Newly-diagnosed Diffuse Large B-cell Lymphoma Research Articles

Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma.

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundredND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL.

Diverse Microbiome Characteristics in Treatment Naïve Extranodal NK/T-Cell Lymphoma Patients

Background: It is still unclear why extranodal NK/T cell lymphoma (ENKTL) emerged in certain regions, such as Asia and South America, and initiated ENKTL lymphomagenesis in restricted upper airway or aerodigestive tract regions. Recently, reports have highlighted the profound relationship between the gut microbiome and immune system modulation. These associations can potentially influence cancer development and impact the effectiveness of chemotherapy. Therefore, we conducted a stool analysis to determine the newly diagnosed ENKTL (ND-ENKTL) microbiome characteristics. Additionally, a comparison analysis of microbiome composition among healthy individuals, newly diagnosed diffuse large B-cell lymphoma (ND-DLBCL), and ND-ENKTL was performed to identify potential clues that could influence ENKTL development and outcomes. Methods: We have gathered and analyzed microbial data from 40 feces samples obtained from 40 ND-ENKTL patients from 2020 to 2022. Fecal samples from ENKTL patients were collected using a stool sampling kit (CJ Bioscience. Inc, Seoul, Korea) designed explicitly for microbial community analysis using shotgun sequencing. We used pre-analyzed gut microbiome data from the healthy control (HC) or newly diagnosed DLBCL (ND-DLBCL) group to compare the gut microbiome specificities. Results : 32 (80.0%) presented stage I/II, and 7 (17.5%) or 6 (15.0%) had a high PINK (≥2) or high PINK-E score (≥3). In the alpha diversity analysis, ENKTL exhibited significantly lower diversity than HC. Additionally, we observed significant differences in microbial composition between these two groups (PERMANOVA, P-value=0.001). Species such as Escherichia coli, Citrobacter portucalensis and Citrobacter freundii were identified as significant biomarkers associated with dysbiosis in ENKTL. All these species belong to the Enterobacteriaceae family, a facultative aerobic opportunistic bacteria group. In the functional analysis, we observed an increase in genes related to aerobic bacterial metabolism in the ENKTL group. Conversely, a trend of decreased short-chain fatty acid (SCFA) metabolism and folate biosynthesis was identified. The noteworthy observation in ENKTL is the dominant Enterobacteriaceae family presence, which bears similarity to the microbiome associated with gut microbial dysbiosis in DLBCL, previously reported. While no significant differences were observed at the family level, a notable distinction was found between ENKTL and DLBCL at the genera. Specifically, a significantly higher proportion of Escherichia was dominant in ENKTL compared to DLBCL, which was dominant in Enterobacter and Citrobacter. In the chi-square analysis, a high abundance of Enterobacteriaceae presented statistically correlated with advanced stage (p=0.001) and PINK-high (≥2, p=0.003). Moreover, statistically significant associations were observed between the high proportion of the Escherichia genus and advanced stage (p=0.037), PINK-High (≥2, p=0.020), and a high PD-L1 CPS (≥10, p=0.029). During the median 21.1 months (95% CI 16.2-25.9) follow-up duration, the patients with high Enterobacteriaceae abundance exhibited significantly poorer progression-free survival (PFS) compared to those without such abundance (5.6 months vs. NR, p=0.001). Furthermore, patients with high Escherichia abundance demonstrated inferior PFS compared to those without (5.2 months vs. NR, p=0.001). Conclusion: By comparing the intestinal microbes of ND-ENKTL with those of healthy individuals and ND-DLBCL, we could determine the distinct distribution of intestinal microbiome specific to ENKTL. Although the finding of the Enterobacteriaceae family was similar result with previously reported microbiome composition in DLBCL, we determined a high abundance of Escherichia genea in ENKTL but high Enterobacter and Citrobacter in DLBCL through subgroup analysis. Interestingly, Escherichia genea in ENKTL showed a statistical correlation with a high disease burden, PD-L1 expression, and inferior PFS. Based on the results, we expected that it would be possible to predict the disease characteristics and treatment susceptibility in ENKTL by intestinal microbes' composition and diversity in the future.

The impact of sMICA/sMICB on immunochemotherapy outcomes in newly diagnosed diffuse large B-cell lymphoma.

Soluble MHC class I-related chain A (sMICA) and B (sMICB) play a critical role tumor evolution and poor prognosis through an immune evasion mechanism. Thus, this study determines the interaction between sMICA/sMICB and the tumor immune environment in newly diagnosed diffuse large B-cell lymphoma (ND-DLBCL). We analyzed sMICA/sMICB, cytokine in serum, and macrophage polarization analysis in tissue samples before the first chemotherapy administration. This research was performed to investigate the correlation between sMICA/sMICB expression and treatment outcomes as well as their influence on the immune system within ND-DLBCL. Of the 262 patients, 47.3% (n = 124) presented stage III or IV at diagnosis and 50.8% (n = 133) had a high International Prognostic Index (IPI ≥ 3). The patients with high (p = 0.034 and 0.004), elevated lactate dehydrogenase (p = 0.002 and 0.030), advanced stage (p = 0.003 and 0.012), and higher IPI risk (p = 0.009, and 0.032) correlated with the detection of sMICA or sMICB. The median progression-free survival (PFS) of patients with sMICA (p = 0.006) or sMICB (p =0.032) was inferior. Among the patients with advanced-stage or high IPI, those with sMICA or sMICB presented an inferior PFS and OS compared to those without. TNF-a, a pro-inflammatory cytokine, showed statistical significance with detected sMICA (p = 0.035) or sMICB (p = 0.044). Among anti-inflammatory cytokines, IL-1RA (P-value = 0.013) and IL-10 (p = 0.005) were associated with detecting sMICB, but not sMICA. In tissue samples, sMICA or sMICB detection did not correlate with the CD68/CD163 ratio. Conclusively, the identification of sMICA/sMICB presented unfavorable immunochemotherapy outcomes, and it was assumed that sMICA or sMICB and various cytokines interact, but the relationship with macrophage differentiation is unclear. Therefore, further research is needed to determine the relationship between sMICA/sMICB and tumor microenvironment in DLBCL.

