High-risk Diffuse Large B-cell Research Articles

Retrospective Review of the Safety and Efficacy of High-Dose Methotrexate for Prevention of CNS Relapse in Diffuse Large B-Cell Lymphoma at Kaiser Permanente- Northern California (Jan 2015 - June 2019)

Retrospective review of the safety and efficacy of high-dose methotrexate for prevention of CNS relapse in diffuse large B-cell lymphoma at Kaiser Permanente- Northern California (Jan 2015 - June 2019)Background: Central nervous system (CNS) relapse occurs in 10-12% of high-risk diffuse large B-cell lymphoma (DLBCL) patients. Prophylactic intravenous high-dose methotrexate (HD-MTX) is recommended by international guidelines to reduce this risk despite limited evidence to support such practice. Recent retrospective studies have cast doubt on the clinical benefit of such treatment. There is limited data on safety and efficacy of such treatment in a community oncology setting.Methods: We conducted a retrospective analysis of adults ≥ 18 years diagnosed with DLBCL treated with systemic therapy and HD-MTX as CNS prophylaxis at Kaiser Permanente Northern California from 1/2015 - 6/2019. We abstracted patient demographics, clinical information, treatment, toxicity, and health care utilization from the electronic health record. Descriptive statistics were used to evaluate patients' outcomes.Results: Of 33 patients (median age: 61; range: 23 - 81; age ≥ 60: 57.5%), most had stage IV disease (78.7%) and an ECOG performance status of 0 or 1 (66.5%). Patients with CNS-IPI score of 2-3 (intermediate-risk) was 30.3%, while higher CNS-IPI scores of 4-6 (high-risk) was 51.5%. Other patient characteristics include double hit lymphoma (12.1%), kidney/adrenal gland involvement (33%), and/or epidural involvement (24.2%). Most common therapies were R-CHOP (51.5%) and R-EPOCH (27.2%). The median number of HD-MTX doses was 3 (range 1-4). The median cumulative dose was 7 gm/m2 (range 3-10.5). With regards to the treatment schedule, 63.6% received HD-MTX intercalated with systemic chemotherapy and 36.4% received HD-MTX after completion of preplanned treatment. Overall, renal toxicity was the most common adverse side effect. The rates of grade 1, 2 and 3 renal toxicity were 12.1%, 9% and 6%, respectively. Other notable side effects experienced were neutropenic fever requiring hospitalization (27.2%) and grade 3 transaminitis (6%). No patients experienced grade 3 mucositis. The median duration of hospital stay was 12 days (range 4-37) and 12.1% required suspension of future HD-MTX. With a median follow up of 31.3 months (range: 0.79 - 58.4) 69.6% are alive and 15.1% had CNS relapse despite prophylactic HD-MTX.Conclusions:In this community oncology setting, patients with DLBCL who were deemed high risk for CNS relapse and received HD-MTX for prophylaxis experienced similar CNS relapse rate compared to those who did not in previous studies. Our findings are in line with recent retrospective reviews, which further support the lack of benefit of such prophylactic treatment. This study underscores the need for further research to prevent CNS disease and improved patient selection criteria for prophylactic treatment among high risk DLBCL patients. DisclosuresNo relevant conflicts of interest to declare.

Subcutaneous Epcoritamab in Combination with R-CHOP in Patients with Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma: Preliminary Results from a Phase 1/2 Trial

Background: In patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) that is considered high risk (revised International Prognostic Index [R-IPI]: 3-5), standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is associated with a 4-year overall survival rate of 55% (Sehn et al, Blood 2007). Epcoritamab (DuoBody ®-CD3×CD20) is a subcutaneously administered bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells to induce T-cell-mediated killing. Single-agent epcoritamab demonstrated a manageable safety profile and substantial antitumor activity in pts with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) in the first-in-human phase 1/2 trial (EPCORE NHL-1; NCT03625037). Among pts with relapsed/refractory DLBCL treated at the identified recommended phase 2 dose (RP2D) of 48 mg (n=8), the overall response rate was 88% and the complete response rate was 38% (Hutchings, Lancet, in press). These encouraging data supported initiation of the EPCORE NHL-2 phase 1/2 trial (NCT04663347), which is evaluating epcoritamab in combination with various standard of care therapies in pts with B-cell NHL. We present data from arm 1 of this trial, in which epcoritamab in combination with R-CHOP is evaluated in pts with previously untreated high-risk DLBCL.Methods: Adults with previously untreated DLBCL and an R-IPI score ≥3 received flat-dose epcoritamab in combination with standard R-CHOP for 6 cycles followed by epcoritamab monotherapy. The study includes a dose-escalation cohort (epcoritamab doses: dose level 1 = 24 mg; dose level 2 = 48 mg). Step-up dosing of epcoritamab (ie, priming and intermediate doses before first full dose) and corticosteroid prophylaxis were used as previously described (Hutchings, Lancet, in press) to mitigate cytokine release syndrome (CRS). Tumor response was evaluated by positron emission tomography-computed tomography obtained once every 6 weeks for the first 24 weeks.Results: As of July 15, 2021, 9 pts have been treated with the combination of epcoritamab + R-CHOP (4 with epcoritamab 24 mg; 5 with 48 mg). Median age was 66 years (range, 56-78). All pts had stage III-IV disease. At data cutoff, all pts remained on treatment with a median follow-up of 12.2 weeks (range, 2.2-28.2). The most common treatment-emergent adverse events were CRS (56%; all grade 1/2), anemia (56%; grade 1-3), neutropenia (44%; all grade 3/4), fatigue (33%; all grade 1/2), and peripheral neuropathy (33%; all grade 1/2). Notably, no grade ≥3 CRS events or cases of febrile neutropenia were reported. No dose-limiting toxicities have been observed. Four pts have had ≥1 response assessment, with 3 achieving complete metabolic response (CMR; all in the epcoritamab 24 mg dose-escalation cohort) and 1 pt achieving partial metabolic response (epcoritamab 48 mg cohort) by week 6; 2 of the 3 pts with CMR had response assessments at 6 months, and both remained in CMR at that time. Both dose cohorts have been cleared by the Dose Escalation Committee and Safety Committee, and the expansion part has been opened to enroll additional pts.Conclusions: These preliminary data from a small number of pts suggest that epcoritamab in combination with R-CHOP has a manageable safety profile with no new safety signals. Adverse events were similar to those previously reported for epcoritamab and R-CHOP individually. All evaluable pts achieved early responses, and all pts remain on treatment. Updated and additional data from pts treated in the expansion phase will be presented. These findings warrant further evaluation of epcoritamab for the treatment of high-risk, newly diagnosed DLBCL. DisclosuresBelada: Genmab: Research Funding. Drott: Roche: Honoraria; Kyowa Kirin: Honoraria; Respiratorius AB: Membership on an entity's Board of Directors or advisory committees. Narkhede: TG Therapeautics: Research Funding; Genmab: Other: Medical writing support, Research Funding; Genentech/Roche: Research Funding; Gilead: Research Funding. Elliot: Genmab: Current Employment, Patents & Royalties: P158-US-PSP3 . Liu: Genmab: Current Employment. Cota Stirner: AbbVie: Current Employment. Abbas: Genmab: Current Employment. Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Autologous Stem Cell Transplantation after Conditioning with Chidamide Plus Carmustine, Etoposide, Cytarabine, and Cyclophosphamide (Chi-BEAC) for Treatment of High-Risk and Relapsed/Refractory Aggressive Lymphoma: Multi-Center, Single-Arm, Open-Label Phase II Clinical Trial

