Outcome In Diffuse Large B-cell Lymphoma Research Articles

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.

Tumour-associated macrophages in diffuse large B-cell lymphoma: the prognostic and therapeutic impact in a South African centre with high HIV seroprevalence.

Diffuse large B-cell lymphoma (DLBCL) is a common malignancy among people living with HIV. Macrophage enrichment of the tumour microenvironment (TME) is a prognostic factor in DLBCL among immunocompetent people, with some studies reporting that macrophage enrichment predicts a superior response to rituximab therapy. The macrophage phenotype is also important, with reportedly poorer outcomes with enrichment of anti-inflammatory (M2) macrophages. To date, the relationship between the type/number of tumour macrophages and outcomes in HIV-associated DLBCL (HIV-DLBCL) has been poorly explored. In this study, we assessed tumour macrophage numbers in a South African cohort of patients with DLBCL and a high HIV-seropositivity rate. Immunohistochemistry for CD68 and CD163 was performed on the diagnostic biopsies of 79 patients with DLBCL. Relevant information was documented from the clinical records, including disease stage, international-prognostic index score, HIV-related parameters, C-reactive protein, ferritin levels and immune cell numbers (monocytes, lymphocytes and neutrophils). Survival analysis was performed using Kaplan-Meier survival estimates, and the correlation between tumour macrophage numbers and a variety of immunological parameters was assessed using Spearman's rho. Of the 79 patients included, 87.2% were living with HIV, and rituximab therapy was used in 46.9%. Tumour macrophage numbers were not related to HIV status, but low pro-inflammatory (M1) macrophage numbers (CD68 + CD163 -) were significantly associated with poorer outcomes (HR 2.02, p = 0.03). M2 macrophage (CD68 + CD163 +) enrichment was not predictive of survival but was associated with improved response to rituximab therapy (HR 0.19; p = 0.002). Macrophage numbers were marginally correlated with ferritin levels, which showed modest performance as a peripheral blood biomarker of the TME macrophage status (AUC 0.6 at a level of 374µg/L), and high ferritin levels were associated with a superior response to rituximab-therapy (HR 0.28, p = 0.034). Pro-inflammatory macrophages are important in tumour control in HIV-DLBCL, while M2 macrophage enrichment improves the response to rituximab therapy. Ferritin shows promise as a biomarker for identifying patients more likely to benefit from rituximab therapy.

Rolling the DICEP on lymphoma salvage treatments? Choose wisely.

Although immunotherapy is rapidly changing the treatment approach to r/r diffuse large B cell lymphoma, there is still a place for autologous stem cell transplantation in some patients. The report by Stewart etal. focuses on induction therapy and the importance of the pretransplantation phase. Commentary on: Stewart etal. Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-Outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19555.

Metabolic pathway-based subtyping reveals distinct microenvironmental states associated with diffuse large B-cell lymphoma outcomes.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease that requires personalized clinical treatment. Assigning patients to different risk categories and cytogenetic abnormality and genetic mutation groups has been widely applied for prognostic stratification of DLBCL. Increasing evidence has demonstrated that dysregulated metabolic processes contribute to the initiation and progression of DLBCL. Metabolic competition within the tumor microenvironment is also known to influence immune cell metabolism. However, metabolism- and immune-related stratification has not been established. Here, 1660 genes involved in 84 metabolic pathways were selected and tested to establish metabolic clusters (MECs) of DLBCL. MECs established based on independent lymphoma datasets distinguished different survival outcomes. The CIBERSORT algorithm and EcoTyper were applied to quantify the relative abundance of immune cell types and identify variation in cell states for 13 lineages comprising the tumor micro environment among different MECs, respectively. Functional characterization showed that MECs were an indicator of the immune microenvironment and correlated with distinctive mutational characteristics and oncogenic signaling pathways. The novel immune-related MECs exhibited promising clinical prognostic value and potential for informing DLBCL treatment decisions.

Racial disparities in the incidence and survival outcomes in diffuse large B-cell lymphoma in adolescents and young adults.

Diffuse large B-cell Lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL). The disease generally occurs in older patients. Although at a lower prevalence, the disease also occurs in the adolescent and young adult group (AYA). There is paucity of data in the literature on racial and ethnic disparities in the incidence and survival outcomes of DLBCL in the AYA group. The objective of our study is to demonstrate the disparities in these outcomes. Utilizing SEER, we obtained data on patient demographics, incidence, and survival from 2000 to 2020. We observed statistically significant reduced incidence of DLBCL in all racial groups, except the non-Hispanic Asian and Pacific Islander group (NHAPI). The non-Hispanic Black group (NHB) had one of the lowest survival despite showing the largest decrease in incidence in DLBCL. The differences in the survival could be secondary to socioeconomic factors, however other reasons need to be explored. The increased incidence among the NHAPI group mirrors that of large population-based studies in East Asian countries, however, underlying reasons have not been elucidated.

Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP.

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.

Advances in proteomics in diffuse large B‑cell lymphoma (Review).