Zanubrutinib-lenalidomide-rituximab (ZR2) in unfit diffuse large B-cell lymphoma: efficient and tolerant.

The objective of this study is to examine the effectiveness and safety of zanubrutinib, rituximab, and lenalidomide (ZR2) in unfit patients with diffuse large B-cell lymphoma (DLBCL). Thrombosis or bleeding risk of ZR2 regimen, especially when antiplatelet agents were co-prescribed, was also evaluated. We retrospectively reviewed unfit newly diagnosed (ND) and refractory or relapsed (R/R) patients with DLBCL who were administered with ZR2 regimen in two medical centers between December 2019 and February 2022. Response rates, progression-free survival (PFS), overall survival (OS), bleeding adverse events (AEs), and thrombosis episodes were analyzed. Furthermore, we investigated the effects of zanubrutinib alone or in combination with lenalidomide on platelet functions in vitro and in vivo. A total of 30 unfit patients (13 ND DLBCL and 17 R/R DLBCL patients) who received ZR2 regimen were enrolled in the study (median age: 69.5years). The ultimate ORRs for the ND DLBCL and R/R DLBCL were 77.0% and 50.1%, respectively. The median follow-up was 16.6months. The median PFS and OS were not achieved during the follow-up time. Subcutaneous hemorrhage AEs occurred in four cases, three cases suffered severe bleeding events, and thrombosis events were observed in two patients. ZR2 regimen inhibited platelet functions (aggregation, clot retraction, spreading and activation) in vitro and in vivo function testing especially in response to collagen. ZR2 is an efficient treatment option for unfit patients with DLBCL and could be well tolerated. Notably, this regimen inhibited platelet functions. Antiplatelet agents should be used with caution in patients treated with this regimen.

Clinical Implications of CSF-Ctdna in CNS Involvement of Newly Diagnosed Diffuse Large B Cell Lymphoma: An Improvement of Diagnosis, Treatment and Evaluation

Background: CNS involvement (CNSi) is a rare and often fatal event, occurring in around 5% of patients (pts) with diffuse large B-cell lymphoma (DLBCL) during primary treatment or shortly after completion (SCNSL). Furthermore, the potential mechanisms of CNS dissemination were limited. Circulating tumor DNA from cerebrospinal fluid (CSF-ctDNA) has played an important part in the application of liquid biopsy in CNS cancers. In this study, we provided new insights into the feasibility of using CSF-ctDNA as an essential tool for CNSi diagnosis, treatment, and evaluation specifically in newly diagnosed (ND) DLBCL pts. Methods : Between December 2021 and April 2023, 168 ND DLBCL pts and 24 ND PCNSL pts have been treated in our center. One hundred DLBCL pts were enrolled in the training cohort while the other 68 pts refused to enter in our study. Another 26 ND DLBCL pts diagnosed between May 2023 and June 2023 were entered into a validation cohort. The flow of treatment and samples collections were according to the study protocol shown in Figure 1A. CSF-ctDNA positive (CSF-ctDNA(+)) criteria: (1) CSF-ctDNA detected mutations consistent with tissue; (2) Mutations detected in CSF-ctDNA were inconsistent with tissues, but were classified as grade I and grade II mutations; (3) At least one mutation was detected with an abundance >0.5%. The criteria of CNSi positive (CNSi(+)) were CSF-ctDNA(+) or/and other evidences detected by conventional methods (CM, including MRI, PET-CT, routine inspection analysis of CSF). Results: In the training cohort, 25 pts (25%) were diagnosed with CSF-ctDNA (+) while 21 pts were according to the first criteria and 4 pts were according to the second criteria. Among the 25 pts (25.0%) who were finally diagnosed with CNSi (+), only 3 pts (12.0%) have evidences of CNSi both in CM and CSF-ctDNA while similar results were shown in validation cohort ( Figure 1B). The unique mutations detected in CSF were rare compared with plasma and tissue mainly due to early detection with no clone evolution ( Figure 1C). The mean variant allele frequency was significantly higher in tumor tissue than CSF in SCNSL ( Figure 1D). The pretreatment ctDNA burden was significantly higher in CSF of PCNSL while higher in plasma of SCNSL ( Figure 1F). The distributions of gene subtypes for the 25 CNSi (+) DLBCL pts were shown in Figure 1E. Only 11 pts (44%) were MCD subtype while nearly 80% PCNSL pts were MCD subtype. There existed significant differences of gene mutation profile between SCNSL and PCNSL ( Figure 1G). We explored the association of clinical and biological factors with CNSi in ND DLBCL pts . Of note, high plasma ctDNA burden (≥2.18) were significantly related to CNSi (+) (Figure 1H). In multivariable analyses, CSF protein level ≥0.4, high plasma ctDNA burden (≥2.18) and high risk CNSi sites involvement were independent risk factors for CNSi ( Figure 1I). We use these 3 risk factors to build CNSi-IPI model which can significantly better predict CNSi than CNS-IPI ( Figure 1I). According to CNSi-IPI, pts were stratified into low-risk (0-1), intermediate-risk (2) and high-risk (3). CNSi (+) were observed in 5.0%, 48.3% and 72.7% in the training cohort and 5.9%, 50.0% and 100.0% in the validation cohort in the 3 risk groups ( Figure 1J). Pts with CARD11, JAK2, ID3, and PLCG2 mutation were more predominant with CNSi while FAT4 mutation seemed to promote tumor cells disseminating to CNS ( Figure 1K). Furthermore, the down-regulated genes of CNSi DLBCL pts significantly enriched in PI3K-AKT signaling pathway, focal adhesion, regulation of action cytoskeleton and tight junction pathways, which might be the potential mechanisms promoting CNS dissemination in ND DLBCL ( Figure 1L). The dynamic change of disease status and ctDNA burden of all the 25 CNSi (+) pts were shown in Table 1. Conclusion :In summary, our study highlighted the clinical implications of CSF-ctDNA in CNSi detection of ND DLBCL pts ( Figure 1M): (1) CSF-ctDNA exhibits higher sensitivity than CM in detecting CNSi in ND DLBCL. (2) Different genomic and clinical landscapes were observed between SCNSL and PCNSL. (3) The CNSi-IPI is a robust, highly reproducible tool that can be used to estimate the risk of CNSi in ND DLBCL. (4) Down-regulation of PI3K-AKT signaling pathway, focal adhesion, regulation of action cytoskeleton and tight junction pathways contribute to CNS dissemination in ND DLBCL. (5) Furthermore, CSF-ctDNA can be used to monitor CNS tumor burden and response to treatment.