Background:Chidamide, as a novel subtype-selective histone deacetylase inhibitors (HDACi), can directly inhibit tumor cell cycle progression and induce tumor cell apoptosis, inhibit phenotypic transformation of tumor cells and pro-drug resistance/pro-metastasis activity of the microenvironment, induce differentiation of tumor stem cells, and reverse epithelial-mesenchymal transformation of tumor cells, thereby restoring the sensitivity of drug-resistant tumor cells to drugs and enhancing the effect of chemotherapy agents through loosening chromatin and exposing DNA. The efficacy and safety of chidamide-BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide, Chi-BEAC) conditioning regimen combined with autologous stem cell transplantation (ASCT) were evaluated in a current phase II clinical trial for the treatment of high-risk and relapsed/refractory aggressive lymphoma.Methods: A total of 70 patients with high-risk diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), or mantle cell lymphoma (MCL) who had achieved complete remission (CR) or partial remission (PR) after first-line therapy or second-/third-line therapy were recruited from January 2018 to June 2021. Three of the patients were not evaluated after ASCT and two patients withdrew from the study; 65 patients were then evaluated for the effectiveness of Chi-BEAC treatment.Results: DLBCL and MCL are referred as B-cell non-Hodgkin lymphoma (B-NHL) and PTCL is referred as T and NK-cell non-Hodgkin lymphoma (T&NK-NHL) in the study. The median neutrophil engraftment time was 10 d (7-13 d) and median platelet engraftment time was 11 d (8-13 d).The CR rate at 3-6 months after transplantation was 75.4% in the 65 evaluable patients. The median progression free survival (PFS) and overall survival (OS) had not reached at the end of the follow-up period (median 18.1 month; range 1.8-42.0 months). The estimated PFS and OS at 24 months was 78.5% and 84.2%, respectively. Stratified analyses showed that in patients with B-NHL who previously received first-line treatment, the CR rate at 3-6 months after transplantation was 77.8%, and 2-year PFS was 74.8%. The survival rate might be better than previously reported for SWOG9704 (Stiff et al., 2013; PMID 24171516)-a 2-year PFS of 69%-and for DLCL04 (Chiappella et al., 2017; PMID 28668386)-a 2-year failure-free survival of 71%. In our patients with B-NHL who previously received second-/third-line treatments, the CR rate at 3-6 months after transplantation was 71.4%, and 2-year PFS was 77.1%. The survival rate might also be higher than previously reported for the CORAL trial (Gisselbrecht et al., 2010; PMID: 20660832), which showed a 2-year PFS of approximately 65%. In our patients with T&NK-NHL the CR rate at 3-6 months after transplantation was 73.3%, and 2-year PFS was 93.3%, The survival rate might be higher than previously reported for the NLG-T-01 trial (Francesco d'Amore et al., 2012; PMID: 22851556), which showed a 2-year PFS of approximately 55%. PFS stratification analysis showed that previous treatment outcomes affected the PFS: patients who had achieved CR before transplantation demonstrated better PFS than patients who had achieved PR (P = 0.199), while there was no significant difference between patients with different pathological subtypes (B or T&NK-NHL) or different risk groups.Most non-hematological adverse events (AEs) were of grade 1/2. Grade 4 AE only occurred in one patient, i.e., γ-glutamyl transpeptidase (GGT) elevation. Grade 3 AEs that occurred in ≥ 5% of the patients included febrile agranulocytosis (37.7%), hypokalemia (24.7%), hyponatremia (23.4%), GGT elevation (9.1%), and diarrhea (5.2%), which were well tolerated.Conclusions: This study showed that inclusion of the HDACi chidamide in conditioning regimen for ASCT greatly increased the PFS and OS, especially in patients with T&NK-NHL, and revealed an acceptable safety profile for refractory and relapsed lymphoma patients. Therefore, chidamide-containing conditioning regimen may be a great choice for patients with refractory and relapsed lymphoma, and awaits further confirmation by additional large-scale multi-center investigations. DisclosuresNo relevant conflicts of interest to declare.