Diffuse large B‑cell lymphoma (DLBCL) is the most common pathological type of non‑Hodgkin's lymphoma. Although the development of monoclonal antibodies, small‑molecule‑targeted drugs and novel chemotherapeutic agents, and the increased use of immunotherapy have markedly improved the outcomes of DLBCL, ~40% of patients cannot be cured following the use of standardized first‑line treatment. In addition, the specific mechanisms of drug resistance and potential factors associated with a poor prognosis in these patients remain unclear. Proteomics research is used to determine potential associations between changes in DLBCL protein expression levels and different stages of disease occurrence and development. Proteomics may aid in the identification of novel molecular mechanisms and drug resistance mechanisms, through identifying multiple associated proteins and monitoring changes in expression levels. Thus, proteomics research may exhibit potential in the development of therapeutic targets and in improving prognostic evaluation in patients with DLBCL. The present study aimed to review the use of proteomic methods for the investigation of DLBCL, including the mechanisms underlying disease progression and drug resistance in DLBCL, and the function of the tumor microenvironment in lymphoma growth. The present review also demonstrated the potential of proteomic‑guided therapeutic strategies for DLBCL and discussed the synergistic benefits of using proteomic methods in DLBCL research.

The impact of race and ethnicity on diffuse large B-cell lymphoma outcomes within the veterans health administration (VHA)

We performed a retrospective chart review of 6266 randomly selected DLBCL patients treated in the VHA nationwide between 1/1/2011 and 12/31/2021. The 3178 patients who met inclusion criteria were predominantly male (97%) and white (75%). Median age of diagnosis for Black patients was 63 years vs 69 years for the entire cohort (p < 0.001). However, patients in each race/ethnicity subgroup presented with similar rates of stage I/II and III/IV disease, IPI score, cell of origin and HIT status. Outcomes analysis revealed similar treatment, response rates, median overall survival, and 1-, 3-, and 5-year survival across all subgroups. Hispanic patients had a 21% lower risk of death (HR = 0.79) than white patients, and Black patients had no significant difference in survival (HR = 0.98). This large retrospective study shows that when standard of care therapy is given within an equal access system, short-term treatment and survival outcomes are the same for all races.

Derangements of immunological proteins in HIV-associated diffuse large B-cell lymphoma: the frequency and prognostic impact.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy of B-cells frequently encountered among people living with HIV. Immunological abnormalities are common in immunocompetent individuals with DLBCL, and are often associated with poorer outcomes. Currently, data on derangements of immunological proteins, such as cytokines and acute phase reactants, and their impact on outcomes in HIV-associated DLBCL (HIV-DLBCL) is lacking. This study assessed the levels and prognostic relevance of interleukin (IL)-6, IL-10 and Transforming Growth Factor Beta (TGFβ), the acute phase proteins C-reactive protein (CRP) and ferritin; serum free light chains (SFLC) (elevation of which reflects a prolonged pro-inflammatory state); and the activity of the immunosuppressive enzyme Indoleamine 2,3-dioxygenase (IDO)in South African patients with DLBCL. Seventy-six patients with incident DLBCL were enrolled, and peripheral blood IL-6, IL-10, TGFβ, SFLC and IDO-activity measured in selected patients. Additional clinical and laboratory findings (including ferritin and CRP) were recorded from the hospital records. Sixty-one (80.3%) of the included patients were people living with HIV (median CD4-count = 148 cells/ul), and survival rates were poor (12-month survival rate 30.0%). The majority of the immunological proteins, except for TGFβ and ferritin, were significantly higher among the people living with HIV. Elevation of IL-6, SFLC and IDO-activity were not associated with survival in HIV-DLBCL, while raised IL-10, CRP, ferritin and TGFβ were. On multivariate analysis, immunological proteins associated with survival independently from the International Prognostic Index (IPI) included TGFβ, ferritin and IL-10. Derangements of immunological proteins are common in HIV-DLBCL, and have a differential association with survival compared to that reported elsewhere. Elevation of TGFβ, IL-10 and ferritin were associated with survival independently from the IPI. In view of the poor survival rates in this cohort, investigation of the directed targeting of these cytokines would be of interest in our setting.

Assessing the Impact of Comorbid Hypercalcemia on Inpatient Outcomes of Patients With Diffuse Large B-cell Lymphoma During Admission for Chemotherapy.

Introduction Diffuse large B-cell lymphoma (DLBCL) may be complicated by hypercalcemia at various stages of treatment. The impact of hypercalcemia on chemotherapy admission outcomes in DLBCL is not well described. Methods In a retrospective analysis, using the National Inpatient Sample database (2018 - 2020), patients with DLBCL admitted for chemotherapy were dichotomized based on the presence of hypercalcemia. Our primary outcome was all-cause mortality. Secondary outcomes included length of stay (LOS), total charge, rate of acute kidney injury (AKI), tumor lysis syndrome (TLS), hyperkalemia, metabolic acidosis, acute encephalopathy, septic shock, Clostridiodes difficile infection, acute respiratory failure, and venous thromboembolic events (VTE). Results We identified 78,955 patients, among whom 1,375 (1.74%) had hypercalcemia. Hypercalcemia was associated with higher odds of all-cause mortality (aOR:3.05, p-value:0.020), TLS (aOR:8.81, p-value<0.001), acute metabolic encephalopathy (aOR:4.89, p-value<0.001), AKI (aOR:5.29, p-value<0.001), hyperkalemia (aOR:2.84, p-value:0.002), metabolic acidosis (aOR:3.94, p-value<0.001) and respiratory failure (aOR:2.29, p-value:0.007) and increased LOS by 1 day andtotal charge by 12, 501 USD. Conclusions In patients with DLBCL admitted for inpatient chemotherapy, those with hypercalcemia compared to a cohort without had higher odds of; all-cause mortality, TLS, AKI, acute encephalopathy, acute metabolic acidosis, hyperkalemia, and acute respiratory failure as well as higher LOS and total charge.