Inferior outcomes with R-CEOP for patients with diffuse large B-cell lymphoma and cardiovascular comorbidities

Anthracycline-based chemoimmunotherapy with R-CHOP is the standard treatment for diffuse large B-cell lymphoma (DLBCL) but is associated with increased risks of cardiotoxicity. The alternative regimen R-CEOP substitutes etoposide for doxorubicin and is commonly administered to DLBCL patients with cardiovascular comorbidities, although there is limited evidence supporting its use. This multicenter real-world study included 138 consecutive patients with newly-diagnosed DLBCL treated with R-CEOP and 414 patients treated with R-CHOP matched 1:3 for age and International Prognostic Index. With median follow-up time 4.6 years, R-CEOP was associated with significantly inferior 4-year progression-free survival (32 vs. 52%, p < 0.0001), overall survival (39 vs. 59%, p < 0.0001), and disease-specific survival (48 vs. 69%, p < 0.0001) compared to R-CHOP. R-CHOP should remain the preferred regimen for most patients with DLBCL. While R-CEOP may be a reasonable choice for patients strictly ineligible for anthracyclines, the inferior outcomes of this regimen suggest that this high-risk population requires novel therapeutic approaches.

ABCL-021: FRONT-MIND: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study Comparing Efficacy and Safety of Tafasitamab + Lenalidomide + R-CHOP vs R-CHOP Alone for Newly-Diagnosed High-Intermediate and High-Risk Diffuse Large B-Cell Lymphoma (DLBCL)

<h3>Context</h3> Tafasitamab is an Fc-modified, humanized anti-CD19 monoclonal antibody, which induces enhanced <i>in vitro</i> antibody-dependent cell-mediated cytotoxicity and phagocytosis. Preclinical studies data suggest that tafasitamab+lenalidomide may synergistically enhance cytotoxicity to malignant B-cells. Tafasitamab+lenalidomide is FDA-approved in adult patients with relapsed/refractory DLBCL who are ineligible for autologous stem cell transplantation. R-CHOP is the current standard of care (SOC) for patients with newly-diagnosed DLBCL. Data from the Phase Ib FIRST-MIND (NCT04134936) study in newly-diagnosed DLBCL patients suggest that tafasitamab+lenalidomide when added to R-CHOP is tolerable in patients with treatment-naïve DLBCL. <h3>Objective</h3> To assess the efficacy and safety of tafasitamab+lenalidomide+R-CHOP <i>vs</i> R-CHOP alone in previously untreated, high-intermediate and high-risk patients with DLBCL. <h3>Design</h3> FRONT-MIND is a Phase III, multicenter, randomized, double-blind, placebo-controlled study. Patients will be followed-up for up to 60 months after end of treatment. <h3>Setting</h3> Patients will be enrolled from approximately 350 centers in America, Europe, and Asia-Pacific. <h3>Patients</h3> Eligible patients (n=880) will be aged 18–80 years with previously untreated local biopsy-proven, CD20-positive DLBCL (IPI ≥3 if >60 years/age-adjusted IPI 2–3 if ≤60 years), and ECOG PS 0–2. Patients with transformed lymphoma (except double or triple hit lymphoma) are excluded. <h3>Interventions</h3> Patients will be randomized to receive six 21-days (D) cycles of tafasitamab (12 mg/kg intravenous [IV], D 1, 8, and 15)+lenalidomide (25 mg orally, D1–10)+R-CHOP or six 21-D cycles of tafasitamab placebo (D1, 8, and 15)+lenalidomide placebo (orally, D1–10)+R-CHOP. <h3>Main Outcome Measures</h3> The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include investigator-assessed event-free survival, overall survival, and safety. <h3>Results</h3> Not yet available. <h3>Conclusions</h3> As 30–50% of patients overall relapse or are refractory to first-line therapy, there remains a high unmet need to improve treatment options for newly diagnosed patients, particularly those with high-risk DLBCL. The combination of tafasitamab, lenalidomide, and R-CHOP may have synergistic potential. Preliminary data from the FIRST-MIND study suggest that tafasitamab±lenalidomide+R-CHOP is tolerable in patients with treatment-naïve DLBCL. The present study will provide further evaluation of clinical benefits and safety when adding tafasitamab+lenalidomide to current SOC in newly diagnosed patients with high-intermediate and high-risk DLBCL treated with R-CHOP.