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.

Comparison of the Efficacy and Feasibility of R-CODOX-M/IVAC-R Versus Conventional R-CHOP As First Line Regimen for High Risk Diffuse Large B-Cell Lymphoma

BACKGROUND AND AIMSDiffuse Large B Cell Lymphoma (DLBCL) is an heterogeneous group of diseases whose behavior can be predicted by clinical risk scores, immuno-histochemistry and cytogenetic. Among DLBCL, patient with high risk features such as high IPI score, high mitotic index, double hit lymphomas display a worse outcome and the standard frontline treatment with R-CHOP usually results in poor outcome. Consequently, many groups have explored more intensified first line regimens for those patients, such as R-DA-EPOCH and R-CODOX-M/IVAC-R.However, no study directly comparing conventional R-CHOP with more aggressive regimens are currently available, so that a clear indication of superior efficacy from an intensified approach has not been provided yet.The aim of the present was to retrospectively compare through a match-paired analysis two cohorts of patients affected by aggressive DLBCL who were treated with either conventional R-CHOP (center 1) or intensified R-CODOX-M/IVAC-R (center 2) as frontline regimen, in order to disclose to identify subgroups of patients who are more likely to benefit from intensive first line approach.PATIENTS AND METHODSHigh Risk DLBCL was defined by at least one among these features: high tumour burden, DPLs, IPI score >3 or the presence of at least 1 extranodal site.In center 1, 6 x R-CHOP is standard therapy for every patient with newly diagnosed DLBCL, whereas in center 2 patients with aggressive DLBCL are treated with R-CODOX/IVAC-R repeated for two courses.Fifty-one patients affected by aggressive DLBCL and treated with R-CHOP or R-CODOX-M/IVAC-R between January 2011 and January 2015 in the two centers were retrospectively included in a match-paired analysis. Median follow up was 36 months.Matching variables were age, IPI score, disease staging according to Ann Arbor, cell of origin according to Hans algorithm. Matching ratio was 2:1 (2 patients treated with conventional R-CHOP were matched with each patient treated with R-CODOX-M/IVAC-R).The two groups of patients had no significant differences in baseline characteristics such as age, stage, IPI and cell of origin.To disclose differences in terms of efficacy, overall response rate, as defined by international standard, overall survival and cumulative incidence of relapse were compared between the two cohorts.RESULTSOverall response rate (ORR) was 44/51 (86.3%). Patient treated with R-CODOX-M/IVAC-R had an higher probability to achieve at least a partial response (17/17, 100%, vs 27/34, 79.4%, p<0.05, respectively for R-CODOX-M/IVAC-R and R-CHOP).Specifically, after a subgroup analysis, patients with age <50 yrs (p<0.05) and stage III/IV (p<0.05) were found to have a significant improvement in ORR if treated with R-CODOX-M/IVAC-R. A trend towards improved chance of response with R-CODOX-M/IVAC-R, however without reaching statistical significance was observed among patients with germinal center DLBCL, according to Hans algorithm.Overall survival (OS) at 3 years was 88.2% (median of reached) and was not significantly different among patients treated with R-CHOP (3 year OS=86.9%) or R-CODOX-M/IVAC-R (3-year OS=93.2%). None of the other analyzed variables significantly impacted OS probability.After subgroup analysis, a trend for improved OS if treated with R-CODOX-M/IVAC-R was found among patients with IPI score >3, age <50 and germinal center DLBLC (Figure 1), again without reaching statistical significance.Patient treated with R-CODOX-M/IVAC-R had a significantly higher probability of experiencing grade III/IV hematological toxicities (p<0.05), grade III/IV mucositis (p<0.05) or grade III/IV infections (p<0.05), whereas cardiovascular and hepatic toxicities were unlikely and non significantly different among the two cohorts.CONCLUSIONSR-CODOX-M/IVAC is an highly effective regimen for patients affected by DLBCL, with an ORR significantly higher than conventional R-CHOP, however at the price of significantly higher therapy-related toxicities. Our results seem to suggest a potential benefit for younger patients with very aggressive DLBCL, where higher risk of toxicities is overcome by the improved probability of cure.Of note, patient with germinal center DLBCL seem to take a greater benefit from the intensified approach, this may be explained by the higher chemo-sensitivity that is usually observed in this setting, however our result must be confirmed in larger trials. [Display omitted] DisclosuresBocchia:Jansen: Other: Travel grant; Novartis: Other: Travel grant; Celgene: Other: Travel grant; Roche: Other: Travel grant.

The Efficacy of Systemic High Dose Methotrexate As Central Nervous System Prophylaxis in Patients with High Risk Diffuse Large B-Cell Lymphoma: A Propensity Score-Matched Analysis