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.

Yin Yang 1 expression predicts a favourable survival in diffuse large B-cell lymphoma

AimsYin Yang 1 (YY1) is a multifunctional transcription factor that plays an important role in tumour development and progression, while its clinical significance in diffuse large B-cell lymphoma (DLBCL) remains largely unexplored. This study aimed to investigate the expression and clinical implications of YY1 in DLBCL. MethodsYY1 expression in 198 cases of DLBCL was determined using immunohistochemistry. The correlation between YY1 expression and clinicopathological parameters as well as the overall survival (OS) and progression-free survival (PFS) of patients was analyzed. ResultsYY1 protein expression was observed in 121 out of 198 (61.1 %) DLBCL cases. YY1 expression was significantly more frequent in cases of the GCB subgroup than in the non-GCB subgroup (P = 0.005). YY1 was positively correlated with the expression of MUM1, BCL6, pAKT and MYC/BCL2 but was negatively associated with the expression of CXCR4. No significant relationships were identified between YY1 and clinical characteristics, including age, sex, stage, localization, and B symptoms. Univariate analysis showed that the OS (P = 0.003) and PFS (P = 0.005) of patients in the YY1-negative group were significantly worse than those in the YY1-positive group. Multivariate analysis indicated that negative YY1 was a risk factor for inferior OS (P < 0.001) and PFS (P = 0.017) independent of the international prognostic index (IPI) score, treatment and Ann Arbor stage. Furthermore, YY1 is more powerful for stratifying DLBCL patients into different risk groups when combined with MYC/BCL2 double-expression (DE) status. ConclusionsYY1 was frequently expressed in DLBCL, especially in those of GCB phenotype and with MYC/BCL2-DE. As an independent prognostic factor, YY1 expression could predict a favourable outcome in DLBCL. In addition, a complex regulatory mechanism might be involved in the interactions between YY1 and MYC, pAKT as well as CXCR4 in DLBCL, which warrants further investigation.

Dissemination feature based on PET/CT is a risk factor for diffuse large B cell lymphoma patients outcome

Background18F-FDG PET/CT provides precise information about dissemination of lymphoma lesions. Dmax, defined as distance between the two lesions that were farthest apart by PET/CT, was found to be a promising predictor of Diffuse large B-cell lymphoma (DLBCL) outcome in a small size of clinical trial data. We analyzed the impact of Dmax on the outcome of a large real-world DLBCL cohort.MethodsData of newly diagnosed DLBCL at the Third Affiliated Hospital of Soochow University were retrospectively collected. Baseline Dmax, clinical data and survival information were recorded. A metabolic parameter, metabolic bulk volume (MBV), was also measured to verify the independent impact of Dmax.ResultsOptimal cut-off values for Dmax and MBV were 45.34 cm and 21.65 cm3. With a median follow-up of 32 months, Dmax significantly impacted progression-free survival (PFS) and overall survival (OS) in 253 DLBCL patients. For Dmaxlow and Dmaxhigh groups, estimated 3-year OS were 87.0% and 53.8% (p < 0.001), while 3-year PFS were 77.3% and 37.3% (p < 0.001). And for MBVlow and MBVhighgroups, 3-year OS were 84.5% and 58.8% (p < 0.001), and 3-year PFS were 68.7% and 50.4% (p = 0.003). Multivariate analysis identified Dmax and Eastern Cooperative Oncology Group performance status (ECOG PS) independently associated with PFS and OS, while MBV only independently associated with OS. A Dmax revised prognostic index (DRPI) combining Dmax and ECOG PS identified an ultra-risk DLBCL population with 3-year PFS of 31.7% and 3-year OS of 38.5%. The area under the curve (AUC) showed that this model performed better than International prognostic Index (IPI).ConclusionDmax is a new and promising indicator to investigate dissemination of lymphoma lesions associated with the outcome of DLBCL. It significantly contributes to stratification of patients with disparate outcomes.Trial registrationThis research has been retrospectively registered in the Ethics Committee institutional of the Third Affiliated Hospital of Soochow University, and the registration number was approval No. 155 (approved date: 31 May 2022).

Examining Racial Disparities in Diffuse Large B-Cell Lymphoma (DLBCL) Outcomes within the Veterans Health Administration (VHA)