Type 2 Diabetes Mellitus Strongly Impacts Survival in Patients with Diffuse Large B Cell Lymphoma

▪Introduction: Accumulating evidence in the past decade suggested that type 2 diabetes mellitus (T2DM) is correlated with elevated cancer risks and cancer mortality via possible underlying mechanisms of hyperglycemia, hyperinsulinemia and chronic inflammation. However, no literature to date has focused on the relation between diffuse large B cell lymphoma (DLBCL) and T2DM. The objective of this study was to assess the prognostic impact of T2DM on diffuse large B cell lymphoma (DLBCL) survival.Methods: Three hundred and sixty-one newly-diagnosed DLBCL patients whose treatments included rituximab between June 2006 and March 2015 were recruited. Pre-existing T2DM was defined as having a medical record of T2DM or elevated fasting glucose level (≥7.0mmol/L) at diagnosis of DLBCL. Pre-diabetes referred to being diagnosed as impaired fasting glucose or impaired glucose tolerance, or fasting blood glucose level ≥6.1 mmol/L and <7.0 mmol/L at enrollment. Multivariate Cox regression analyses screened the prognostic risk factors associated with progression free survival (PFS) and overall survival (OS). Receiver-operator characteristic curves and the corresponding areas under the curve (AUC) assessed the predictive accuracy of International Prognostic Index (IPI) and T2DM.Results: In total, 61 patients (16.90%) had pre-existing T2DM and 57 (15.79%) patients had pre-diabetes. Diabetic patients were more likely to have old age, poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) and low IPI score. T2DM was associated with unfavorable PFS and OS in rituximab era (Figure 1a and b), and it was an independent risk factor for inferior OS (HR=1.930; 95% CI: 1.092−3.411; p=0.024), especially in patients with the IPI 0−2, age under 60 years, early stage disease, ECOG PS 0−1 and Hans classification of germinal center B-cell. Pre-diabetics also shared inferior PFS and OS compared with patients with no T2DM tendency (Figure 1c and d). Additionally, we introduced a novel Prognostic Index (PI) which was calculated as the sum of IPI and one additional point for having T2DM weighed by their Cox regression coefficients. PI demonstrated significantly larger AUCs than IPI alone and could accurately differentiate the survival outcomes of DLBCL patients. Adding the criterion of T2DM could improve the prognostic capacity of IPI for OS prediction (Figure 1g). Moreover, diabetic DLBCL patients on oral anti-diabetic drugs (primarily metformin) presented better PFS and OS in comparison with those on insulin and non-medication after multivariable adjustments including diabetic duration and fasting glucose level (Figure 1e and f).Conclusion: Our findings suggested that pre-existing T2DM could serve as an important prognostic factor for survival in DLBCL patients. Clinicians' attention of T2DM at DLBCL diagnosis should be aroused to help predict life expectancy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Primary prophylaxis with pegfilgrastim in patients with newly-diagnosed diffuse large B-cell lymphoma: propensity score and instrumental variable analyses

The clinical impact of pegfilgrastim in day-to-day practice remains unclear. This study evaluated the effectiveness of pegfilgrastim compared with daily filgrastim in patients with DLBCL who received the first-cycle of R-CHOP treatment by using a Japanese national inpatient database. Patient characteristics were adjusted by using propensity-score matching and stabilized inverse probability of treatment weighting (IPTW). In 1295 propensity-score-matched pairs, the incidence of febrile neutropenia was significantly lower in the pegfilgrastim group (risk difference 6.1%, 95% CI 4.1%–8.1%) than in the filgrastim group. In the pegfilgrastim group, the length of hospital stay and the total costs were also significantly reduced (percent reduction 34% [95% CI: 31%–37%], percent reduction 12% [95% CI: 9%–15%], respectively). The stabilized IPTW showed comparable results. In day-to-day practice, the simple mode of pegfilgrastim administration may be advantageous.

The clinical outcomes of rituximab biosimilar CT-P10 (Truxima®) with CHOP as first-line treatment for patients with diffuse large B-cell lymphoma: real-world experience

We evaluated real-world effectiveness and safety of CT-P10 (Truxima®) compared with originator rituximab in diffuse large B-cell lymphoma (DLBCL) treatment. Before and after the introduction of CT-P10 to our institute (November 2017), 221 newly-diagnosed DLBCL patients received rituximab with standard cyclophosphamide, vincristine, doxorubicin and prednisone. Patients received originator rituximab throughout (n = 95), switched from originator rituximab to CT-P10 (n = 36), or received CT-P10 throughout (n = 90). There were no significant differences between groups in overall response rate (91.6% vs 94.4% vs 96.7%, respectively; p = 0.403) or complete response rate (84.2% vs 77.8% vs 86.7%, respectively; p = 0.467). Kaplan–Meier survival curves also showed no significant differences in progression-free survival and overall survival between groups (log-rank p = 0.794 and p = 0.955, respectively). Safety profiles were comparable between treatment groups. These data support the ability of CT-P10 to successfully replace originator rituximab in DLBCL treatment and, given the lowered financial barrier, to improve the overall prognosis for DLBCL patients.