Background: While the outcome of patients with diffuse large B-cell lymphoma (DLBCL) has been improved with the introduction of rituximab, central nervous system (CNS) relapse is still associated with poor prognosis. Although intrathecal methotrexate has been widely used for prophylaxis, its role has been questioned. Another way of utilizing the agent, systemic high dose methotrexate (HD-MTX) has been advocated from a few retrospective studies. However, they had no comparison group or they were compared with imbalanced, unmatched group even if existed. With prospectively collected cohort, we performed a propensity score-matched analysis to evaluate the efficacy of IV HD-HTX as CNS prophylaxis in high risk DLBCL patients.Methods: The registry data set of DLBCL patients, collected from January 2010 through March 2015 at a single institute, Asan Medical Center, was retrospectively reviewed. From July 2013, all consecutive DLBCL patients who were considered at high risk for CNS recurrence received systemic HD-MTX with standard R-CHOP therapy. High risk CNS relapse was defined by the involvement of ≥2 extranodal sites and elevated lactic dehydrogenase (LDH); or high-risk CNS international prognostic index (CNS-IPI ≥4); or involvement of specific high-risk extranodal sites including bone marrow, breasts, testes, paranasal sinuses. HD-MTX was administered at a dose of 3-3.5 g/m2 on day 15 of alternating cycles of R-CHOP or delivered 2 to 5 weeks after the completion of the primary therapy. We analyzed the progression-free survival (PFS), CNS relapse-free survival (CNS-RFS) and overall survival (OS) of the patients receiving CNS prophylaxis and compared with the patients who received R-CHOP only. Multivariate Cox regression and propensity score analysis were used to evaluate the treatment effect of systemic HD-MTX on survival with multiple covariates including age, sex, LDH, ECOG score, stage, CNS-IPI, extranodal involvement and involved sites.Results: A total of 197 patients with DLBCL and CNS risk factors who were treated with standard R-CHOP therapy were identified between January 2010 and March 2015. Among them, 47 patients received systemic HD-MTX as CNS prophylaxis. In the R-CHOP only group (n=150), with a median follow-up of 58.88 (1.34-84.3) months, 14 CNS relapses occurred within 2 years. The estimated 2-year PFS, CNS-RFS and OS rates were 58.6%, 89.5%, 71.3%, respectively. In the HD-MTX prophylaxis group (n=47), with a median follow-up of 27.24 (3.38-42.02) months, 3 CNS relapses occurred within 2 years. The estimated 2-year PFS, CNS-RFS and OS rates were 62.3%, 93.1% and 74.5%, respectively. Systemic HD-MTX did not significantly increase the PFS (HR 0.619, 95% CI 0.363-1.057, P = .079), CNS-RFS (HR 0.547, 95% CI 0.156-1.924, P=.347), and OS (HR 0.628, 95% CI 0.331-1.19, P = .154) in the multivariate survival analysis. The results seems to consistently show no survival benefit of systemic HD-MTX regardless of the different propensity score analysis methods except for PFS by weighting HR: PFS (matching HR 0.652, 95% CI 0.36-1.18, P=.157; weighting HR 0.689, 95% CI 0.503-0.945, P=.02),CNS-RFS (matching HR 0.635, 95% CI 0.161-2.499, P=.516; weighting HR 0.587, 95% CI 0.287-1.203, P=.146), OS (matching HR 0.625, 95% CI 0.319-1.227, P=.172; weighting HR 0.726, 95% CI 0.505-1.044, P=.083).Conclusion: Systemic HD-MTX prophylaxis for CNS relapse did not show significant survival improvement in high risk DLBCL patients in this study although there was a trend for better outcomes in patients given HD-MTX, as different statistical methods incorporating stringent propensity score-matched analysis were applied. However, these results are still limited by small cohort size its retrospective nature. Multi-center, prospective randomized studies are necessary to appraise the efficacy of systemic HD-MTX as CNS prophylaxis in high risk DLBCL patients. DisclosuresNo relevant conflicts of interest to declare.

Th1/2 Immune Response Signature Predicts Outcome after Dose-Dense Immunochemotherapy in Patients with High Risk Diffuse Large B-Cell Lymphoma - Results from Nordic Lymphoma Group Trials

Introduction: Despite better therapeutic options and improved survival of diffuse large B-cell lymphoma (DLBCL), 30-40% of the patients still relapse and have dismal prognosis. Recently, the impact of genomic aberrations, allowing lymphoma cells to escape immune recognition on DLBCL pathogenesis has been recognized. However, whether immune related signatures could be used as determinants for treatment outcome has not been rigorously evaluated. Here, our aim was to elucidate the immunologic characteristics of the tumor microenvironment, and associate the findings with outcome in patients with high-risk DLBCL.Patients and methods: We specifically examined gene expression in the tumor microenvironment, using RNA isolated from formalin fixed paraffin-embedded (FFPE) tumor samples from 81 patients with DLBCL. Gene expression analysis was conducted on the NanoString nCounter gene expression platform using a 770-gene PanCancer Immune panel. The predictive impact of the gene expression signatures was assessed using a cohort of 65 high risk DLBCL patients enrolled in the Nordic CHIC trial (Leppä et al., 2016). The findings were validated using exon array data from an independent cohort of 38 high risk DLBCL patients treated in the Nordic CRY-04 trial (Holte et al., 2013; Leivonen et al., 2017a). In both trials, the patients received dose-dense immunochemotherapy (R-CHOEP-14) and systemic central nervous system prophylaxis (HD-Mtx and HD-Ara-C).Results: Unsupervised hierarchical clustering revealed three major clusters of genes with differential expression between the patients. The clusters were enriched for the genes related to focal adhesion and extracellular matrix (ECM) receptor interactions (eg. COL3A1, ITGA, ITGB, VEGFC, VEGFA, PDGFRB, PDGFC, FN1 ), T/NK-cell signaling (eg. ICAM1, CD3, CD4, CD8 GZMB, ITGB2 ), and type 1/2 immune responses (eg. IL4, IFNL1, IFNL2, IL13, IL24 ). Interestingly, type 1/2 immune response signature correlated with survival. In the CHIC cohort, the group of patients (n=10) with high expression of type 1/2 immune response signature genes had a 4-year PFS of 60% in comparison to 91% for those (n=55) with low expression (p = 0.021). The corresponding 4 y OS rates were 64% vs 90% (p=ns). The risk of progression was 4.0 fold higher for the patients with high expression of type 1/2 immune response signature genes (95% CI 1.120-14.280, p=0.033). No differences were observed in sex, age, stage, IPI scores, or molecular subgroups between the low and high type 1/2 immune response subgroups. The prognostic impact of the signature was confirmed in the CRY-04 exon array cohort (4-y PFS; 46% vs 80%, p = 0.021, 4-y OS 62% vs 88%; p = 0.014). In the CRY-04 cohort, the risk of progression was 3.6 fold (95% CI 1.13-11.20, p=0.030) and death 4.8 fold (95% CI 1.20-19.26, p=0.027) higher for the group of patients with high expression of the type 1/2 immune response signature genes. In contrast to our data on primary testicular lymphomas (PTLs) (Leivonen et al., 2017b), T/NK cell signature did not correlate with outcome in either of the trial cohorts. Correspondingly, type 1/2 immune signature was not associated with outcome in the cohorts of PTL or DLBCL patients treated with conventional R-CHOP regimen.Conclusion: Our data suggest that immune related signatures exhibit treatment-specific roles in diffuse large B-cell lymphoma. For the high risk DLBCL patients treated with dose-dense immunochemotherapy, high expression of type 1/2 immune response signature genes predicts a poor outcome. A detailed characterization of immune cell composition in the tumor microenvironment and its impact on survival is ongoing. DisclosuresJørgensen:Roche: Research Funding. Holte:Novartis: Consultancy, Honoraria; Celgene: Consultancy; Janssen Cilag: Consultancy; Nordic Nanovector: Consultancy; Mundipharma: Consultancy. Leppa:Merck: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Research Funding; Bayer: Research Funding.