INTRODUCTION: The incidence of DLBCL in the United Sates is projected to increase to 32, 443 new cases per year by 2025. With increasing incidence and prevalence, DLBCL prognosis has improved significantly in the past decade through the addition of novel therapies such as new monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) therapy, antibody-drug conjugates, and most recently bispecific T-cell engagers. Despite these improvements, racial and ethnic disparities continue to impact outcomes in DLBCL patients (Flowers 2012). The purpose of this study was to assess racial and ethnic differences in DLBCL patients and outcomes within the VHA, an equal access system where confounding factors such as disease biology and socioeconomic status are more controlled giving us an opportunity to examine racial disparities. The aim of this study is to present a final analysis the final analysis of racial and ethnic differences in DLBCL patients within the VHA over a time span of 11 years. METHODS: Trained abstractors performed a retrospective chart review of 6266 randomly selected DLBCL patients treated in the VHA nationwide between 1/1/2011 and 12/31/2021. Patients diagnosed with DLBCL were included. Patients were excluded if they had a diagnosis other than DLBCL, had incomplete records, or were diagnosed and treated outside the VHA. Data was collected on baseline patient demographics, disease characteristics, and treatment. Survival time was determined via electronic health record query on 1/4/2023. The study population was divided into non-Hispanic Black (NHB), non-Hispanic White (NHW), Hispanic (H), and other. Chi-squared tests were used to analyze the relationship between race and variables of interest. RESULTS: 3178 patients met inclusion criteria for analysis. Patients were predominantly male with a median age of 69 and presented primarily with advanced disease (Baseline Characteristics-Table 1). NHB were diagnosed at a younger median age (63 years) when compared to the NHW, H and other (69 years, P &amp;lt; 0.001). Patients in each subgroup presented with similar rates of stage I/II and III/IV disease with no statistically significant difference in stage at presentation amongst each racial subgroup (P=0.61). Of all the patients who received chemotherapy, the objective response (OR) rate was 79.2% with a complete response (CR) rate of 66.4%. The response rates were similar across the 4 subgroups with most patients achieving a CR after first-line therapy (P=0.74). There were no statistically significant differences in OR rates amongst subgroups (P = 0.95). Median overall survival (mOS) for the entire population was 69.6 months (95% CI = 65-75), with a mOS of 85.1 months (67-112), 85.9 months (60-112), 67.4 months (60-73), and 71.2 months (49-122) for NHB, H, NHW, and other patients respectively (Figure 1). There was no statistically significant difference in mOS amongst subgroups (P = 0.13). The 1-year, 3-year, and 5-year survival rates were also similar between subgroups (P=0.97, P= 0.39, P=0.32 respectively). CONCLUSION: This study represents one of the largest retrospective analyses of DLBCL in the VHA nationwide, highlighting that there is no statistically significant racial difference in DLBCL outcomes for patients treated within the VHA. Our study highlights the significance of equal access system and that disease biology and other social factors can be mitigated resulting in equal response to treatment and OS amongst all groups. Potential limitations of this study include using retrospective data on a predominantly white, male population that may not truly represent general DLBCL population data. The study period is mainly until 2021 with limited data on the accessibility of newer, novel treatments. With the development of newer, expensive treatments, especially Bispecific T Cell Engagers and CAR-T therapy, it is imperative to study utilizations of these novel treatments and study racial differences in this new treatment non-chemotherapy-based era.

Selinexor in Combination with Salvage Regimen for Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Patients with TP53 Alterations

Background TP53 has been identified as one of the most frequently altered gene in diffuse large B-cell lymphoma (DLBCL). The prognosis of DLBCL patients with TP53 mutations ( TP53mut) was poor prognosis in R-CHOP era, even with treatments like autologous stem-cell transplantation (ASCT) or anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy. Moreover, TP53 mutations are more prevalent at relapse and are associated with therapeutic resistance. Selinexor is a selective inhibitor of nuclear export with promising anti-cancer properties and preclinical studies have shown its potential to suppress tumor cells with TP53 mutations. Several clinical studies proved selinexor in combination with R-GDP/R-ICE/R-Gemox was effective in relapsed/refractory DLBCL. Method The study enrolled relapsed/refractory DLBCL patients with TP53 alterations (including TP53 mutation and/or deletion) for treatment with selinexor in combination with salvage regimens (R-GDP/R-ICE/R-Gemox) since November 2021 in our center. The treatment was administered orally as 40 mg of selinexor on days 1, 8, and 15, combined with one of the following regimens: R-GDP (R 375mg/m2 d0, gemcitabine 1g/m2*d1, cisplatin 25mg/m2 d1-d3, dexamethasone 40mg d1-d4). R-ICE (R 375mg/m2 d0, ifosfamide 1.5g/m2*3d, carboplatin (AUC 5) and etoposide 100mg/m2*3d). R-Gemox ((R 375mg/m2 d0, gemcitabine 1g/m2*d1, oxaliplatin 100mg/m2*d1) every 3 weeks as per physician's choice. Objective response rate (ORR) was evaluated every 3 cycles based on Lugano 2014 criteria and Adverse events (AE) were rated according to the NCI CTCAE 5.0. Results 20 patients were treated with selinexor plus salvage regimen in this study and received at least two cycles of treatment, making them eligible for analysis. The median age of the 20 patients was 54 years (range 15 to 77), of this patients, 12 (60%) were male, 12 (60%) patients had disease stage III-IV at screening, and 45% with IPI&amp;gt;2. The median number of prior regimen was 1 (range, 1-4) with 2 patients (2 L) and 1 patient (3L). ALL patients were refractory to the last line of treatment. The patients received a median of three cycles (range, 2-6) of selinexor 40mg once a week combined with salvage regimen (13 patients received selinexor plus R-GDP, 6 with selinexor plus R-ICE and 1 with selinexor plus R-Gemox). The mutational profile of patients was presented in Figure A (14 patients with TP53 mutation, 5 patients with TP53 mutation and deletion, 1 with TP53 deletion). The best overall and complete response rates were 75% and 25%, respectively. Among them, 6 patients in PR and 1 patient in SD received CART treatment, and 5 achieved PR and 2 with CR after CART treatment (Figure B). One patient experienced PD after selinexor+R-GDP and died of disease progression within one month after CART transfusion. 1 SD patient transferred to CD3/CD20 bispecific antibody clinical trial and still progressed during the bispecific treatment. Taken together, selinexor-based salvage regimen had promising response rate in refractory DLBCL with TP53 alterations, and could be a potential bridging approach before CART therapy. Patients responded to selinexor-based regimen tended to have better outcome after CART or bispecific antibody treatment. Conclusions TP53 alterations are associated with poor outcomes in DLBCL. We identified an effective dosing schedule of selinexor (40mg QW) in combination with R-GDP/R-ICE/R-Gemox for TP53-altered refractory DLBCL patients. Further research is warranted to investigate the mechanism of action behind this treatment approach

Germinal Center B-Cell-like (GCB) Phenotype Predicts Improved Outcomes in Central Nervous System Diffuse Large B-Cell Lymphoma Patients Receiving Stereotactic Radiosurgery (SRS)

Background: Diffuse large B cell lymphoma (DLBCL) constitutes most cases of both primary and secondary central nervous system lymphoma (CNSL). They represent a highly aggressive subset of non-Hodgkin lymphoma and prognosis varies depending on the cell of origin. Immunohistochemistry using antibodies for CD10, BCL-6, and MUM-1, also known as the Hans algorithm, is the most common method for determining the cell of origin and predicting outcomes in DLBCL. The study by Hans et al. found that the germinal center B-cell-like (GCB) group had a much better prognosis compared to the non-GCB group, with 5-year overall survival (OS) of 76% and 34% respectively. Despite chemotherapy, recurrence is common in these patients, and up to 40-50% do not achieve durable remission. It is important to identify who may benefit from more aggressive or experimental therapy at diagnosis. Stereotactic radiosurgery (SRS) is the administration of a localized, high dose of ionizing radiation and limited studies exist exploring SRS as a treatment modality in relapsed/refractory (r/r) CNSL or prognostic implications of the Hans algorithm in these patients. Aim/Objective: To perform a retrospective analysis of outcomes of patients with CNSL, phenotypes determined by the Hans algorithm, treated with SRS at a single comprehensive cancer center. Methods: We studied the demographic, clinical, pathological, and treatment characteristics of r/r CNSL patients (N=27), age ≥ 18 years, who received SRS at Roswell Park Comprehensive Cancer Center between 01/2000 and 01/2023. The Hans algorithm was used to group the patients into non-GCB (N=17) and GCB (N=10) cohorts. Overall survival (OS) and progression-free survival (PFS) were calculated and reported using Kaplan-Meier analyses and log-rank tests. Cox regression models were used to describe cross-cohort comparisons of survival. Results: The median Karnofsky performance status at diagnosis was 70 for both groups. The overall response rate (ORR) to SRS in GCB-type was 80% (7 complete response and 1 partial response; CR, PR). The ORR in non-GCB type was 58% (6 CR and 4 PR). Post-SRS, stem cell transplant (SCT) was avoided in 100% of the patients in the GCB group, while 17% of the patients in the non-GCB group received SCT. The 6-month overall survival (OS) rate was 100% and 46% for the GCB-type and non-GCB type respectively (p=0.096, Figure 1A). The 6-month progression-free survival (PFS) rate was 80% for the GCB-type and 33% for the non-GCB type (p=0.024, Figure 1B). In the GCB group, the median OS was 18.0 months while the median PFS was 13.8 months. In the non-GCB group, the median OS was 4.9 months while the median PFS was 3.6 months. The median time from chemotherapy completion to SRS administration was 8.0 months in the GCB-type and 2.0 months in the non-GCB type. Conclusion: Our data support that the GCB-type predicts a more favorable outcome in CNSL, with improved OS and PFS rates compared to the non-GCB type. In addition, the non-GCB type patients required earlier SRS administration and had a lower ORR to SRS. Classifying CNSL into GCB and non-GCB phenotypes using the Hans algorithm might help characterize patients into groups with different prognoses.

Real-World Use of Tafasitamab (tafa) for Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Among Racial and Ethnic Minorities in the United States