Safety and Efficacy of R-CEEP (Rituximab, Cyclophosphamide, Epirubicin, Etoposide, Prednisolone) in Elderly or Unfit Patients with Diffuse Large B-Cell Lymphoma (DLBCL): A Retrospective Single-Centre Experience

Background DLBCL is the most common subtype of non-Hodgkin lymphoma in elderly patients (age ≥70). R-CHOP is the standard of care for upfront treatment of fit patients, but may not be tolerated in patients with advanced age and/or comorbidities. There is no established standard of care for this group of patients and dose reduction (R-miniCHOP) or avoidance/replacement of anthracyclines are common strategies, aiming to deliver tolerable immunochemotherapy and provide meaningful outcomes and potential cure. R-CEEP is a dose-reduced regimen that incorporates etoposide and an alternate anthracycline epirubicin. We describe our single-centre experience with R-CEEP for elderly (age ≥70) or unfit patients (CIRS-G &gt;6) with newly-diagnosed or relapsed DLBCL deemed unsuitable for R-CHOP. Method All patients receiving R-CEEP for a histological diagnosis of DLBCL at Royal Prince Alfred Hospital from 2000 to 2019 were retrospectively reviewed. R-CEEP (rituximab 375mg/m2 day 1, cyclophosphamide 300mg/m2 day 1, epirubicin 50mg/m2 day 1, etoposide 100mg/m2 day 1 and prednisolone 50mg daily for days 1-5) was delivered every 14 or 21 days at physician discretion planning for 6 cycles. GCSF and antimicrobial prophylaxis were used at physician discretion. The cardiac ejection fraction was assessed as satisfactory (&gt;50%) prior to commencement. Baseline demographics, R-IPI, co-morbidities as assessed by CIRS-G, treatment response and adverse events (AEs) were recorded. Results Data from 61 patients were reviewed; 54 received R-CEEP for de novo DLBCL and 7 for DLBCL with a background of previously-treated lymphoma (1 DLBCL; 6 low-grade NHL). The median age at diagnosis was 80 (range 34-93), with 79% aged 75 and 28% aged 85. Thirty-three patients (54%) were female; 87% had Ann Arbor stage III/IV and 52% had R-IPI 3-5. Median CIRS-G was 9 (range 2-20) with 74% of patients having CIRS-G &gt;6. GCSF prophylaxis was used in 67%. The median follow-up was 2.7 years (range 0.1-10.0 years). Overall response was 54/61 (89%), with complete response (CR) in 42 (69%), partial response (PR) in 12 (20%) and progressive disease (PD) in 1 (2%). Response was not assessed in 6 patients due to early treatment discontinuation for palliation or AEs (4), cerebral palsy (1) and loss to follow-up (1). In patients receiving R-CEEP as upfront therapy, CR was obtained in 38/54 (70%), PR in 10/54 (19%) and 6 were not assessed as above. In the 7 patients receiving R-CEEP as salvage therapy, 4 obtained CR, 2 PR and 1 had PD. Median PFS and OS for the total cohort were 5.2 and 9.4 years respectively; for de novo DLBCL patients, 7.1 and 9.4 years and for patients receiving salvage therapy, 1.1 and 2.0 years. There was no statistically significant difference in PFS or OS when comparing patients aged &lt;80 and ≥80, or with CIRS-G ≤6 and &gt;6, or CIRS-G ≤9 and &gt;9. Relapsed disease was identified in 19 patients (31%) during follow-up. Of the 75 AEs reported, grade 3/4 AEs accounted for 67%. Infective complications were the most frequent (53%; 40) and febrile neutropenia accounted for 8 AEs. Grade 3/4 haematological toxicity occurred in 19% (14). Despite this, the majority (43/61; 70%) received six cycles of R-CEEP. In the remaining 18 patients, 5 completed 6 cycles with dose-reduction and 13 patients discontinued therapy due to serious AEs (9), treatment intolerance (2) or patient preference (2). Of the 29 deaths recorded during the follow-up period, 18 were due to relapsed/progressive disease; 5 to infection (4 of these in CR, 0.5 to 9 years after the end of treatment, and 1 of urinary sepsis in a patient 3 months after early treatment discontinuation due to toxicity) and 6 to unrelated causes. Discussion We demonstrate that R-CEEP is an effective and deliverable immunochemotherapy in elderly or unfit patients with DLBCL. Furthermore, survival outcomes were not impacted by CIRS-G &gt;9 or age ≥80, illustrating efficacy and tolerability even in patients predicted to have a particularly poor prognosis. Our cohort outcomes are not inferior to those reported in elderly fit patients treated with other dose-reduced regimens including R-miniCHOP (Peyrade et al, Lancet Oncology 2011) and R-miniCEOP (with epirubicin; Merli et al, Leukemia and Lymphoma 2012). This data supports the use of R-CEEP as an alternative immunochemotherapy option for patients with DLBCL who may not be candidates for R-CHOP. Disclosures Iland: Celgene: Other: Speaker honorarium. Ho:La Jolla: Other: investigator meeting travel costs; Novartis: Other: investigator meeting travel costs; Janssen: Other: investigator meeting travel costs; Celgene: Other: investigator meeting travel costs.

Long Non-Coding RNAs as Molecular Signatures for Canine B-Cell Lymphoma Characterization.