Efficacy and safety of prophylactic high-dose MTX in high-risk DLBCL: a treatment intent–based analysis

AbstractDespite central nervous system (CNS) relapse occurring in >10% of high-risk diffuse large B-cell lymphoma (DLBCL) patients, the role of CNS-directed prophylaxis is controversial in the absence of randomized controlled trials. In this retrospective study, we aimed to evaluate the safety and efficacy of prophylactic high-dose methotrexate (HD-MTX) on CNS relapse and survival outcomes in 258 newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated high-risk DLBCL patients, based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX. Patients were classified into an ITT HD-MTX group (n = 128) and a non-ITT HD-MTX group (n = 130). The CNS relapse rate was not significantly different between these groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = 0.96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs 64.5% (P = 0.94) and 71.7% vs 71.4% (P = 0.7), respectively. Also, propensity score–matched analyses showed no significant differences in the time-to-CNS-relapse, progression-free survival, or overall survival. The ITT HD-MTX group showed a higher incidence of grade ≥ 3 oral mucositis and elevated alanine aminotransferase. Prophylactic HD-MTX does not improve CNS relapse rate or survival outcomes in high-risk DLBCL patients, and it is accompanied by increased toxicities.

Soluble PD-1 but Not PD-L1 Levels Predict Poor Outcome in Patients with High-Risk Diffuse Large B-Cell Lymphoma.

Simple SummarySoluble forms of checkpoint protein PD-1 and its ligand PD-L1 can be measured from circulation, but their source, function, and clinical impact in cancer remain incompletely understood. In this study, we used serum samples collected during a conduction of a prospective immunochemotherapy trial in patients with high-risk diffuse large B-cell lymphoma (DLBCL) and assessed their clinical significance. Our results demonstrate that sPD-1 levels in the peripheral blood at the time of diagnosis correlate with the quantities of tumor infiltrating PD1+ T cells and translate to inferior survival. To our knowledge, this is the first study to identify sPD-1 as a prognostic factor, providing interesting perspectives on future clinical trials in DLBCL, including patients’ stratification associated with checkpoint blockade.Interaction of checkpoint receptor programmed death 1 (PD-1) with its ligand 1 (PD-L1) downregulates T cell effector functions and thereby leads to tumor immune escape. Here, we aimed to determine the clinical significance of soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) in patients with diffuse large B-cell lymphoma (DLBCL). We included 121 high-risk DLBCL patients treated in the Nordic NLG-LBC-05 trial with dose-dense immunochemotherapy. sPD-1 and sPD-L1 levels were measured from serum samples collected prior to treatment, after three immunochemotherapy courses, and at the end of therapy. sPD-1 and sPD-L1 levels were the highest in pretreatment samples, declining after three courses, and remaining low post-treatment. Pretreatment sPD-1 levels correlated with the quantities of PD1+ T cells in tumor tissue and translated to inferior survival, while no correlation was observed between sPD-L1 levels and outcome. The relative risk of death was 2.9-fold (95% CI 1.12–7.75, p = 0.028) and the risk of progression was 2.8-fold (95% CI 1.16–6.56, p = 0.021) in patients with high pretreatment sPD-1 levels compared to those with low levels. In conclusion, pretreatment sPD-1 level is a predictor of poor outcome after dose-dense immunochemotherapy and may be helpful in further improving molecular risk profiles in DLBCL.

The DLBCL90 gene-expression assay identifies double-hit lymphomas with high sensitivity in patients from two phase II clinical trials with high-risk diffuse large B-cell lymphoma.

The DLBCL90 gene-expression assay identifies double-hit lymphomas with high sensitivity in patients from two phase II clinical trials with high-risk diffuse large B-cell lymphoma.

Retraction Note to: High-dose therapy and autologous stem cell transplantation for relapsed or high-risk diffuse large B-cell lymphoma: a nationwide survey.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s12185-020-03018-1.