Introduction: Tafa, a CD19-targeting immunotherapy, received accelerated approval by the FDA in combination with lenalidomide (len) for the treatment of patients with R/R DLBCL ineligible for autologous stem cell transplantation. In a recent real-world study (RWS) of tafa for R/R DLBCL, nearly one-third of patients were from typically underrepresented racial groups (abstract submitted to ASH 2023). Research has shown that patient characteristics, risk factors, and outcomes for DLBCL can differ by race and ethnicity (Li Y, et al. Cancer Epidemiol. 2015;39:8-13; Ermann D et al. J Clin Oncol. 2022;40(suppl):7507). The purpose of this analysis is to understand the patient characteristics, treatment patterns, and outcomes observed in the tafa RWS by race and ethnicity. Methods: This was a retrospective cohort study in which participating physicians from Cardinal Health's Oncology Provider Extended Network abstracted data from eligible patients' medical records into electronic case report forms. Eligible patients were ≥18 years of age who initiated tafa for R/R DLBCL on or after Oct 21, 2020. Included patients had ≥4 months of follow-up unless the patient died during this period. Use of tafa in combination with len was not a requirement for study eligibility. Patients who received tafa as part of a clinical trial were excluded. Results were summarized by race (White, Black/African American, “Other”) and ethnicity (Non-Hispanic, Hispanic) using descriptive statistics. The “Other” racial category included patients with mixed race or a race other than White, Black/African American, or Unknown. The Kaplan-Meier method was used to measure time to tafa discontinuation. Due to limited follow-up and small sample size, effectiveness outcomes for subgroups smaller than 20 patients are not presented. Results: A total of 181 patients who initiated tafa for R/R DLBCL were included in this analysis. Table 1 shows patient characteristics, treatment patterns, and outcomes by racial and ethnic groups. The racial composition of the study population was 64% White, 22% Black/African American, 8% “Other,” and 6% Unknown (Unknown not displayed in Table), and ethnic composition was 82% non-Hispanic, 17% Hispanic, and 1% Unknown (Unknown not displayed in Table). Most physicians who participated in this study were from community oncology practices (83%). The median follow-up time from tafa initiation to data collection among all patients was 6.5 (interquartile range [IQR], 5.0-8.6) months. The majority of patients (96%) received tafa in combination with len. At the time of data collection, 144 patients (80%) were alive, among whom 121 (84%) were still receiving tafa. The median age at which tafa was initiated ranged from 70 to 72 years for all racial and ethnic groups. Among the racial groups, the White cohort had the highest percentage of patients with an ECOG PS ≥2 (53%) and Ann Arbor Stage IV (68%) at time of tafa initiation. Among the racial categories, the median time (IQR) from initial DLBCL diagnosis to initiation of tafa was longest in Black/African Americans (23.3 [12.6-34.8] months) and shortest in the “Other” group (18.0 [15.0-21.4] months). In non-Hispanics and Hispanics, the median (IQR) duration from initial DLBCL diagnosis to tafa initiation was 20.0 (12.4-35.0) and 19.0 (14.0-34.0) months, respectively ( Table 1). Among patients who had disease response data, the real-world overall response rate (95% CI) was 75.0% (66.8-83.2) and 77.5% (64.6-90.4) for the White and Black/African American cohorts, and 74.5% (67.3-81.7) and 80.8% (65.7-95.9) for non-Hispanic and Hispanic groups, respectively ( Figure 1). Conclusions: The diverse population in this RWS is reflective of the heterogeneous patient population with R/R DLBCL treated primarily at community oncology centers in the United States. In addition, the study results support the clinical benefit of tafa across racial and ethnic groups. The majority of patients were still receiving tafa at data cutoff and follow-up was limited in duration; the median follow-up time in this study was shorter than the median time to complete response observed in L-MIND (NCT02399085; Duell J, et al. Haematologica. 2021;106:2417-2426), the pivotal phase 2 trial that contributed to the accelerated FDA approval of tafa for R/R DLBCL. A longer follow-up is required to better assess long-term outcomes of tafa treatment for R/R DLBCL among racial and ethnic patient groups.

Personalized Monitoring of Circulating Tumor DNA By a Specific Signature of Trackable Mutations after Chimeric Antigen Receptor t-Cell Therapy in Non-Hodgkin B Cell Lymphoma