Background: Diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL) and follicular lymphoma (FL) are the most common B-cell lymphomas (BCL) in dogs. Recent investigations have demonstrated overlaps of these histotypes with the human counterparts, including clinical presentation, biologic behavior, tumor genetics, and treatment response. The molecular mechanisms that underlie canine BCL are still unknown and new studies to improve diagnosis, therapy, and the utilization of canine species as spontaneous animal tumor models are undeniably needed. Recent work using human DLBCL transcriptomes has suggested that long non-coding RNAs (lncRNAs) play a key role in lymphoma pathogenesis and pinpointed a restricted number of lncRNAs as potential targets for further studies. Results: To expand the knowledge of non-coding molecules involved in canine BCL, we used transcriptomes obtained from a cohort of 62 dogs with newly-diagnosed multicentric DLBCL, MZL and FL that had undergone complete staging work-up and were treated with chemotherapy or chemo-immunotherapy. We developed a customized R pipeline performing a transcriptome assembly by multiple algorithms to uncover novel lncRNAs, and delineate genome-wide expression of unannotated and annotated lncRNAs. Our pipeline also included a new package for high performance system biology analysis, which detects high-scoring network biological neighborhoods to identify functional modules. Moreover, our customized pipeline quantified the expression of novel and annotated lncRNAs, allowing us to subtype DLBCLs into two main groups. The DLBCL subtypes showed statistically different survivals, indicating the potential use of lncRNAs as prognostic biomarkers in future studies. Conclusions: In this manuscript, we describe the methodology used to identify lncRNAs that differentiate B-cell lymphoma subtypes and we interpreted the biological and clinical values of the results. We inferred the potential functions of lncRNAs to obtain a comprehensive and integrative insight that highlights their impact in this neoplasm.

Comprehensive geriatric assessment is useful in an elderly Australian population with diffuse large B-cell lymphoma receiving rituximab-chemotherapy combinations.

Elderly patients may be heterogeneous in their abilities to tolerate immunochemotherapy-associated toxicities. We describe the morbidity of rituximab-chemotherapy combinations among 205 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients aged ≥60years from 3 tertiary hospitals between 2009 and 2016, and explore the utility of retrospectively-assigned baseline Comprehensive Geriatric Assessment (CGA) in predicting these toxicities. Seventy-three percent (146/201) experienced grade ≥3 toxicities, 81% (163/201) needed admission, 52% (107/205) had ≥2 unplanned admissions, 82/201 (41%) required dose reductions (DR) subsequent to Cycle 1, 39/166(23%) had chemotherapy delays and 26/198(13%) ceased therapy early. CGA was associated with pre-emptive baseline DR and perhaps because of this, did not predict grade ≥3 toxicities, ≥2 unplanned admissions or subsequent DR. Three-year overall survival (OS) of CGA-fit, CGA-unfit and CGA-frail patients was 82%, 60% and 53%, respectively. Three-year progression-free survival (PFS) of CGA-fit, CGA-unfit and CGA-frail patients was 66%, 58% and 46%, respectively. OS of CGA-fit patients was not statistically different from CGA-unfit patients, but was superior to CGA-frail patients (hazard ratio 2·892, 95% confidence interval 1·275-6·559, P=0·011). PFS differences were not statistically significant. Baseline DR and early therapy cessation were associated with inferior OS and PFS independent of CGA. Prospective studies are needed to confirm if CGA-adapted treatment strategies minimize morbidity and improves survival.

C‐REACTIVE PROTEIN‐TO‐ALBUMIN RATIO IS AN INDEPENDENT POOR PROGNOSIS AND IMPROVING NCCN‐IPI SCORE IN NEWLY DIAGNOSED DIFFUSE LARGE B‐CELL LYMPHOMA: A CLINICAL ANALYSIS OF 414 CASES

Introduction: In recent years, increasing evidences have validated that cancer-associated systemic inflammation and malnutrition had exact prognostic impact on the majority of patients with malignancies. Numerous circulating inflammatory and nutritive indicators have been proposed as prognostic indicators for malignant tumors including DLBCL. Among them, the Glasgow Prognostic Score (GPS), the modified Glasgow Prognostic Score (mGPS) are novel inflammatory indicators which consist of C-reactive protein (CRP) and albumin (ALB) and reflect both the systematic inflammatory response and nutritional status. Recently, the ratio of CRP-to-ALB (CAR) has been identified as another serum-based inflammatory indicator and several studies have reported that the CAR is significantly related to prognosis in various types of cancers. Methods: Four hundred and fourteen newly-diagnosed DLBCL patients were enrolled in the retrospective study. The univariate and multivariate Cox proportional hazards models were established for the estimation of prognostic factors. Receiver-operator characteristic (ROC) curves and the corresponding areas under the curve (AUC) were calculated to predicted probability of variables. Results: With a median follow-up of 40 months (range, 0 to 105 months), patients with higher CAR displayed unfavorable progression-free survival (PFS) (P<0.001) and overall survival (OS) (P<0.001) (Figure 1). Multivariate Cox regression analysis validated that CAR was independent risk factor for both PFS (HR, 1.548; 95% CI, 1.224 to 1.958; P<0.001) and OS (HR, 1.763; 95% CI, 1.291 to 2.335; P<0.001). It was demonstrated that CAR + NCCN-IPI had a superior prognostic significance than NCCN-IPI alone (P=0.0028 for PFS, P=0.0011 for OS) Keywords: diffuse large B-cell lymphoma (DLBCL).