Feasibility of up-front autologous stem cell transplantation for high risk diffuse large B-cell lymphoma – non-randomized analysis of 58 consecutive patients

AbstractIntroductionHigh-dose chemotherapy supported by autologous stem cell transplantation (ASCT) continues to be a standard of care for relapsed diffuse large B-cell lymphoma (DLBCL) and may be considered as a frontline consolidation for a proportion of patients with high-risk features.AimWe evaluated the feasibility and safety of ASCT for high-risk DLBCL who are in first complete remission after standard treatment with chemotherapy ± rituximab.Material and methodsA retrospective analysis of 58 patients (36 males and 22 females) receiving up-front ASCT between 1996 and 2018 for remission consolidation.ResultsOf the diagnosed, fifty patients were in clinical stage ≥ III. Forty-two (72%) of transplanted patients had age-adjusted IPI ≥ 2. The “B” symptoms were present in 34 patients. The conditioning consisted of cyclophosphamide, carmustine, etoposide (CBV) in 32 patients, carmustine, cytarabine, etoposide, melphalan (BEAM) in 18, and 8 patients received bendamustine, cytarabine, etoposide, melphalan (BeEAM). The transplant-related mortality was 0% at day +30 and +100 after ASCT. Median overall survival (OS) was 4.2 years whereas progression-free survival (PFS) reached 3.0 years. The estimated 5-year OS and PFS were found to be 66% and 64%, respectively. The presence of “B” symptoms remained significance in multivariate analysis (HR 4.17 [95% CI: 1.19–14.5];p= 0.02). No grade 3 or 4 non-hematological adverse events were observed.ConclusionsUp-front ASCT was found to be a safe and feasible procedure with long-term remission in approximately 70% of patients.

Favourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3–5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial

BackgroundOutcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen.Patients and methodsEligible patients were aged 18–65 years with stage II–IV untreated DLBCL and an International Prognostic Index (IPI) score of 3–5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS).ResultsA total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9–74.6] and 2-year overall survival was 76.0% (90% CI 68.5–82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9–58.0).ConclusionsThis trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care.Trial RegistrationClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19).

Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis

AbstractSurvival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P = .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.gov as #NCT01325194.

Clinical study of DA-EPOCH regimen combined with or without rituximab in treatment of young newly diagnosed patients with middle and high-risk diffuse large B-cell lymphoma

Objective To observe the clinical efficacy and prognosis of DA-EPOCH regimen combined with or without rituximab [(R)-DA-EPOCH regimen] in treatment of young newly diagnosed patients with middle and high-risk diffuse large B-cell lymphoma (DLBCL). Methods The clinical data of 107 young newly diagnosed middle to high-risk DLBCL patients treated with (R)-DA-EPOCH regimen at Guizhou Cancer Hospital between November 2014 and December 2018 were retrospectively analyzed. The efficacies were analyzed by grouping according to rituximab (65 cases in R-DA-EPOCH group and 42 cases in DA-EPOCH group), and according to involved-filed radiotherapy (IFRT) after chemotherapy (99 cases with chemotherapy indications including 59 cases with IFRT and 40 cases without IFRT). Results The objective response rate (ORR) was 86.0% (92/107). The 1-, 2-year overall survival (OS) rate was 90.6% and 75.3%. The 1-, 2-year progression-free survival (PFS) rate was 79.1% and 56.5%. The ORR, 1-year OS rate, 2-year OS rate, 1-year PFS rate and 2-year PFS rate in R-DA-EPOCH group were higher than those in DA-EPOCH group [87.7% (57/65) vs. 83.3% (35/42), 94.8% vs. 84.9%, 80.4% vs. 68.2%, 90.5% vs. 77.0%, 61.0% vs. 50.8%, respectively), but there were no statistical differences (all P > 0.05). The ORR of IFRT group and non-IFRT group was 98.2% (56/57) and 80.0% (32/40) (χ 2 = 7.225, P = 0.007). The 2-year OS rate was 86.0% and 63.3% (P < 0.05). Main adverse reactions caused by radiotherapy were local skin mucosa reactions of grade Ⅰ-Ⅱ [42.4% (25/59)]. Multivariate analysis showed that albumin value after treatment was an independent prognosis factor affecting OS rate (95% CI 2.709-21.433, P < 0.01). Gender (95% CI 0.020-0.318, P < 0.01), albumin level (95% CI 2.097-12.219, P < 0.01), Beta 2 microglobulin level (95% CI 0.080-0.602, P < 0.01) and absolute lymphocyte count/absolute monocyte count (95% CI 0.113-0.720, P < 0.01) after treatment were independent prognosis factors affecting PFS rate. Conclusions The young newly diagnosed patients with middle and high-risk DLBCL are highly heterogeneous. Rituximab combined with DA-EPOCH regimen can improve the efficacy of patients. IFRT after chemotherapy may increase the short-term efficacy and OS, and the adverse reactions are tolerant. Key words: Lymphoma, large B-cell, diffuse; Chemotherapy, adjuvant; Molecular targeted therapy; Young adult; Prognosis

High-dose therapy and autologous stem cell transplantation for relapsed or high-risk diffuse large B-cell lymphoma: a nationwide survey.

To investigate the use of high-dose therapy and autologous stem cell transplantation (ASCT) for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL) between 1990 and 2007, we conducted a nationwide survey using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Of the 1222 patients in the database, 576 (47%) received ASCT in first complete remission (CR1), 140 (12%) in first partial remission, 281 (23%) in sensitive relapse, 150 (12%) in resistant or sensitivity-unknown relapse, and 75 (6%) in primary refractory status. With a median follow-up of 22months, the 2-year overall survival (OS) and progression-free survival rates were 71% and 68%, respectively. The cumulative incidences of 2-year non-relapse mortality and relapse/progression were 6% and 26%, respectively. Relapse/progression after ASCT in the rituximab era (2002-2007) was significantly lower than that in the pre-rituximab era (1990-2001; P < 0.001). Older age, male gender, poor performance status at ASCT, non-CR1 at ASCT, ASCT performed in 1990-2001, and LEED or MCEC regimen were adverse predictors of OS. Because ASCT for newly diagnosed high-risk DLBCL has not been performed recently, a registry database study to assess the impact of ASCT for relapsed or refractory DLBCL in the rituximab era is warranted.

High Risk DLBCL in Younger Patients: Should ASCT be Declined in the Era Pos-Rituximab?

