of Lonca (median: 4.0 cycles [range: 1-17]) and were evaluable for safety and efficacy analyses. The median number of prior lines of therapies was 3.0 (range: 2-12), with 67.2% of patients having ≥ 3 lines of prior therapies. Four patients (6.3%) had received prior CD19 CAR-T therapy. Forty-three patients (67.2%) were refractory to the first-line therapy (primary refractory), 56 patients (87.5%) were refractory to the most recent line of therapy and 40 patients (62.5%) were refractory to all prior lines of therapies. At data cutoff, the median follow-up was 8.5 months. The ORR by IRC was 51.6% (95% CI: 38.7% to 64.2%), and CRR was 23.4%. The median DOR (mDOR) was 6.37 months as assessed either by IRC or by investigator. For patients with a CR, the mDOR was 10.22 months (6.08 months for patients with PR). The median time to first response was 41.0 days. The median PFS and median OS were 4.96 and 9.33 months, respectively. Responses, including CRs, were observed in several high-risk subgroups (Fig. 1): ORR was 54.7% in patients with advanced stage disease (Stage III/IV) and 50.0% in patients with transformed disease. Patients who were refractory to first-line therapy, to the most recent therapy, or to all prior therapies had ORRs of 44.2%, 51.8% and 42.5%, respectively. Three patients who had received a prior SCT had an ORR of 100%. Lonca was also effective in elderly patients ≥ 65 years (ORR of 45.8%, mDOR of 6.37 months) and in patients who had received prior CD19 CAR-T therapy (ORR of 50%). Overall, 64 (100%) patients had at least one TEAE and 61 (95.3%) patients had at least one TEAE ≥ Grade 3. The most common (≥30%) all-grade TEAEs were GGT increased (71.9%), followed by anaemia (70.3%), platelet count decreased (65.6%), AST increased (64.1%), WBC count decreased (64.1%), neutrophil count decreased (60.9%), ALT increased (51.6%), hypokalaemia (37.5%), and blood ALP increased (32.8%). The most common (≥15%) TEAEs of Grade ≥3 were platelet count decreased (34.4%), neutrophil count decreased (28.1%), WBC count decreased (28.1%), GGT increased (25.0%), anaemia (18.8%), hypokalaemia (18.8%), neutropenia (17.2%), and lymphocyte count decreased (15.6%). The rate of febrile neutropenia was low (3.1%). The majority of Grade ≥ 3 TEAEs were abnormalities of clinical laboratory values as opposed to clinical symptoms and were generally reversible. Treatment-related TEAEs leading to treatment discontinuation occurred in 10 patients (15.6%), most commonly GGT increased (3 patients; 4.7%). No increase in toxicity was seen in patients aged ≥65 years compared with younger patients. Conclusions: Lonca demonstrated substantial and clinically meaningful single-agent efficacy and was well-tolerated in heavily pretreated Chinese patients with R/R DLBCL. Toxicities were generally manageable and reversible in most patients by routine clinical practice and/or with dose modifications, with neither unexpected safety concerns nor different toxicity profile in patients aged ≥65 years. Encouraging and durable responses were also observed in high-risk patient groups, including patients with advanced stage, transformed or refractory DLBCL.

Consolidative Radiotherapy after Complete Remission following R-CHOP Immunochemotherapy in Stage III-IV Diffuse Large B-Cell Lymphoma Patients: A Systematic Review and Meta-Analysis.

Patients with diffuse large B-cell lymphoma (DLBCL) are treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The role of consolidative radiation therapy (RT) remains unclear among patients with advanced DLBCL who achieved complete remission (CR) after R-CHOP immunochemotherapy. The current systematic review and meta-analysis aimed to clarify the role of consolidative RT among these patients. The MEDLINE, Embase, and Cochrane Library databases were searched for studies comparing RT to no RT following CR after R-CHOP immunochemotherapy in Ann Arbor stage III-IV DLBCL patients. Overall survival (OS) was the primary endpoint, and disease-free survival (DFS) was the secondary endpoint. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the primary and secondary outcomes. Review Manager (version 5.4) was used to analyze the data. Six retrospective studies involving 813 patients who received R-CHOP ± consolidative RT were identified. OS was higher in the consolidative RT group, with an HR of 2.01 and a 95% CI of 1.30 to 3.12 (p = 0.002). DFS was also higher in the RT group, with an HR of 2.18 and a 95% CI of 1.47 to 3.24 (p < 0.0001). The results suggested that consolidative RT improved OS and DFS compared to no RT among advanced-stage DLBCL patients. Further research is needed to determine the optimal radiation fields and the appropriate indications for consolidative RT for advanced-stage DLBCL patients in the rituximab era.

CAR-T therapy access with Louisiana Medicaid: A single institution retrospective analysis.

e18580 Background: Chimeric antigen receptor (CAR)-T therapy has revolutionized the treatment of hematologic malignancies over the past few years. Axicabtagene-ciloleucel was initially approved by the food and drug administration in October 2017 for relapsed/refractory diffuse large B cell lymphoma (DLBCL) after 2 or more lines of systemic therapy. In April 2022, it was approved as second-line therapy for DLBCL that is refractory to first-line or relapses within 12 months of chemoimmunotherapy. Studies have reported complete responses in 50-60% and prolongation of overall survival by 12-18 months. However, CAR-T remains an expensive therapy that can cost up to 1 million USD. Accessibility to CAR-T is governed by various socioeconomic factors including insurance status. The state of Louisiana currently does not have any institution which offers CAR-T therapy. Our Medicaid population is further disadvantaged by the fact that their insurance does not cover out-of-state services. Hence, we conducted this institutional study to evaluate the accessibility to CAR-T and the factors associated with it. Methods: Our retrospective study included adult patients with a diagnosis of DLBCL treated at LSU Shreveport between January 2018 to December 2022. We excluded all other types of B-cell lymphomas, prisoners, and pregnant women. Our primary objective was to evaluate whether the lack of access to CAR-T due to insurance status affected mortality. Our secondary objective was to examine the various demographic factors associated. Analysis was conducted using SAS. Descriptive statistics, Chi-square tests were used to report the results. Results: Our study included a total of 84 patients with a mean age of 59 years. 58% were Caucasian and 38% were African American. 65% were male. 33% had Medicaid coverage and 31% had Medicare. 60% had advanced-stage DLBCL, and 40% had early-stage (Stages I and II). 6% had either double-hit or triple-hit lymphomas. 17% of patients were considered eligible for CAR-T at relapse as per clinician discretion. 33% of patients who were eligible could not get a referral for CAR-T due to factors like insurance status and costs associated with out-of-state living. This led to an increased mortality of 60% in that cohort vs 0% in those who got referrals (p-value of 0.02). Medicaid was the predominant insurance (67%) among those who were unable to get referrals for CAR-T, thus strengthening our hypothesis. Conclusions: Through our study, we aim to bring to light the disparity faced by Louisiana Medicaid patients wherein they don’t have access to a potentially curative therapy for DLBCL. While we do recognize the expenses associated with CAR-T, we wish to highlight that not all states have direct access to this therapy. Seeing how our patients must already uproot their lives temporarily to get CAR-T, their decision could be made easier if insurance can cover the cost at least on a case-to-case basis.

Racial and ethnic disparities in risk of second primary malignancies among diffuse large B-cell lymphoma survivors.

7567 Background: Previous studies have shown an increased risk of second primary malignancies (SPMs) among diffuse large B-cell lymphoma (DLBCL) survivors; however, this has not been comprehensively examined by race/ethnicity. We utilized a large population-based database to examine disparities in SPM risk by race/ethnicity. Methods: From 17 United States population-based Surveillance, Epidemiology and End Results (SEER) program cancer registry areas, we identified 57,262 ≥12-month first-primary DLBCL survivors diagnosed between 2000-2019. Standardized incidence ratios (SIRs) and accompanying 95% confidence intervals (CIs) quantified SPM risk by race/ethnicity (non-Hispanic White, Black, Asian/Pacific Islander [API] and Hispanic), compared with the general population. Results: Overall, we observed 4,719 SPMs after DLBCL representing a 1.2-fold significantly increased risk (95% Confidence Interval [CI] = 1.16-1.23) compared to the general population and an excess of 23 cases per 10,000 person-years. SIRs for all second cancers combined varied significantly by race/ethnicity with APIs and Hispanics presenting higher overall SPM risk [SIRAPI: 1.42 (CI = 1.27-1.59), and SIRHispanic: 1.31 (CI = 1.19-1.43)] compared to the White or Black patients [SIRwhite: 1.17 (CI = 1.13-1.21), SIRBlack: 1.16 (CI = 1.03-1.30)] (p-heterogeneity &lt; 0.001). Heterogeneity by race/ethnicity in SIRs was even more pronounced in DLBCL survivors diagnosed at a younger age, those who were ≥5 years into their survivorship, those who had received chemotherapy, or those who had received no radiation as their initial treatment. Although SIRs for SPM was significantly higher for advanced stage DLBCL survivors (compared to those with a localized/regional disease), heterogeneity by race/ethnicity in SPM risk was significant regardless of the stage. Results from site specific analyses reported significantly higher overall SIRs for second hematological malignancies compared to solid cancers [SIRhemat: 3.52 (CI = 3.22-3.85), and SIRsolid: 1.08 (CI = 1.04-1.11)]. Patterns by race/ethnicity also varied significantly by second cancer type, particularly for second primary anal cancer, Hodgkin’s lymphoma (HL), and Acute Non-Lymphocytic Leukemia (ANLL) (p &lt; 0.001 for each). Strikingly elevated SPM risks (SIRs &gt; 10) were observed for second primary anal cancer, HL and ANLL among the Black patients, and HL among the APIs and Hispanic DLBCL survivors, compared to the white patients. Conclusions: Using a large-scale population-based data, we observed substantial disparities in SPM risk by race/ethnicity, with patients belonging to minority groups experiencing higher risks. SPMs have emerged as an important challenge for DLBCL survivors, therefore, further research to understand drivers of the observed race/ethnicity heterogeneity is warranted.

Elevated FDG Uptake in the Lung Is a Characteristic Finding of Intravascular Large B-Cell Lymphoma

[Introduction] Intravascular large B-cell lymphoma (IVBCL) is a rare subtype of extra-nodal diffuse large B-cell lymphoma (DLBCL), characterized by preferential growth of lymphoma cells within the lumina of small vessels. Clinical presentation of IVBCL is highly variable, and it often includes organ dysfunction related to obstruction of blood vessels. Up to 80% of IVBCL cases experienced hypoxemia at initial presentation, suggesting a high rate of respiratory involvement. In recent years, some IVBCL cases with diffuse pulmonary uptake on 18F-fluorodeoxyglucose (FDG) PET/CT have been reported from Asia and Western countries. It may also reflect the pulmonary infiltration of IVBCL; however, there are no reports of detailed studies with a large number of IVBCL cases. [Methods] We retrospectively evaluated patients with histopathologically proven newly diagnosed IVBCL according to the 2008 World Health Organization criteria between January 2010 through February 2022 from hospitals participating in the North Japan Hematology Study Group (NJHSG). PET/CT images were reviewed by an experienced nuclear medicine physician (S.W.). In addition to the general PET/CT evaluation, the ratio of the lung to mediastinum standardized uptake value (SUV) peaks (L/M ratio) was calculated to assess the degree of FDG accumulation in the lungs objectively. Lung SUV peaks were measured uniformly about 1 cm medial to the right lower lobe pleura, and mediastinum SUV peaks were measured in the left atrium. The L/M ratio of 226 advanced stage DLBCL cases diagnosed within the same periods was also calculated and compared with IVBCL cases. [Results] We identified fifty-one IVBCL patients (age 30-89 years, median 65 years; 56.9% male) who performed PET/CT at diagnosis, and 29 of whom also underwent after chemotherapy. IVBCL was diagnosed via skin biopsy in 31 (60.8%) cases, bone marrow biopsy in 15 (29.4%) cases, and lung biopsy in 8 (15.7%) cases. Hypoxemia were observed in 25 (49.0%) patients. Twenty-eight (54.9%) patients had poor performance status (ECOG score ≥2). Elevated LDH level was observed in 48 (94.1%) cases (median, 631 IU/L; range, 147-4907 IU/L). Diffusely elevated FDG uptake was seen at the lung in 28 (54.9%) patients, bone marrow in 40 (78.4%), and spleen in 32 (62.7%). Chest CT evaluation revealed that ground-glass opacity lesion corresponding to the areas of FDG accumulation on PET was observed in 14 of 28 patients. At diagnosis, the median L/M ratio was significantly higher in IVBCL patients than in DLBCL patients (IVBCL: median, 0.903; range, 0.22-2.583 vs. DLBCL: median, 0.421; range, 0.177-0.639, P < 0.0001, Fig.). ROC analysis revealed that the cutoff value of the L/M ratio of 0.649 predict IVBCL diagnosis. Area under curve was 0.916 (95% CI: 0.859-0.974). Thus, we classified patients with a threshold of 0.649 for the definition of "high” or "low” levels of the L/M ratio. At the time of diagnosis, 38 of 51 (74.5%) IVBCL cases were classified as having a high L/M ratio. The L/M ratio decreased to low levels in all patients who underwent FDG PET/CT after chemotherapy (median, 0.471; range, 0.269-0.647, Fig.). The high L/M ratio was significantly correlated with diffuse FDG uptake in the lung (P < 0.0001), bone marrow (P = 0.0507) and spleen (P < 0.001) and the presence of hypoxemia (P < 0.01). Surprisingly, 14 of 26 (53.8%) patients who did not present with hypoxemia showed high L/M ratio. Fifty (98%) patients received rituximab-containing chemotherapy. Of the patients treated, 13 (26%) patients experienced a relapse, and 9 (18%) patients eventually died. The 2-year overall survival (OS) was 84.6 % (range, 70.3-92.4 months). Median follow-up duration was 48.8 months (range, 4.7-140.5 months) in survivors. The L/M ratio did not stratify the prognosis significantly (L/M high: 2-year OS, 82.3%; 95% CI, 64.6-91.6 vs L/M low: 2-year OS, 90.9%; 95% CI, 64.6-91.6, P = 0.7). [Conclusion] To our knowledge, this is the largest study to assess pulmonary PET/CT findings in newly diagnosed IVBCL cases. A high L/M ratio was found in about 75% of patients with IVBCL while not in advanced stage DLBCL. Given that the L/M ratio decreased after treatment, the high L/M ratio reflects pulmonary infiltration of lymphoma cells. In cases of suspected IVBCL, FDG-PET can be a good indicator of whether to perform a lung biopsy, even in patients without hypoxemia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk and outcome of acute myeloid leukaemia among survivors of primary diffuse large B-cell lymphoma: a retrospective observational study based on SEER database

ObjectivesSurvivors of diffuse large B-cell lymphoma (DLBCL) are at an increased risk of developing second primary malignancies. However, the risk of secondary acute myeloid leukaemia (sAML) has not been previously...

Short- and long-term outcomes from the upfront high-dose chemotherapy, followed by autologous hematopoietic stem cell transplantation in diffuse large B-cell lymphoma

Introduction. Diffuse large B-cell lymphoma (DLBCL) is the most common (30-35%) type of B-cell lymphomas. Only about 60% of all newly diagnosed advanced-stage DLBCL can be completely treated by x6 CHOP-R only. High dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation in the first remission (upfront auto-HSCT) can serve an option to improve prognosis in these patients (pts).Aim. To improve prognosis in DLBCL IV stage, IPI ≥2 pts by upfront auto-HSCT.Materials and methods. Included 105 pts: DLBCL NOS, age 18-65, stage IV, IPI ≥2, CR/PR after x6 CHOP/EPOCH + R from 2010 to 2019 at NMRC of Oncology named after N.N. Petrov of MoH of Russia were retrospectively analyzed. HSCT group includes pts with upfront HDCT followed by auto-HSCT (n = 35). The control group includes pts with non-invasive follow-up after induction only (n = 70). Primary endpoints were overall (OS) and progression-free survival (PFS). Secondary endpoints were response rate, relapse rate and treatment toxicity.Results and discussion. The 3-yr OS (p = 0.01) and 3-yr PFS (p = 0.018) were significantly higher in HSCT group. The complete response rate was significantly increased after upfront auto-HSCT (p &lt; 0.001). Early relapse served as an independent negative prognostic factor in OS (p &lt; 0.001) and experienced statistically less in HDCT group (p = 0.027). Early (ER) and late relapse (LR) rate were higher in pts with DEL (ER - p &lt; 0.001, LR - p &lt; 0.001 in control group and ER - p &lt; 0.001, LR -p = 0.013 in all pts). The overall relapse rate was higher if pts had &gt;1 extranodal site with lung involvement (p &lt; 0.004 in the control group and p = 0.021 in all pts). Prognostic models suggested DEL and presence of &gt;1 extranodal site with lung involvement as an independent negative prognostic factors for increasing the relapse probability in two years after treatment.Conclusion. Upfront HSCT can serve as a clinical option to consolidate the first remission in IV stage DLBCL pts with DEL and/or &gt;1 extranodal sites with lung involvement.

Risk factors for cardiovascular events and mortality in patients diagnosed with diffuse large B-cell lymphoma and treated with anthracyclines.

There is an increased risk of congestive heart failure (CHF) following anthracycline-based chemotherapy in patients with Diffuse Large B-cell lymphoma (DLBCL). Little is known about risk factors of CHF, other cardiovascular events (CVE), and CVE effect on outcomes. We conducted a retrospective review of 463 newly diagnosed DLBCL patients treated between 2002 and 2016 with anthracycline containing regimens. At a median follow up of 71.3months, 10.4% patients developed new CHF, 4.97% had new atrial fibrillation and 3.2% had new coronary artery disease. Age over 65, advanced stage DLBCL and diabetes were associated with increased cumulative incidence of CVE. Patients with prior diabetes had decreased progression-free survival and overall survival in comparison to non-diabetics. Patients who had a CVE in the first year had significant worse OS then patients who did not have a CVE (Hazard Ratio 10.0, 95% CI, 7.24-13.88). A risk score incorporating age at DLBCL diagnosis, baseline lymphocyte count, disease stage and diabetes stratified into groups with low, intermediate and high risk for CVE, with 1-year cumulative incidence of CVE of 5.3%, 7.9% and 13.4%. Diffuse large B-cell lymphoma patients treated with anthracycline containing regimens have high incidence of CVE, which are not limited to CHF. Clinical variables at the time of diagnosis can identify the group of DLBCL patients at highest risk of CVE, for whom preventive interventions should be considered.

Agent Repurposing for the Treatment of Advanced Stage Diffuse Large B-Cell Lymphoma Based on Gene Expression and Network Perturbation Analysis.

Over 50% of diffuse large B-cell lymphoma (DLBCL) patients are diagnosed at an advanced stage. Although there are a few therapeutic strategies for DLBCL, most of them are more effective in limited-stage cancer patients. The prognosis of patients with advanced-stage DLBCL is usually poor with frequent recurrence and metastasis. In this study, we aimed to identify gene expression and network differences between limited- and advanced-stage DLBCL patients, with the goal of identifying potential agents that could be used to relieve the severity of DLBCL. Specifically, RNA sequencing data of DLBCL patients at different clinical stages were collected from the cancer genome atlas (TCGA). Differentially expressed genes were identified using DESeq2, and then, weighted gene correlation network analysis (WGCNA) and differential module analysis were performed to find variations between different stages. In addition, important genes were extracted by key driver analysis, and potential agents for DLBCL were identified according to gene-expression perturbations and the Crowd Extracted Expression of Differential Signatures (CREEDS) drug signature database. As a result, 20 up-regulated and 73 down-regulated genes were identified and 79 gene co-expression modules were found using WGCNA, among which, the thistle1 module was highly related to the clinical stage of DLBCL. KEGG pathway and GO enrichment analyses of genes in the thistle1 module indicated that DLBCL progression was mainly related to the NOD-like receptor signaling pathway, neutrophil activation, secretory granule membrane, and carboxylic acid binding. A total of 47 key drivers were identified through key driver analysis with 11 up-regulated key driver genes and 36 down-regulated key diver genes in advanced-stage DLBCL patients. Five genes (MMP1, RAB6C, ACCSL, RGS21 and MOCOS) appeared as hub genes, being closely related to the occurrence and development of DLBCL. Finally, both differentially expressed genes and key driver genes were subjected to CREEDS analysis, and 10 potential agents were predicted to have the potential for application in advanced-stage DLBCL patients. In conclusion, we propose a novel pipeline to utilize perturbed gene-expression signatures during DLBCL progression for identifying agents, and we successfully utilized this approach to generate a list of promising compounds.

Safety, Feasibility, and Effects of Short-Term Calorie Reduction during Induction Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma: A Pilot Study.

Short-term calorie reduction (SCR) requires individuals to reduce their calorie intake to less than 50% of normal requirements and has shown good tolerance and potential benefits in prior studies addressing gynecological cancer patients. More studies are needed to further confirm its safety, feasibility, and effects in patients with different cancers, including hematological malignancies. This pilot cohort study with a matched-pair comparison group was registered at ClinicalTrails.gov [201810112RIND]. Adult patients diagnosed with advanced-stage diffuse large-B cell lymphoma were recruited (SCR group) and matched with one comparison patient (comparison group), each in a manner blinded to their outcomes. The SCR group undertook at least two cycles of 48 h water fast along with their chemotherapy R-CHOP. Descriptive analysis and generalized estimating equations were used to analyze the data. Six participants completed multiple cycles of SCR and were compared to their six counterparts in the comparison group. The results showed that SCR is safe and feasible in terms of a high compliance rate and stable nutritional status. The SCR was associated with benefits in post-chemotherapy hematological parameters (i.e., erythrocyte [p < 0.001] and lymphocyte counts [p < 0.001]). More randomized controlled trials are needed to validate the effects of SCR on different types of cancer populations.

Improved Progression-Free Survival for Bulky and Non-Bulky Advanced Stage Diffuse Large B-Cell Lymphoma With Consolidative Radiation Therapy: A Bi-Institutional Analysis.

BackgroundThe role of consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) is not fully established. A growing body of data suggests a role for consolidative RT in select stage III-IV DLBCL patients and emerging data from randomized studies further address the role of RT in advanced-stage patients initially presenting with bulky disease.MethodsPatients with treatment-naive stage III-IV DLBCL treated at two institutions who achieved a clinically complete response to systemic therapy were included. Patients with either bulky or non-bulky disease were included, but those with the relapsed or refractory disease were excluded. Kaplan-Meier analysis was performed to determine the impact of consolidative RT. Univariate and multivariable analyses were performed using a Cox proportional hazards model.ResultsOne hundred eighty-eight patients received systemic therapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 79%), another rituximab-based regimen (9%), or chemotherapy alone (12%). Clinical response was assessed using conventional CT or PET-CT. Sixty-eight patients (36%) received consolidative RT (median dose 30 Gy). Consolidative RT conferred a 36.7% absolute benefit in five-year progression-free survival (PFS; 85.9% vs. 49.2%, log rank p < 0.0001), a 14.5% absolute benefit in five-year overall survival (OS; 87.4% vs. 72.9%, log rank p = 0.0134), and a 37.0% absolute benefit in five-year LC (91.9% vs. 54.9%, log rank p < 0.0001). On multivariable analysis, consolidative RT was associated with improved PFS (HR 0.23, 95% CI 0.10-0.52, p < 0.001) and LC (HR 0.20, 95% CI 0.07-0.59, p = 0.003). Patients receiving consolidative RT demonstrated significantly improved PFS for tumors measuring both <5 cm (log rank p = 0.0454) and ≥5 cm (log rank p = 0.0003).ConclusionsFor patients with stage III-IV DLBCL who achieve clinical complete response after systemic therapy, consolidative RT improves PFS for all patients, including those with the non-bulky disease. This benefit persists in the setting of rituximab-based systemic therapy.

Characteristics and Outcomes of Patients with Double-Protein Expression in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of SWOG Study S1001 (NCT01359592)

Characteristics and Outcomes of Patients with Double-Protein Expression in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of SWOG Study S1001 (NCT01359592)

Emerging Role of Consolidative Radiotherapy After Complete Remission Following R-CHOP Immunochemotherapy in Stage III-IV Diffuse Large B-Cell Lymphoma: A Single Institutional and Case-Matched Control Study.

PurposeThe role of consolidative radiotherapy (RT) after complete-remission (CR) following rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in advanced-stage diffuse large B-cell lymphoma (DLBCL) remains unclear. We retrospectively analyzed the survival outcomes and patterns of failure with our institutional experience.Material and MethodsBetween 2009 and 2018, 206 patients with stage III-IV DLBCL achieved CR after receiving R-CHOP. Propensity-score matching was used to analyze the role of consolidative RT. The consolidative RT group (n = 34) and the R-CHOP alone group (n = 68) were matched at a 1:2 ratio. After propensity-score matching, 102 patients were analyzed.ResultsWith a median follow-up of 39.7 months, 26 patients (25.5%) showed local recurrence. Only one patient failed at the previous RT field. RT was delivered to bulky sites, head and neck lesions, testes, and bone with median dose of 30.6 Gy. The most common site of failure was head and neck lesions followed by bulky sites. The 5-year overall survival (OS), progression-free survival (PFS), and isolated-local recurrence free survival (LRFS) were 73.5, 64.0, and 79.9%. In univariate and multivariate analysis, bone marrow involvement and consolidative RT were associated with isolated LRFS (p = 0.006 and 0.032) significantly.ConclusionConsolidative RT improved isolated local control. Based on the pattern of failure, we carefully suggest to radiate on initially involved bulky sites or head and neck lesions. Further studies need to be done to find out the optimal radiation dose and selection of RT site.

Long-term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP

AbstractConsolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative [PET-NEG]) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.

Interim PET/CT result is the sole prognostic factor of survival in patients with advanced-stage diffuse large B-cell lymphoma: a subset analysis of a prospective trial

This study aimed to evaluate the prognostic value of interim positron emission tomography (iPET) in diffuse large B-cell lymphoma (DLBCL). Among 53 enrolled patients, 39 had iPET-negative (iPET−) and 14 had iPET-positive (iPET+) scans. The objective response rate was 94.3%. The 3-year progression-free survival was 65.7% and the 3-year overall survival was 79.9%. The iPET− patients had significantly higher 3-year PFS rate (78.1% vs. 34.3%) and improved OS (87.1% vs. 62.3%) than iPET+ patients. In the univariate analysis, iPET− was the sole independent prognostic factor for PFS. In conclusion, PET/CT has a good prognostic value in patients with advanced-stage DLBCL. Trial registration: ClinicalTrials.gov, NCT 01804127. Registered on March 5th, 2013, https://www.clinicaltrials.gov/ct2/show/NCT01804127?term=01804127&rank=1 .

Use of Medium Potency Statins Is Associated with Improved Outcomes after Frontline RCHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Background: Pre-clinical studies show that statins may improve the efficacy of chemoimmunotherapy in patients with DLBCL, through interference with cell membrane-initiated signaling pathways. Clinical retrospective studies, however, yield conflicting data, due to heterogeneous properties of statins, including potency and hydrophilicity. Methods: This is a retrospective analysis of patients with previously untreated, advanced stage DLBCL, non-double hit, treated with frontline R-CHOP between 01/01/2000 and 09/01/2019 (data cut-off 04/15/2020) at MD Anderson Cancer Center, and for whom data regarding statin use at time of initiation of treatment were available. Lugano 2014 response criteria were applied retrospectively for response assessment. Cellular cholesterol levels were analyzed in 6 DLBCL cell lines using an Amplex red fluorometric assay. A doxorubicin (DXR)-resistant cell line was generated exposing SUDHL4 cells to escalating doses of DXR; a DXR-resistant DLBCL patient-derived xenograft (PDX) model was established through serial transplantation and exposure to DXR. Results: 271 patients were included in the analysis, 182 (67%) were older than 60 years, 134 (49%) were male, 212 (72%) had stage IV disease, and 217 (80%) had an IPI score &amp;gt; 3; upon pathological review, 38 (36%) cases were non-GCB type, and 18 (28%) were double-expressors; 214 (79%) were able to complete all planned 6 cycles of RCHOP. Seventy-nine (29%) patients received statins at time of initiation of chemoimmunotherapy: 15 patients received low potency statin, 51 medium and 13 high; 18 patients received hydrophilic statins and 61 lipophilic. Patients receiving statins were significantly older as compared to patients who did not (p&amp;lt;0.001); no other significant difference in baseline characteristics was observed when comparing the 2 groups. Overall, 265 out of 271 patients were evaluable for response, as 6 stopped treatment because of toxicity before first response assessment. Among these, ORR was 95% (252/265) and CR rate was 62% (165/265). ORR rate was identical in patients who were treated with statin and those who did not (95% both, p=1). After a median follow-up of 77 months (95% CI, 70-84 months), 119 patients progressed/died, median PFS was not reached and 6-year PFS was 57%. 6-year PFS rate according to statin intensity was: 48% (low), 72% (medium), 57% (high). PFS. 6-year PFS rate was 64% for hydrophilic and 72% for lipophilic statins. Patients treated with statins had a trend for longer PFS (p=0.06), significantly longer for patients receiving medium potency statins (p=0.04). No significant difference in PFS was observed when comparing patients treated with lipophilic statins to all others (not reached vs 84 months, p=0.22). To confirm these clinical data, in-vitro and in-vivo studies were performed. Six cell lines were tested: 4 with high cholesterol content (SUDHL4, HBL1, HT, and U2932; 5.0-8.0 µg/mg protein), and 2 with low cholesterol content (DOHH2 and OCI-LY19; 1.5-2.0 µg/mg protein); the latter showed the highest sensitivity to DXR-mediated killing. The combination of lovastatin and DXR (10nM) was tested in all 4 cell lines with high cholesterol content, resulting in more cell death than either treatment alone. Lovastatin (at the nanomolar range) resensitized DXR-resistant SUDHL4 cells to DXR. Finally, in a DXR-resistant PDX model, the combination of lovastatin and DXR resulted in delayed tumor growth as compared to chemotherapy alone. Conclusions: Use of medium potency statins is associated with improved outcomes after frontline RCHOP in patients with DLBCL. This was further confirmed in functional in-vitro and in-vivo studies. Future interventional studies, aimed at improving outcomes in these patients using this novel combination, are warranted. Disclosures Westin: Amgen: Consultancy; 47: Research Funding; Kite: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding. Nastoupil:Gamida Cell: Honoraria; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Gilead/KITE: Honoraria. Neelapu:Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Karus Therapeutics: Research Funding; N/A: Other; Takeda Pharmaceuticals: Patents &amp; Royalties; Acerta: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Adicet Bio: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Calibr: Other; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding. Landgraf:NCI/NIH: Research Funding. Vega:NCI: Research Funding.

Safety and Efficacy of CD19-CAR T Cells in Richter's Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia

Background: Richter's transformation (RT) is a rare complication of Chronic Lymphocytic Leukemia (CLL), usually into clonally related diffuse large B cell lymphoma (DLBCL). Currently there is no effective therapy to RT and CLL relapse after targeted therapy. Chimeric antigen receptor-modified T (CART) cells directed to CD19+ B-cell malignancies have promising results in relapsed DLBCL. However, its effectiveness in CLL relapse after targeted therapy and RT is less clear and no systematic reports are available. Methods: From July 2019 to May 2020 we enrolled eight CLL patients with disease transformation after chemoimmunotherapy and therapy with BTK and/or BCL2 inhibitors as part of single center phase 2 CAR T-cell therapy in B-cell malignancies (NCT02772198). Following lymphodepletion consisting of cyclophosphamide and fludarabine patients received an infusion of locally produced 1x106 CD19-CART- cells/kg, which were generated by modifying autologous T cells with retroviral vector encoding a CAR comprising FMC63 anti-CD19 ScFv linked to a CD28 costimulatory domain, and CD3-zeta intracellular signaling domain. Results: All 8 patients (pts) were relatively young with median age at CLL diagnosis of 56y (47-62). Disease transformation developed after a median of 8 years (range 1-16) from CLL diagnosis. Patients treated with CD19-CAR T-cells at median age of 64 y (54-73) having median comorbidity G-CIRS score 2 (0-5), performance status ECOG 1 (0-2) and CCT 66ml/min (26-89). Pts had history of CLL with del17p/TP53 in 83%, 5/6 available, del11q 2/6 prior to transformation. Disease transformation included RT in 6 pts with DLBCL, 1 accelerated CLL and 1 prolymphocytic transformations. Among RT pts 67% (4/6) had advanced stage DLBCL, 50% (3/6) extarnodal and 33% (2/6) bulky disease. Patients received median of 3 (0-5) CLL therapies and 2 (1-3) large cell lymphoma directed therapy. CLL therapies included chemoimunotherpay: 5 Fludarabine, cyclophosphamide, rituximab/obinutuzumab (FCR/FCO), 1 bendamustin rituximab (BR); 5 dual targeted therapy (ibrutinib and Venetoclax), 2 ibrutinib only, 1 venetoclax only. Last CLL treatment was Venetoclax in 71% (5/7) and ibrutinib in 29% (2/7) with 32 (range 15-39) months duration on ibrutinib and 10 (2-17) months on venetoclax. The reason for ibrutinib discontinuation was CLL progression (PD) in 5, disease transformation in 2, and venetocalx discontinuation due to progressive disease (PD) - 4 and transformation - 2. Post transformation all RT pts were treated with R-CHOP, second line tx 2, one patient with prolymphocytic transformation was treated with alemtuzumab, allo-SCT, ibrutinib and venetoclax. All pts had PD before treatment with CAR T-cells, 63% (5/8) had elevated LDH and 5/8 evaluable PET CT before treatment had deauville score (DS) 5 with median SUVmax 8.7 (3.7-21). After infusion of CAR T-cells 7 patients had cytokine release syndrome (CRS), 4 grade 1 and 3 grade 3-4 that required tocilizumab. Three patients had CNS toxicity, two grade 3. Seventy five percent (6/8) developed neutropenia, (3/8) grade 3-4, all neutropenia resolved except in one patient that succumbed to PD, 2 pts had infections (campylobacter and H1N1 influenza, each). There were no fatalities due to CAR T-cell toxicity. There were two fatalities due to disease progression. All 71% (5/8) responders achieved complete response with DS1 in PET CT scan on day 28. After median follow up duration of 6 (4-10) months, 2 patients proceeded to allo-SCT. Conclusion: CD19-CART-cell therapy in CLL patients with disease transformation is safe and has high complete remission rate with promising clinical response. Long term remission rate after CD19-CART-cell therapy for RT needs to be further evaluated in more patients. Disclosures Benjamini: Abbvie Inc: Consultancy, Research Funding. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Fineman:Abbvie Inc: Consultancy, Research Funding. Jacobi:Novartis: Consultancy. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding.

Biomarkers and novel therapeutic approaches for diffuse large B-cell lymphoma in the era of precision medicine.

Despite the great efforts for better treatment options for diffuse large B-cell lymphoma (DLBCL) (most common form of non-Hodgkin lymphoma, NHL) to treat and prevent relapse, it continues to be a challenge. Here, we present an overview of DLBCL and address the diagnostic assays and molecular techniques used in its diagnosis, role of biomarkers in detection, treatment of early and advanced stage DLBCL, and novel drug regimens. We discuss the significant biomarkers that have emerged as essential tools for stratifying patients according to risk factors and for providing insights into the use of more targeted and individualized therapeutics. We discuss techniques such as gene expression studies, including next-generation sequencing, which have enabled a more understanding of the complex pathogenesis of DLBCL and have helped determine molecular targets for novel therapeutic agents. We examine current treatment approaches, outline the findings of completed clinical trials, and provide updates for ongoing clinical trials. We highlight clinical trials relevant to the significant fraction of DLBCL patients who present with complex cases marked by high relapse rates. Supported by an increased understanding of targetable pathways in DLBCL, clinical trials involving specialized combination therapies are bringing us within reach the promise of an effective cure to DLBCL using precision medicine. Optimization of therapy remains a crucial objective, with the end goal being a balance between high survival rates through targeted and personalized treatment while reducing adverse effects in DLBCL patients of all subsets.

Type 2 diabetes mellitus compromises the survival of diffuse large B-cell lymphoma patients treated with (R)-CHOP \u2013 the PLRG report

Comorbidities impair the prognosis of diffuse large B-cell lymphoma (DLBCL). Type 2 diabetes mellitus (DMT2) increases the risk of other comorbidities, e.g., heart failure (HF). Thus, we hypothesized that pre-existing DMT2 may negatively affect the outcome of DLBCL. To verify this, DLBCL patients treated with (R)-CHOP were enrolled. 469 patients were eligible, with a median age of 57 years; 356 patients had advanced-stage DLBCL. 126 patients had high-intermediate and 83 high-risk international prognostic index (IPI). Seventy-six patients had DMT2, 46 HF; 26 patients suffered from both DMT2 and HF. In the analyzed group DMT2 or HF significantly shortened overall survival (OS) and progression free survival (PFS): the 5-year OS for patients with DMT2 was 64% vs 79% and for those with HF: 49% vs 79%. The 5-year PFS for DMT2 was 50.6% vs 62.5% and for HF 39.4% vs 63.2%. The relapse/progression incidence was comparable between groups; the non-relapse/progression mortality (NRPM) was significantly higher solely in DMT2 patients (5-year NRPM 22.5% vs 8.4%). The risk of death was higher in patients with higher IPI (HR = 1.85) and with DMT2 (HR = 1.87). To conclude, pre-existing DMT2, in addition to a higher IPI and HF, was a negative predictor for OS and PFS.