Diagnosis to Treatment Interval in DLBCL Is Predictive of Overall Survival in a Large, Population-Based Registry

Despite advances in treatment for diffuse large B cell lymphoma (DLBCL), approximately one third of patients will relapse, with known risk factors largely limited to the biology of the disease. Recently, patient selection bias has been highlighted as a concern in patients enrolled in DLBCL trials, as the need to categorize patients by cell-of-origin necessitates a prolonged screening period that might exclude patients with a need for urgent treatment and thus more aggressive biology (Maurer et al., JCO 2018). Whether an abbreviated diagnosis to treatment interval represents a surrogate for more aggressive disease and adverse prognosis is unclear in a “real-world” setting. We evaluated the time from diagnosis to treatment (and other pre-treatment time intervals) and additional socioeconomic and system-based variables and their impact on lymphoma outcomes.Methods: Using population-based health administrative databases held at the Institute of Clinical and Evaluative Sciences, Ontario, Canada, we identified adults ≥18 years with DLBCL or transformed lymphoma. We explored the impact of timelines prior to commencing treatment and socio-economic status, distance to treating hospital, inpatient/outpatient status, and type of treatment centre on overall survival (OS) and progression-free survival (PFS). Patients were followed from index (first rituximab treatment) until death, occurrence of a new primary cancer, or March 31, 2017. Cox regression analyses were completed to evaluate the impact of predictor variables on OS.Results: In the population evaluated (n=9446), the median age was 66 years and 54% were of male gender. Forty-four percent were from the top two income quintiles and 86% from urban settings. Educational attainment was evenly distributed. Median number of co-morbidities using the John Hopkins aggregated diagnostic groups (ADGs) was 11 (IQR 9-14) with 61% of patients having a high AGD score (≥10). Patients waited a median of 37 days from diagnosis to treatment (IQR 39), with 25% waiting > 60 days. From diagnosis, patients waited a median of 19 days to see a hematologist/oncologist (diagnosis to consult time; IQR 24), followed by a further 15 days before chemotherapy was initiated (consult to treatment time; IQR 22). The first cycle was delivered as an inpatient in 4%. Median number of cycles was 6 (IQR 2) with 61% of patients completing ≥ 6. Most patients lived within 20 km of the treating centre (64%); however, 13% travelled > 60 km. At the conclusion of study follow-up, 57% of the cohort were alive with median OS not yet reached (Figure 1). Of the 3499 patients with the cause of death available, 73% had DLBCL listed as primary cause with 9.3% of patients dying on active treatment.In Cox regression analysis, an extended time from diagnosis to treatment was associated with improvement in overall survival. Compared to patients who required treatment within 30 days of diagnosis, patients who were treated within 30 - 60 days of diagnosis (HR 0.72; CI 95% 0.67 - 0.78) and > 60 days from diagnosis (HR 0.78; CI 95% 0.71 - 0.85) experienced improved survival (Figure 2). Compared to patients who lived close to the initial treatment centre (< 20 km), the survival of those patients who travelled more significant distances (> 60 km was not meaningfully impacted (HR 0.91; CI 95% 0.82-1.01).Conclusion:An abbreviated diagnosis to treatment time in newly-diagnosed DLBCL predicts for inferior overall survival in a “real-world” setting, and is potentially reflective of more aggressive disease biology or clinical behaviour. Clinical trials that require extended screening periods may be inadvertently enriched with patients with lymphomas that exhibit less aggressive clinical behaviour (and improved prognosis). In daily practice, patients with less clinically aggressive presentations should be reassured that their outcome should not be adversely impacted by a reasonable wait time. Forthcoming multivariable analyses will be presented to evaluate the impact of additional socioeconomic and system based variables on survival. [Display omitted] DisclosuresBuckstein:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Prognosis of diffuse large B cell lymphoma related to occupational exposure to pesticides: A cohort study

Summary Importance Professional use of pesticides is a risk factor for non-Hodgkin lymphoma. The main biological mechanisms of both pesticides and chemotherapy are genotoxicity and reactive oxygen species generation. Cellular adaptation among patients exposed to low doses of genotoxic and oxidative compounds may hinder chemotherapy efficiency in lymphoma patients. Objective We aim to determine the influence of occupational exposure to pesticides on response to immuno-chemotherapy and survival of patients treated for Diffuse Large B Cell Lymphoma (DLBCL). Design The ProLyPhy study is a retrospective cohort of patients treated between 2010 and mid-2015, for DLBCL, with a least 2-year follow-up. Setting The study took place in six hospitals of central southern France (Languedoc-Roussillon district): two university hospitals, three general hospitals, and one private hospital. Participants We pre-included 404 patients with newly-diagnosed DLBCL treated with anthracycline-based immuno-chemotherapy (R-CHOP like). Occupational history was reconstructed for 244 patients. Occupational data were analysed with the Pestipop French job-exposure matrix to determine probability of occupational exposure to pesticides, and with the Pestimat French crop exposure matrix for farming activities to characterise the probability of using specific compounds. Main outcome and measure We have compared complete response (CR), 2-year event-free survival (EFS) and overall survival (OS) of exposed and non-exposed patients, after adjustment on confounding factors. Results Average age was 61.3 years (range 19–90), 62.7% of patients were male, 67 had occupational exposure to pesticides, of which 38 from farming activities. Occupational exposure did not impact clinical and biological characteristics at diagnostic. We observed that exposed patients had significantly lower CR rate: 77.6% versus 88.7% (P = 0.027), OR = 0.31 (0.55–0.09, P = 0.007); this difference was higher among farmers: 68.6% CR versus 87.2%, P = 0.005, OR = 0.22 (0.56–0.09, P = 0.001). Two-year EFS was 70% in the occupationally-exposed group versus 82%, HR = 2.1 (95% CI: 1.2–3.6, P = 0.008). Among farmers, the difference was more pronounced: 2-year EFS was 56% versus 83%, HR = 3.1 (95% CI: 1.7–5.6, P Conclusion and relevance This retrospective study suggests that agricultural occupational exposure to pesticides is an independent risk factor for treatment failure, EFS and OS in DLBCL. Trial registration The study was registered in ClinicalTrials.gov ( NCT02898870 ).