Introdution Optimal treatment of young patients with high-risk diffuse large B-cell lymphoma (DLBCL) remains a matter of debate. With the addition of rituximab, response rates (RR) and overall survival (OS) have improved significantly, but the best treatment option for this subset of patients with high risk DLBCL is not consensual. Historically, these patients are treated with conventional immunochemotherapy protocols (RCHOP - Rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by autologous stem cell transplantation (ASCT) as a consolidation treatment. Several studies tried to clear the exact role of ASCT, and others were design to answer about addition of other drugs to RCHOP, without conclusive results. Recently, our department review the protocol according to the state of the art, and an intensification of treatment was made for high risk DLBCL in young patients (&lt;65 years), without comorbidities. Since then, this group of patients is treated with the RCHOEP protocol (Rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone in addition to etoposide), omitting ASCT. Aim Comparison of conventional immunochemotherapy followed by ASCT with high dose immunochemotherapy in young, high risk patients with DLBCL. Analyze the impact of ASCT in the outcomes. Methods We evaluated 478 patients with confirmed diagnosis of DLBCL at our institution, between January 2012 and December 2017. 10 patients with CNS involvement and 108 patients with primary extranodal disease at diagnosis were excluded. A retrospective analysis was performed in the group of young, high risk patients with DLBCL. For study purpose 2 subgroups were defined: RCHOP plus ASCT (n=17) and RCHOEP (n=32) treated patients. Analysis of survival and statistical comparison between these two subgroups was made using the SPSS computing platform. Results In this study, 360 patients were analyzed. The median follow-up of the cohort was 46 months [4-86 months]. In the subgroup of RCHOP plus ASCT (n=17) the median age at diagnosis was 57 years [22-65]. LDH distribution showed a maximum of 3989 U/L and a minimum of 158 U/L, with a median value of 449 U/L. IPI median value was 3. 5 patients had involvement of extranodal areas and all presented at diagnosis with stage 3 (n=4) or 4 (n=13). Analysis of histological subtype (classified by Hans algorithm) , revealed 9 patients with germinal center DLBCL (GC DLBCL) and 8 patients with activated B Cell DLBCL (ABC DLBCL). Complete response (CR) was obtained in 15 patients and 3 patients relapsed. In the subgroup of RCHOEP (n=32) the median age at diagnosis was 51 years (31-63). LDH range between 150 and 2695 U/L, with a median value of 399 U/L. IPI median value was 3 with a minimum value of 2. 11 patients had involvement of extranodal areas and only 1 patient doesn´t presented with advanced disease at diagnosis. In concern to histological subtype, 18 patients had GC DLBCL and 14 patients had ABC DLBCL. CR was achieved in 28 patients and 4 patients relapse during follow up. Prior to analysis of survival a statistical comparison between the 2 subgroups was performed and did not identify any significant difference between the main demographic and analytical clinical variables (age at diagnosis, sex, ECOG, presence of B symptoms, LDH, hemoglobin concentration, clinical status, medullary involvement, presence of bulky mass, IPI score and histological subtype). As regards the analysis of survival in both subgroups, the median OS was not attained. The 2-year OS was 87,5% in the group of patients treated with RCHOEP and 82% in the subgroup of patients submitted to RCHOP plus ASCT, not presenting this difference statistical value. Conclusion No randomized trials have been conducted comparing R-CHOP and R-CHOEP and there is only one retrospective study population based cohort from the Danish Lyfo Registry comparing young high risk DLBCL treated with R-CHOP or R-CHOEP. This study aims to explore the RCHOEP potential comparing to RCHOP plus ASCT in this peculiar group of patients, as an alternative regimen. Despite the retrospective character of this study, our results demonstrates the non-inferiority of RCHOEP relatively to RCHOP plus ASCT. RCHOEP is an effective treatment for young patients with high risk DLBCL, an excellent alternative, with high efficacy and a tolerable toxicity. This result should be validated in a prospective randomized study. Disclosures No relevant conflicts of interest to declare.

Open-Label, Phase 2 Study of Blinatumomab after First-Line Rituximab-Chemotherapy in Adults with Newly Diagnosed, High-Risk Diffuse Large B-Cell Lymphoma

Background: Rituximab combined with chemotherapy (R-chemotherapy) is the standard of care first-line treatment for diffuse large B-cell lymphoma (DLBCL). Despite success with R-chemotherapy, 30% to 50% of patients with high-risk DLBCL will relapse, and outcomes are poor among patients who relapse within one year of diagnosis. Given the challenge of successful salvage, novel first-line therapies are needed. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct that directs cytotoxic T cells to lyse CD19-expressing B cells, has shown efficacy as salvage therapy in patients with relapsed or refractory DLBCL. This open-label, multicenter, phase 2 study (ClinicalTrials.gov, NCT03023878) assessed the efficacy and safety of blinatumomab after first-line R-chemotherapy for patients with newly diagnosed, high-risk DLBCL. Methods: Patients (≥18 y) had proven high-risk DLBCL (International Prognostic Index [IPI] 3−5 and double/triple hit or double MYC/BCL2 expressor) and Eastern Cooperative Oncology group performance status ≤2. To be eligible for blinatumomab, patients were required to achieve complete metabolic response (CMR), partial metabolic response (PMR), or stable metabolic response by PET/CT after a run-in period with 6 cycles of R-chemotherapy (R-CHOP, R-DA-EPOCH, or R-CHOEP). Blinatumomab was given by continuous intravenous infusion in a single 84-day cycle 1 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 42 days, followed by a 28-day treatment-free interval) and an optional 28-day cycle 2 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 14 days) for patients without progressive metabolic disease (PMD). The primary endpoint was the incidence and severity of adverse events (AEs). Additional endpoints were objective response rate (ORR [CMR + PMR]) per Lugano criteria, minimal residual disease (MRD) by plasma cell−free circulating tumor DNA, overall survival (OS), and pharmacokinetics (PK). Results: Of 47 patients enrolled, 17 (36%) discontinued R-chemotherapy run-in (protocol criteria, n=6; patient request, n=5; disease progression, n=3; ineligibility, n=1; AE, n=1; death, n=1) and 30 (64%) completed the run-in (2 did not proceed to blinatumomab). Of 28 patients who received blinatumomab, 26 (93%) had high or high-intermediate IPI; 8 (29%) were double/triple hit and 10 (36%) were double protein expressors (Table). In total, 26 (93%) patients completed cycle 1; ten of 11 (91%) patients completed optional cycle 2. Blinatumomab PK were consistent with those in previous studies. After the R-chemotherapy run-in before starting blinatumomab, 24 patients had objective metabolic responses and 4 had no metabolic response (NMR). After blinatumomab treatment, the ORR (within 12 weeks of starting blinatumomab) was 89% (25/28 patients; 95% CI, 72−98; Table). The 4 patients with NMR before blinatumomab had objective responses after blinatumomab treatment. Three patients with objective responses before blinatumomab relapsed after blinatumomab. Twenty-six (93%) patients were still alive with a median follow-up time of 8.6 months; 2 died (disease progression; n=1; infection not related to treatment, n=1). Nine of 13 (69%) patients during the R-chemotherapy run-in were MRD positive, all of whom converted to MRD negative after treatment with blinatumomab. After treatment with blinatumomab, 17 of 18 (94%) patients were MRD negative; the MRD positive patient had PMD. During blinatumomab treatment, 11 (39%) patients had grade ≥3 AEs, and 5 (18%) had grade ≥4 AEs. Two (7%) patients discontinued treatment due to AEs (grade 3 neurotoxicity; grade 4 neutropenia). Consistent with previous blinatumomab reports, neurologic events (NEs) were reported in 17 (61%) patients, including 3 (11%) with grade 3 NEs and 1 (4%) with NEs leading to treatment discontinuation. No patients had grade ≥3 cytokine release syndrome. Other grade ≥3 events of interest included neutropenia and febrile neutropenia (n=4; 14%) and infection (n=3; 11%). Conclusions: In patients with newly diagnosed, high-risk DLBCL, blinatumomab monotherapy after first-line R-chemotherapy led to an 89% ORR, and safety was consistent with that in earlier studies in DLBCL. Thus, blinatumomab is a potential treatment option for patients with newly diagnosed disease. Disclosures Katz: Stemline: Speakers Bureau; Dova: Consultancy. Chu:Celgene: Honoraria; Teva: Consultancy; AstraZeneca: Honoraria; Amgen Inc.: Honoraria; Gilead: Honoraria. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Chen:Amgen Inc.: Employment, Equity Ownership. Kalabus:Amgen Inc.: Employment, Equity Ownership. Morris:Amgen: Employment, Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Avilion:Amgen Inc.: Employment, Equity Ownership. González-Barca:Takeda: Honoraria; Kiowa: Consultancy; Celtrion: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

Hitting back at lymphoma: How do modern diagnostics identify high-risk diffuse large B-cell lymphoma subsets and alter treatment?

Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. Diagnostic tools in the clinic can now identify distinct subsets characterized by unique molecular features, which are increasingly transforming how these patients are managed. Activated B-cell-like DLBCL is characterized by NF-κB activation and chronic B-cell receptor signaling and may be targeted with lenalidomide or ibrutinib in the relapsed setting. Germinal center-like DLBCL is enriched for activating EZH2 mutations, and encouraging activity has been observed for the EZH2 inhibitor tazemetostat, which now has a fast-track US Food and Drug Administration designation. Double-hit lymphoma is a high-grade B-cell lymphoma characterized by translocations of MYC and BCL2 and/or BCL6 and carries a poor prognosis. Intensive chemoimmunotherapy strategies appear to be superior to standard R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone) as initial therapy, and anti-CD19 chimeric antigen receptor T cells are inducing remission in patients with relapsed/refractory disease who previously had few available options. Primary mediastinal (thymic) large B-cell lymphoma is a molecularly distinct large-cell lymphoma with clinical and molecular features that overlap with those of classical Hodgkin lymphoma. R-CHOP has been associated with an unacceptably high rate of primary treatment failure in this young population, whereas dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) produces durable remissions without the need for radiotherapy in most patients. For relapsed/refractory disease, immune checkpoint inhibitors targeting PD-1 have shown promising activity in chemotherapy-refractory disease, as have anti-CD19 chimeric antigen receptor T cells. Additional therapeutic targets, including JAK2, continue to be evaluated. The identification of discrete biological subsets is steadily moving us away from a "one-size-fits-all" approach in DLBCL.

ENGINE: Phase III randomized study of enzastaurin/R-CHOP versus placebo/R-CHOP in frontline high-risk diffuse large B-cell lymphoma patients with novel genomic biomarker DGM1.

TPS7569 Background: Progress in genome technology allows analysis of previously completed trials to identify patients subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC- b) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of Enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of Enzastaurin vs Placebo, N=758) ( Crump, 2016), and (2) S028 (A randomized phase II study of Enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) ( Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to Enzastaurin treatment ( Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring Enzastaurin (p=0.018). These data suggest that addition of Enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study. Methods: Adult patients must have untreated CD20+ DLBCL, IPI ≥ 3. Patients are randomized 1:1 to Enzastaurin/R-CHOP or Placebo/R-CHOP for 6 cycles during combination phase. Each subject’s treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive Enzastaurin for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. The study is ongoing with 51 sites open in the US and China. As of 22 Jan 2019, 70 patients have been randomized. Clinical trial information: NCT03263026.