Introduction CART-cell therapy (CART) has produced a paradigm shift in the treatment of relapsing non-Hodgkin B-cell lymphoma (NHBcL). However, patients continue to relapse. Thus, developing strategies to optimize disease surveillance after this therapy is becoming increasingly important to attain disease-free survival and predict a potential relapse in advance. To facilitate its applicability, such strategies should also be minimally invasive. Hence, this study aims to explore the value of CloneSight, a circulating tumor DNA (ctDNA) monitoring approach based on a signature of personalized trackable mutations for the follow-up of NHBcL under CART. Methods A total of 30 NHBcL patients treated with CD19 CART-cell therapy were included in this work. Ten patients were diagnosed with Follicular Lymphoma (FL), and 20 with Diffuse Large B-Cell-Lymphoma (DLBCL). Genomic profiling was performed at relapse using FFPE biopsies and cfDNA liquid biopsies to detect somatic mutations by a custom capture enrichment panel (Twist, USA) covering 134 genes. Sequencing was conducted with the Illumina NextSeq platform. Then, the patient-specific somatic mutations were used as biomarkers for quantifying Minimal Residual Disease (MRD) on liquid biopsy follow-up samples with a sensitivity of 10 −4 (Jiménez-Ubieto A et al., Leukemia 2023). The amplicon-based, patient-specific MRD mini-panel also included primers to quantify the CART Phi construct relative to the albumin control gene. A total of 118 peripheral blood samples were collected. Plasma was isolated at day +7, +14, +30, +60, +90, and before progression (59 DLBCL and 59 FL samples). PET/CT examinations were performed on days +90, +180, +365 and every six months in FL, and the same for DLBCL but additionally on day +30. Results We found 185 trackable somatic mutations suitable for MRD monitoring (mean: 6.2 per patient). The most frequently mutated genes were CREBBP (80%), KMT2D (50%) and EP300 (30%) in FL, and KMT2D (45%), CREBBP (40%), and TP53 (35%) in DLBCL. The applicability of the test (detection of at least one somatic mutation) was 100%. Nineteen patients presented a cfDNA evaluation between days +30 and +60 ( Figure, left). Twelve progressed and ten of them were CloneSight-positive. Patient FL107, negative at day 28, presented a positive result at progression (day 180). For patient DLBCL16, the last sample available was at day +30, but the progression occurred at day 80, highlighting the need for sequential response assessment. Regarding the remaining nine cases in CR, five were negative and two positives by the test (SE 83%, SP 71%, PPV 83%, NPV 67%). Of note, FL101 becomes CloneSight-negative in the next Time-point (TP) available (day 112) and maintains MRD negativity in three more TPs (last at day 907). The remaining discordant case, DLBCL21, has a follow-up of only 60 days. Of note, patient DLBCL3 did not respond to CART but achieved CR and Clonesight-negativity under immune checkpoint inhibitor therapy. The ctDNA surveillance highly correlated with the PET/CT results ( Figure, right). Remarkably, 27 out of 32 PET/CT-negative TPs (84%) were consistent with a CloneSight-negative determination on belong two patients that did not progress. Four of five TPs with PET/CT-negative and CloneSight-positive status were classified as false negative PET/CTs, as those patients finally progressed. On the other hand, 13 out of 16 positive PET/CT samples (81%) were CloneSight-positive and the patient progressed. Of the remaining three PET/CT positive CloneSight-negative, two belong to patients that also progressed. Conclusions: In CAR-T therapy, monitoring with MRD by ctDNA is consolidated as a useful and necessary tool. Our CloneSight test can predict DLBCL and FL outcomes in advance and could be of high utility to detect false positive or negative PET/CT assessments during follow-ups. However, dynamic response assessment is crucial to draw meaningful conclusions. Further research and a larger cohort will be presented at the meeting.

Validating the Systemic Inmmune-Inflamation Index (SII) As a Prognostic Biomarker of Overall Survival in Diffuse Large B-Cell Lymphoma: A Retrospective Analyses By the Gruppo De Estudio Latinoamericano De Linfoproliferativos (GELL)

Introduction: Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy and the most common type of non-hodgkin´s lymphoma. Biologically, survival of neoplastic lymphoid cells depends on self-mediated mechanisms and the tumor microenvironment ( Steen CB,2021) leading to an inflammatory state. Although a better understanding of lymphoma biology has helped predict outcomes in DLBCL, modern tools such as next generation sequencing are not available in Latin America ( LATAM). The systemic immune-inflammation index (SII) is a score based on neutrophil, platelet, and lymphocyte counts that has proven to be useful in DLBCL ( ZanZan W, 2021 &amp; Xiao-Bo,2021). Moreover, its variables can be easily evaluated at resource-limited healthcare setting. Thus, we aim to validate this new SII score in our LATAM DLBCL population. Methods. A retrospective analysis of patients aged ≥18 years with a new diagnosis of DLBCL between 2010 and 2018 were included. Data were obtained from 7 LATAM countries: Argentina, Colombia, Chile Mexico, Peru, Uruguay, and Venezuela. Clinical features including the international Prognostic Index (IPI) variables (i.e. age≥60 years, ECOG performance status ≥2, &amp;gt;1 site extranodal involvement, elevated serum LDH, and advanced clinical stage) and low serum albumin defined as &amp;lt;3.5mg/dL (divided in low 3.4-2.5mg/dL &amp; very low &amp;lt;2.5mg/dL) were recorded. We calculated the neutrophil/lymphocyte ratio (NLR) and use the cut-off previously published by our group (Beltran&amp;Villela,2020). The SII score was calculated using the following formula: (absolute neutrophil count x platelet count) divided by absolute lymphocyte count x100; The cut-off was calculated by the ROC method. Demographics characteristics are reported using descriptive statistics. Cox proportional-harzard regression model was used to evaluate parameters associated with OS curves estimated with the Kaplan-Meier (KM) method. Outcomes. A total of 1032 patients were identified of whom 1029 received standard dose RCHOP (n=862,84%), R-miniCHOP (43,4.17%), R-EPOCH (n=61,5.92%) and CHOP (n=63,6.12%) with a curative intent. A total of 992 patients had suffcient data for analysis. Median follow.up for all cohort was 45 months (IQR: 7 to 60). Median age at diagnosis was 63 years (58.4%, age ≥60;IQR: 50 to 73), 50% was female, 33% had ECOG ≥2, 22% extranodal involvement (EN) &amp;gt;1 sites, 48% elevated serum lactate dehydrogenase (LDH), 41% advanced stage (Stage III/IV). Patients with hypoalbuminemia (Low &amp; very low) were 25% &amp; 6%, respectively; NLR &amp;gt;4 was 14%. The median calculated SII score for the entire cohort was 1774 (IQR:523 to 1856) with a cut-off of &amp;gt;1636 (AUC 0.55[95%C.I. 0.53 to 0.59], p=0.004). The clinical characteristics of non-inflammation group [NIG,n=736,71.5%] (below cut-off) and inflammation group [IG,n=293,28.5%] (above cut-off) are presented in Table 1. ECOG ≥2; elevated serum LDH, advanced stage; low &amp; very low albumin; and NLR &amp;gt;4 were assocated to de IG ( all of them p&amp;lt;0.0001). The KM for NIG and IG showed better OS for the NIG at 3 years (67% vs. 49%, p&amp;lt;0.0001). Table 2 shows the univariate and multivariate analysis of variables with independent influence on OS. All but EN involvement were independent factors to prognosticate OS with a Harrell´s C-Index of 0.73 (95% C.I. 0.69 to 0.76). Conclusions. In this large cohort of LATAM DLBCL patients, we were able to validate the SII score. We found the SII score was able to discriminate low from hogh risk DLBCL inflammatory groups. Moreover, these findings were coupled to the validation of other prognostic factors such as the IPI score, hypoalbuminemia, and high NLR.

The Presence of Bulky Disease and/or Very High LDH Defines a High-Risk Subset of IPI 1-2 for Eligibility in Clinical Trials of Newly Diagnosed Aggressive B-Cell Lymphoma

Background: The goal of clinical trial eligibility criteria is to identify a population of patients that have high risk disease or have unmet needs with standard of care therapy. Frontline trials of diffuse large B-cell lymphoma (DLBCL) include patients with International Prognostic Index (IPI) scores of 3-5 as a way to identify a high risk population. Trials typically include patients with IPI score=2, and sometimes IPI score=1, to expand the eligible patient population. However, broader patient populations must be balanced by the potential inclusion of low-risk patients with excellent outcomes to standard of care therapy, leading to potentially underpowered trials. IPI is a sum of dichotomous variables which makes implementation easy but can result in heterogeneity in outcomes within IPI scores. This heterogeneity may be caused by unequal prognostic information across IPI variables, loss of information within IPI variables due to the use of cutoffs, as well as information captured by variables that are not included in the IPI. In prior modeling of outcomes in DLBCL (Maurer et al, AJH 2016), we identified that: i) LDH has a strong prognostic ability beyond the upper limit of normal (ULN) and ii) bulky disease is an independent variable for prognosis. Here we evaluate if the presence of either of these two variables, easily captured at diagnosis within the current standard clinical work-up, can identify a high-risk subset of patients within the population of those with IPI scores of 1-2. Methods: Patients with newly diagnosed lymphoma were enrolled within 6 months of diagnosis in the LEO Cohort at 8 academic medical centers from 2015-2020 and prospectively followed. Inclusion criteria for this analysis was aggressive B-cell lymphoma typically included in frontline trials (e.g. DLBCL, high grade B-cell lymphoma, FL3B), IPI 1-5, frontline therapy with rituximab and anthracycline-based chemotherapy, stage II-IV disease and ages 18-80 years. Event-free survival (EFS) was defined as the time from diagnosis until progression, initiation of 2 nd line therapy, or death due to any cause; EFS was evaluated at 24 months (EFS24). Very high LDH was defined as LDH&amp;gt;1.3xULN based on prior modeling (Maurer et al, AJH 2016) and bulky disease was defined as maximum tumor diameter (MTD) of 7cm or greater. IPI 1 and 2 were first evaluated separately and then combined due to similar outcomes in patients with very high LDH and/or bulky disease. High risk IPI1-2 was defined as the presence of either bulky disease and/or very high LDH within an IPI score of 1-2. Confirmation was performed in a similar cohort of patients enrolled in the Iowa/Mayo SPORE Molecular Epidemiology Resource (MER) from 2002-2015; bulky disease was defined using a 10cm cutoff per availability in MER data collection forms. Results: 1560 patients from LEO were analyzed; median age was 64 years (IQR: 54-71), 42% were female and 83% had stage III/IV disease; subtype was DLBCL, NOS in 1335 (86%). IPI was 1-2 in 766 patients, 3 in 496 patients and 4-5 in 298 patients ( table). 391 (51%) with IPI1-2 had either bulky disease and/or very high LDH (high risk IPI1-2) and 375 had low-risk IPI1-2. EFS24 in high risk IPI1-2 (71.6%, 95% CI: 67.2-76.3) was significantly inferior to IPI1-2 without bulky disease or very high LDH (85.2, 95% CI: 81.7-88.9 logrank p=0.0035, figure) and similar to patients with IPI3 (70.7%, 95% CI: 66.8-74.9). Consistent results were observed in 1014 patients analyzed in the MER using a higher cutoff for bulky disease (10cm) due to data availability ( table). Patients with high risk IPI1-2 had significantly shorter diagnosis to treatment interval (DTI) in both the LEO (per-week OR=0.83, 95% CI: 0.77-0.88) and MER (per-week OR=0.77, 95% CI: 0.68-0.87) cohorts compared to low risk IPI1-2, both p&amp;lt;0.0001). In sensitivity analysis, LEO results were similar when performed in the subset of patients with DLBCL, NOS. Conclusion: The presence of either bulky disease and/or very high LDH at presentation identifies a high-risk subset of patients with IPI 1-2 that have similar outcomes to patients with IPI 3 disease. These simple criteria can be easily implemented within existing clinical trial diagnostic work-ups. Future trial designs in frontline aggressive B-cell lymphoma should include patients with IPI 3-5 and patients with IPI 1-2 with either bulky disease and/or very high LDH to better define a high-risk population of patients for clinical trial eligibility.