The prognostic significance of CD11b+CX3CR1+ monocytes in patients with newly diagnosed diffuse large B-cell lymphoma.

Despite their critical roles in angiogenesis and host immunosuppression within the tumor microenvironment, the prognostic significance of myeloid-lineage cells expressing CD11b and CX3CR1 in diffuse large B-cell lymphoma (DLBCL) has not been well studied. We prospectively enrolled newly-diagnosed DLBCL patients at two Korean institutions between May 2011 and Aug 2015. CD11b+CX3CR1+ cells were analyzed by flow cytometry using peripheral blood (PB) and bone marrow (BM) aspirate samples before treatments. Eighty-nine patients (52 males) were enrolled. The median age was 65 years (range, 19–88 years). Thirty-seven patients (42%) were classified as high-intermediate or high risk according to the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI). Patients were categorized into either high or low PB-/BM-CD11b+CX3CR1+ monocyte group according to the cutoffs identified by the receiver-operating-characteristics analysis (PB, 3.68%; BM, 3.45%). The high PB-CD11b+CX3CR1+ monocyte group was significantly associated with high-intermediate and high risk NCCN-IPI group (P = 0.004). With a median follow-up of 27.7 months (range, 1.7-60.4 months), the low PB-CD11b+CX3CR1+ monocyte group showed significantly better overall survival (OS) than the high PB-CD11b+CX3CR1+ monocyte group (3-year, 92.3% vs. 51.2%, respectively; P < 0.001). In contrast, no significant difference was observed between the high and low BM-CD11b+CX3CR1+ monocyte groups. Among patients with high-intermediate to high risk NCCN-IPI, the high PB-CD11b+CX3CR1+ monocyte group showed significantly worse OS than the low PB-CD11b+CX3CR1+ monocyte group (3-year, 29.3% vs. 80.2%, respectively; P = 0.008). Taken together, PB-CD11b+CX3CR1+ monocyte percentage correlates with the NCCN-IPI risk stratification, which enables identification of subgroups with extremely poor clinical outcomes.

Prognostic significance of baseline peripheral absolute neutrophil, monocyte and serum β2-microglobulin level in patients with diffuse large b-cell lymphoma: a new prognostic model.

There are limited reports that baseline peripheral absolute neutrophil count (ANC), absolute monocyte count (AMC), absolute lymphocyte count (ALC) and serum β2-microglobulin level independently predict survival in patients with diffuse large B-cell lymphoma (DLBCL). To confirm these findings, we analysed these parameters together with components of the International Prognostic Index (IPI) in patients with newly-diagnosed DLBCL. We evaluated baseline clinical features for their ability to predict survival in 817 newly diagnosed, previously untreated patients with DLBCL who received frontline treatments between October 2001 and December 2011. The median age at diagnosis was 58years. Multivariate analysis identified elevated baseline ANC (P=0·036), AMC (P=0·028) and serum β2-microglobulin level (P<0·001), poor performance status (P<0·001) and high number of extranodal disease sites (P=0·0497) as independent unfavourable predictors of OS; serum β2-microglobulin level was the strongest predictor of survival outcomes among all the parameters. High baseline serum β2-microglobulin, ANC and AMC levels are independent prognostic factors for short overall survival in patients with newly diagnosed DLBCL. Our new model, based on the above five parameters, better stratifies patients into various risk categories than the IPI for newly diagnosed DLBCL.

Cross-platform assessment of genomic imbalance confirms the clinical relevance of genomic complexity and reveals loci with potential pathogenic roles in diffuse large B-cell lymphoma

Genomic copy number alterations (CNAs) in diffuse large B-cell lymphoma (DLBCL) have roles in disease pathogenesis, but overall clinical relevance remains unclear. Herein, an unbiased algorithm was uniformly applied across three genome profiling datasets comprising 392 newly-diagnosed DLBCL specimens that defined 32 overlapping CNAs, involving 36 minimal common regions (MCRs). Scoring criteria were established for 50 aberrations within the MCRs while considering peak gains/losses. Application of these criteria to independent datasets revealed novel candidate genes with coordinated expression, such as CNOT2, potentially with pathogenic roles. No one single aberration significantly associated with patient outcome across datasets, but genomic complexity, defined by imbalance in more than one MCR, significantly portended adverse outcome in two of three independent datasets. Thus, the standardized scoring of CNAs currently developed can be uniformly applied across platforms, affording robust validation of genomic imbalance and complexity in DLBCL and overall clinical utility as biomarkers of patient outcome.

Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56dim and CD16+ NK cells, and a higher frequency of GrzB+ cells in CD56dim, CD56bright, and CD16+ NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon γ (IFNγ) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower “natural” cytotoxicity. A marked and prolonged therapy-induced reduction of both “natural” and CD16-dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56dim subset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNγ production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies.