High-risk Diffuse Large B-cell Research Articles

Pola-R-CHP or R-CHOEP for first-line therapy of younger patients with high-risk diffuse large B-cell lymphoma: a retrospective comparison of two randomized phase 3 trials.

Pola-R-CHP or R-CHOEP for first-line therapy of younger patients with high-risk diffuse large B-cell lymphoma: a retrospective comparison of two randomized phase 3 trials.

Effectiveness of R-CHOP versus R-CHOEP for treatment of young patients with high-risk diffuse large B-cell lymphoma: A Danish observational population-based study.

Etoposide to standard R-CHOP is used for high-risk diffuse large B-cell lymphoma (DLBCL) in some countries. Due to the lack of randomized trials, a real-world data study using matching methods was used to test the potential effectiveness of R-CHOEP over R-CHOP. This study included patients from the Danish Lymphoma Register diagnosed between 2006 and 2020 at the age of 18-60 years with de novo DLBCL and age-adjusted IPI ≥2. R-CHOEP treated patients were matched 1:1 without replacement to R-CHOP treated patients using a hybrid exact and genetic matching technique. Primary endpoints were progression-free survival (PFS) and overall survival (OS). In total, 396 patients were included; 213 received R-CHOEP and 183 received R-CHOP. Unadjusted 5-year PFS and OS for R-CHOEP were 69% (95% Confidence intervals [CI]; 63%-76%) and 79% (CI;73%-85%) versus 62% (CI;55%-70%) and 76% (CI;69%-82%) for R-CHOP (log-rank test, PFS p = .25 and OS p = .31). A total of 127 patients treated with R-CHOEP were matched to 127 patients treated with R-CHOP. Matching-adjusted 5-year PFS and OS were 65% (CI; 57%-74%) and 79% (CI; 72%-84%) for R-CHOEP versus 63% (CI; 55%-73%) and 79% (CI;72%-87%) for R-CHOP (log-rank test, PFS p = .90 and OS p = .63). The present study did not confirm superiority of R-CHOEP over R-CHOP for young patients with high-risk DLBCL.

PET-based radiomic feature based on the cross-combination method for predicting the mid-term efficacy and prognosis in high-risk diffuse large B-cell lymphoma patients.

This study aims to develop 7×7 machine-learning cross-combinatorial methods for selecting and classifying radiomic features used to construct Radiomics Score (RadScore) of predicting the mid-term efficacy and prognosis in high-risk patients with diffuse large B-cell lymphoma (DLBCL). Retrospectively, we recruited 177 high-risk DLBCL patients from two medical centers between October 2012 and September 2022 and randomly divided them into a training cohort (n=123) and a validation cohort (n=54). We finally extracted 110 radiomic features along with SUVmax, MTV, and TLG from the baseline PET. The 49 features selection-classification pairs were used to obtain the optimal LASSO-LASSO model with 11 key radiomic features for RadScore. Logistic regression was employed to identify independent RadScore, clinical and PET factors. These models were evaluated using receiver operating characteristic (ROC) curves and calibration curves. Decision curve analysis (DCA) was conducted to assess the predictive power of the models. The prognostic power of RadScore was assessed using cox regression (COX) and Kaplan-Meier plots (KM). 177 patients (mean age, 63 ± 13 years,129 men) were evaluated. Multivariate analyses showed that gender (OR,2.760; 95%CI:1.196,6.368); p=0.017), B symptoms (OR,4.065; 95%CI:1.837,8.955; p=0.001), SUVmax (OR,2.619; 95%CI:1.107,6.194; p=0.028), and RadScore (OR,7.167; 95%CI:2.815,18.248; p<0.001) independently contributed to the risk factors for predicting mid-term outcome. The AUC values of the combined models in the training and validation groups were 0.846 and 0.724 respectively, outperformed the clinical model (0.714;0.556), PET based model (0.664; 0.589), NCCN-IPI model (0.523;0.406) and IPI model (0.510;0.412) in predicting mid-term treatment outcome. DCA showed that the combined model incorporating RadScore, clinical risk factors, and PET metabolic metrics has optimal net clinical benefit. COX indicated that the high RadScore group had worse prognosis and survival in progression-free survival (PFS) (HR, 2.1737,95%CI: 1.2983, 3.6392) and overall survival (OS) (HR,2.1356,95%CI: 1.2561, 3.6309) compared to the low RadScore group. KM survival analysis also showed the same prognosis prediction as Cox results. The combined model incorporating RadScore, sex, B symptoms and SUVmax demonstrates a significant enhancement in predicting medium-term efficacy and prognosis in high-risk DLBCL patients. RadScore using 7×7 machine learning cross-combinatorial methods for selection and classification holds promise as a potential method for evaluating medium-term treatment outcome and prognosis in high-risk DLBCL patients.

Circulating-tumor DNA Assessment in Diffuse Large B-cell Lymphoma to Determine Up-front Stem Cell Transplantation: A Pilot Study.

This study evaluated the possibility of clinical use of circulating-tumor DNA (ctDNA) as a biomarker to determine up-front autologous stem cell transplantation (auto-SCT) for patients with high-risk diffuse large B-cell lymphoma (DLBCL) in practice. To explore the dynamics of ctDNA in DLBCL, blood samples were collected sequentially before and after treatment from patients with newly diagnosed DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. To conduct ctDNA genotyping and ctDNA monitoring simultaneously, targeted sequencing by cancer personalized profiling using deep sequencing was used. Ten patients between the ages of 50 and 60 years were enrolled. Based on the international prognostic index (IPI), seven patients were classified as high-IPI-risk group, and three patients were classified as low-IPI-risk group. The IPI risk group correlated with total metabolic tumor volume. All patients completed six cycles of R-CHOP chemotherapy, and seven patients achieved complete response. Changes in ctDNA mutation numbers did not correlate with changes in PET scan images and treatment response. In most high-risk patients, new mutations appeared in ctDNA after completion of chemotherapy that conceivably marked resistant clones. Notably, disease relapse did not occur in high-risk patients with poor prognostic mutations who underwent autologous SCT. ctDNA monitoring was meaningful in high-risk patients. Moreover, ctDNA and well-known prognostic factors should be considered in the decision making for auto-SCT. If a new genetic mutation in ctDNA with a negative prognosis would emerge during treatment, high-risk patients should consider auto-SCT.

Genotyping on circulating tumor DNA improves mutation detection rate in high-risk diffuse large B-cell lymphoma

Genotyping on circulating tumor DNA improves mutation detection rate in high-risk diffuse large B-cell lymphoma

POSTER: ABCL-429 Epcoritamab + R-CHOP in Patients With Previously Untreated (1L) High-Risk Diffuse Large B-Cell Lymphoma, Including Double-Hit/Triple-Hit Lymphoma: Updated EPCORE NHL-2 Data

POSTER: ABCL-429 Epcoritamab + R-CHOP in Patients With Previously Untreated (1L) High-Risk Diffuse Large B-Cell Lymphoma, Including Double-Hit/Triple-Hit Lymphoma: Updated EPCORE NHL-2 Data

ABCL-429 Epcoritamab + R-CHOP in Patients With Previously Untreated (1L) High-Risk Diffuse Large B-Cell Lymphoma, Including Double-Hit/Triple-Hit Lymphoma: Updated EPCORE NHL-2 Data

ABCL-429 Epcoritamab + R-CHOP in Patients With Previously Untreated (1L) High-Risk Diffuse Large B-Cell Lymphoma, Including Double-Hit/Triple-Hit Lymphoma: Updated EPCORE NHL-2 Data

Metabolic response rates of epcoritamab + R-CHOP in patients with previously untreated (1L) high-risk diffuse large B-cell lymphoma, including double-hit/triple-hit lymphoma: Updated EPCORE NHL-2 data.

7519 Background: Patients (pts) with 1L diffuse large B-cell lymphoma (DLBCL) typically receive rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, around 40% relapse. Complete response rates and long-term outcomes are worse for high-risk pts with International Prognostic Index (IPI) 3–5 or double-hit/triple-hit lymphoma, representing an underserved pt population requiring better curative options. Data from the pivotal study of single-agent epcoritamab, a T-cell–engaging bispecific antibody, demonstrated impressive efficacy and a manageable safety profile (Thieblemont et al, JCO 2022). Preliminary data for epcoritamab + R-CHOP in 1L DLBCL (NCT04663347) showed encouraging efficacy. Here we present results for a larger cohort with longer follow-up. Methods: Pts with 1L CD20+ DLBCL and IPI ≥3 received subcutaneous epcoritamab (cycle [C] 1–4, QW; C5–6, Q3W) + R-CHOP for 6 Cs (21 d each) followed by epcoritamab monotherapy Q4W (28-d Cs) up to a total of 1 y. Results: As of Oct 31, 2022, 47 pts (median age, 64 y) had received epcoritamab 48 mg + R-CHOP with a median follow-up of 11.5 mo (range, 0.8–15.5). All pts had IPI 3–5, 37 (79%) had stage IV disease, and of 25 pts with FISH data available, 11 (44%) had double-hit/triple-hit DLBCL. Median time from diagnosis to first dose was 28 d (range, 3–423). Median dose intensity for R-CHOP was ≥95%. The most common treatment-emergent AEs (TEAEs) of any grade (G) were neutropenia (64%), anemia (62%), CRS (60%), fatigue (40%), pyrexia (40%), injection-site reactions (38%), and nausea (38%). TEAEs led to epcoritamab discontinuation in 3 pts; 1 pt had a G5 TEAE (COVID-19, unrelated to treatment). CRS was predominantly low grade (57% G1–2, 2% G3) and occurred mostly after the first full dose (C1D15); all cases resolved. One pt experienced G2 ICANS, which resolved. All response-evaluable pts (100%) had a response, and 76% had a complete metabolic response (CMR; Table). Notably, response rates were similar for double-hit/triple-hit pts (CMR rate, 82% [9/11]). The median durations of response, progression-free survival, and overall survival were not reached. Responses were durable; at 9 mo, an estimated 96% of pts with CMR remained in CMR. Updated data will be presented. Conclusions: Subcutaneous epcoritamab + R-CHOP induces high CMR rates with a manageable safety profile in pts with 1L high-risk DLBCL, including double-hit/triple-hit pts. These results support the ongoing phase 3 study of epcoritamab + R-CHOP in 1L pts (NCT05578976). Clinical trial information: NCT04663347 . [Table: see text]

508 - CAR-T Cell Therapy in First Line for High Risk Diffuse Large B-Cell Lymphoma: Review of Efficacy Against Standard of Care Chemo-Immunotherapy

508 - CAR-T Cell Therapy in First Line for High Risk Diffuse Large B-Cell Lymphoma: Review of Efficacy Against Standard of Care Chemo-Immunotherapy

Clinical Efficacy of Rituximab Combined with CHOP Regimen Sequential or Non-Sequential Local Radiotherapy in Diffuse Large B-Cell Lymphoma

To probe the clinical efficacy of rituximab combined with cyclophosphamide, adriamycin, vincristine together with prednisone regimen sequential or non-sequential local radiotherapy in patients with stage III-IV diffuse large B-cell lymphoma. The clinical data of 126 patients with high-risk diffuse large B-cell lymphoma in the First Affiliated Hospital of Hainan Medical University from January 2018 to December 2021 were retrospectively analyzed. Among them, the patients in the cyclophosphamide, adriamycin, vincristine together with prednisone group were adopted cyclophosphamide, adriamycin, vincristine together with prednisone regimen, the patients in the radiotherapy group were adopted radiotherapy in addition to cyclophosphamide, adriamycin, vincristine together with prednisone regimen and the patients in the combined group were treated with rituximab in addition to the radiotherapy group. The short-term and long-term efficacy, adverse reactions and immunoglobulin levels were compared in these three groups. In comparison with cyclophosphamide, adriamycin, vincristine together with prednisone group, the total effective rate of combined group and radiotherapy group was elevated and the whole effective rate of combined group was increased relative to radiotherapy group. Spearman correlation analysis unveiled that the clinical efficacy of the radiotherapy group together with the combined group was negatively correlated with the serum immunoglobulin M level after 4 courses and 6 courses of treatment. Rituximab combined with radiotherapy is effective in diffuse large B-cell lymphoma therapy, which can significantly promote the short-term efficacy of patients with high safety.

Phase I study of novel SYK inhibitor TAK-659 (mivavotinib) in combination with R-CHOP for front-line treatment of high-risk diffuse large B-cell lymphoma.

Background: TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We report results of a phase I single-institution escalation study of front-line treatment with R-CHOP and TAK-659 in treatment-naïve high-risk DLBCL. Methods: Patients with high-risk DLBCL were treated with R-CHOP for 1 cycle, followed by combined R-CHOP and TAK-659 for an additional five cycles, with TAK-659 dosing escalated from 60mg, to 80mg, to 100mg daily, based on a 3 + 3 design. The primary objective was to determine the safety and establish the maximum tolerated dose (MTD) of TAK-659 in this setting. Results: Twelve patients were enrolled. Dose level 3 (100mg) was established as the MTD. Dose level 1 (60mg) maintained a similar area under the curve (AUC) to the MTD. With a median follow-up of 21 months, 92% of patients achieved complete response (CR). The most common treatment-emergent adverse events were lymphopenia (100%), infection (50%, n=3 opportunistic), aspartate aminotransferase elevation (100%), and alanine aminotransferase elevation (83%). Conclusion: A TAK-659 dose of 60mg was well tolerated, did not require dose modifications, and maintained a similar AUC to the MTD. The combination of R-CHOP and TAK-659 in patients with newly diagnosed high-risk DLBCL produces promising CR rates.

CAR-T Cell Therapy in First Line for High Risk Diffuse Large B-Cell Lymphoma: Review of Efficacy and Cost-Effectiveness Against Standard of Care Chemo-Immunotherapy

CAR-T Cell Therapy in First Line for High Risk Diffuse Large B-Cell Lymphoma: Review of Efficacy and Cost-Effectiveness Against Standard of Care Chemo-Immunotherapy

ABCL-452 First-Line Treatment With Subcutaneous Epcoritamab + R-CHOP in Patients With High-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Phase 1/2 Data Update

Patients with newly diagnosed high-risk DLBCL have suboptimal outcomes. Subcutaneous epcoritamab is a CD3xCD20 bispecific antibody well suited for combination with standard of care therapies. Evaluate safety and efficacy of epcoritamab + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in previously untreated patients with high-risk DLBCL in arm 1 of a phase 1/2, open-label trial (EPCORE NHL-2; NCT04663347). Adults with previously untreated CD20+ DLBCL and IPI ≥3 were included. As of December 1, 2021, 33 patients (median age, 66 y) had enrolled. Patients received subcutaneous epcoritamab (QW, cycles 1-4; Q3W, cycles 5-6) + R-CHOP for 6 cycles (21 d) followed by epcoritamab monotherapy Q4W up to 1 y (in cycles of 28 d). Step-up dosing and corticosteroid prophylaxis were required. All 33 patients treated (epcoritamab 24 mg, n=4; 48 mg, n=29) had IPI ≥3, and ≥24% had double/triple-hit DLBCL. Median follow-up was 3 mo (range, 0-9.7), median number of total cycles initiated was 5 (1-13), and 94% of patients (31/33) remained on treatment. Treatment-emergent AEs (TEAEs) in ≥35% of patients were neutropenia (48%; febrile neutropenia in 9% of all patients), CRS (45%), infections (42%), anemia (39%), and injection-site reactions (36%). No TEAEs led to epcoritamab discontinuation. Most CRS events were low grade (42% grade [G] 1-2, 3% G3), occurred in cycle 1, and resolved after a median of 2 d (1-11); 4 patients received tocilizumab. G2 ICANS occurred in 1 patient. No fatal TEAEs occurred. In efficacy-evaluable patients, the overall response rate (ORR) was 96% (24/25); 68% (17/25) had complete metabolic response (CMR) by PET-CT. In the 10 patients who completed 6 cycles of R-CHOP by the cutoff date, ORR and CMR rate were 100% and 90%, respectively; all patients remained in response at data cutoff (longest duration of response, 7.1+ mo, ongoing). Epcoritamab + R-CHOP had manageable safety, mostly low-grade CRS that did not lead to treatment discontinuation, and high response rates in patients with previously untreated DLBCL. Updated data will be presented. This study was funded by Genmab A/S and AbbVie.

FrontMIND: A phase III, randomized, double-blind study of tafasitamab + lenalidomide + R-CHOP versus R-CHOP alone for newly diagnosed high-intermediate and high-risk diffuse large B-cell lymphoma.

TPS7590 Background: Up to 40% of patients relapse or are refractory (R/R) to R-CHOP, the current standard of care for diffuse large B-cell lymphoma (DLBCL), indicating an unmet need, particularly in patients with high-intermediate and high-risk disease (IPI 3–5). POLARIX (NCT03274492) evaluated a modified regimen substituting polatuzumab vedotin for vincristine (pola-R-CHP), demonstrating modest improvement in PFS with no OS benefit between treatment arms. The addition of lenalidomide (LEN) to R-CHOP improved both PFS and OS in the ECOG-ACRIN E1412 trial but not in the Phase III ROBUST study, in which a lower dose of LEN was used, despite a positive trend toward 2-year PFS in a subgroup analysis. The chemo-free immunotherapy tafasitamab + LEN has received accelerated approval in the United States (2020), and conditional marketing authorization in Europe and Canada (2021) in adult patients with R/R DLBCL ineligible for ASCT based on L-MIND (NCT02399085). The primary analysis of First-MIND (NCT04134936), a Phase Ib randomized safety study of R-CHOP + tafasitamab ± LEN in patients with previously untreated and newly diagnosed DLBCL, demonstrated that adding tafasitamab + LEN does not impair dosing and scheduling of R-CHOP, with toxicities similar to those expected with R-CHOP alone (ASH 2021; #3556). frontMIND (NCT04824092) will investigate the efficacy and safety of R-CHOP + tafasitamab + LEN vs R-CHOP alone in previously untreated patients with high-intermediate and high-risk DLBCL. Methods: frontMIND is a Phase III, multicenter, randomized, double-blind, placebo-controlled study. Approximately 880 patients are planned to be randomized at ̃350 centers in North and South America, Europe, and Asia-Pacific. Eligible patients aged 18‒80 years with previously untreated local biopsy-proven, CD20+ DLBCL with IPI score 3–5 (age-adjusted IPI 2–3 if ≤60 years), and ECOG PS 0–2 will be enrolled. Patients with transformed lymphoma (except double or triple hit lymphoma) are excluded. Patients will be randomized 1:1 to receive six 21-day (D) cycles of either R-CHOP + tafasitamab (12 mg/kg intravenously, D 1, 8, and 15) + LEN (25 mg orally, D1–10) or R-CHOP + tafasitamab and LEN placebos. Patients will be followed for up to 5 years after the end of treatment. The primary endpoint is investigator-assessed PFS. Secondary endpoints include investigator-assessed event-free survival, OS, safety, and tafasitamab serum concentration (trough and Cmax levels). Sensitivity and specificity of minimal residual disease for early detection of disease progression is an exploratory endpoint; further MRD parameters may also be investigated. The study is funded by MorphoSys AG and conducted with the scientific support of members of the Fondazione Italiana Linfomi and the German Lymphoma Alliance. Clinical trial information: NCT04824092.

First-line treatment (Tx) with subcutaneous (SC) epcoritamab (epco) + R-CHOP in patients (pts) with high-risk diffuse large B-cell lymphoma (DLBCL): Phase 1/2 data update.

7523 Background: Outcomes of pts with newly diagnosed DLBCL with high/poor risk according to the revised International Prognostic Index (IPI) treated with immunochemotherapy (IC) remain suboptimal, with a 4-year survival rate of 55% (Sehn et al, Blood 2007). SC epco is a well-tolerated bispecific antibody with single-agent activity in the relapsed/refractory (R/R) aggressive B-cell NHL setting. The mechanism of action and safety profile of epco are distinct from IC, and epco is well suited for use in combinations and in earlier lines of therapy. Addition of a novel agent to standard of care IC may overcome the adverse prognosis of high-risk pts. Presented here are updated results of epco + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in previously untreated DLBCL pts with IPI 3–5 (EPCORE NHL-2 arm 1; NCT04663347). Methods: Adults with previously untreated CD20+ DLBCL and IPI ≥3 received SC epco (every week, cycle [C] 1–4; every 3 weeks, C5–6) + R-CHOP for 6 cycles (21 d) followed by single-agent epco every 4 weeks up to 1 y (in cycles of 28 d). To mitigate CRS, epco step-up dosing and corticosteroid prophylaxis were required. Response was assessed by PET-CT with contrast per Lugano 2014 criteria. Results: As of Dec 1, 2021, 33 pts (median age, 66 y; range, 19–82) received epco + R-CHOP (epco 24 mg, n = 4; 48 mg, n = 29). Median time from diagnosis to first dose was 25 d (range, 5–70). All pts had IPI ≥3 and ≥24% had double- or triple-hit DLBCL. Median follow-up was 3 mo (range, 0–9.7); median number of total cycles initiated was 5 (1–13). Overall, 94% of pts (31/33) remained on Tx. Tx-emergent adverse events (TEAEs) in ≥30% of pts were neutropenia (48%; febrile neutropenia in 9% of all pts), CRS (45%), infections (42%), anemia (39%), injection-site reactions (36%), nausea (33%), constipation (30%), and pyrexia (30%). No TEAEs led to epco discontinuation. AEs of special interest included CRS (42% grade [G] 1/2, 3% G3) and ICANS (3% G2); 1 pt had tumor lysis syndrome (3% G3). Most CRS events occurred in C1 and resolved after a median of 2 days (1–11); 4 pts with CRS received tocilizumab. No fatal TEAEs were reported. In efficacy-evaluable pts, the overall response rate (ORR) was 96% (24/25); 68% (17/25) had complete metabolic response (CMR). For the 10 pts who received 6 cycles of R-CHOP and had a subsequent response assessment, the ORR and CMR rate were 100% and 90%, respectively. As of the data cutoff, all of these 10 pts remained in response, with the longest duration of response 7.1+ mo and ongoing. Updated data will be presented. Conclusions: Epco is the first SC bispecific antibody assessed in combination with standard of care in previously untreated DLBCL. The safety profile of epco + R-CHOP is manageable. CRS events were mostly of low grade and did not lead to Tx discontinuation. ORR and CMR rate were high with no relapses as of the data cutoff date. Clinical trial information: NCT04663347.

Cost-effectiveness of CD19 chimeric antigen receptor T-cell (CAR-T) therapy versus autologous stem cell transplantation (ASCT) for high-risk diffuse large B-cell lymphoma (DLBCL) in first relapse.

7537 Background: The recently reported ZUMA-7 and TRANSFORM trials demonstrate superior event-free survival among patients with primary refractory or early relapsed DLBCL compared to salvage chemotherapy with ASCT. However, given a cost of &gt;$370,000, it is not known whether second-line CAR-T is cost-effective compared to ASCT. Thus, we developed a state-transition microsimulation model to simulate clinical outcomes and costs associated with therapy for DLBCL patients in first relapse, using ZUMA-7 and TRANSFORM data. Methods: The model begins at initiation of second-line therapy comparing salvage chemotherapy with ASCT or CAR-T therapy. We examined a three-year time horizon, including crossover to the alternative strategy therapy in the third line, as well as subsequent lines of therapy, using open-source Amua 0.3.0 software. Base case analysis was performed using 1000 first-order Monte Carlo simulations and probabilistic sensitivity analysis (PSA) was performed with 1000 simulations to test model uncertainty. Conditional probabilities of survival and disease progression were extracted from Kaplan-Meier curves from pivotal clinical trials using the WebPlotDigitizer tool. Costs were estimated from public sources in US Dollars ($) and effects were estimated in quality-adjusted life years (QALY) using published utility values. Results: Median overall survival was 15 months (95% confidence interval [CI] 13-19 months) with ASCT and 21 months (95% CI 17-29 months) with CAR-T. The PSA demonstrated costs and effectiveness per patient of $243,581 and 1.06 QALYs with ASCT and $470,150 and 1.22 QALYs with CAR-T with an incremental cost-effectiveness ratio (ICER) of $1,383,320/QALY. Incremental net monetary benefit of CAR-T versus ASCT, based on a willingness-to-pay (WTP) threshold of $200,000/QALY, was -$193,812. The break-even price for CAR-T and all subsequent therapies, based on a one-way sensitivity analysis, was $170,489. Conclusions: The model demonstrated improved survival and QALYs for the second-line CAR-T therapy, but was not cost-effective, as the ICER exceeded $1,000,000/QALY, which is higher than most accepted WTP thresholds. A limitation of these early data is that they only assess outcomes over three years. To estimate the full effect of these therapies, we will extrapolate the Kaplan-Meier curves for additional analyses. Clinical outcomes of second-line CAR-T are promising, but prices would need to be considerably lower to enable equitable access and affordability.[Table: see text]

Open-label, phase 2 study of blinatumomab after frontline R-chemotherapy in adults with newly diagnosed, high-risk DLBCL

This open-label, multicenter, single-arm, phase 2 study assessed the safety and efficacy of blinatumomab consolidation therapy in adult patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL; International Prognostic Index 3–5 and/or double-/triple-hit or double MYC/BCL-2 expressors) who achieved complete response (CR), partial response (PR), or stable disease (SD) following run-in with 6 cycles of R-chemotherapy (NCT03023878). Of the 47 patients enrolled, 28 received blinatumomab. Five patients (17.9%) experienced grade 4 treatment-emergent adverse events of interest (neutropenia, n = 4; infection, n = 1). Two deaths reported at the end of the study were unrelated to treatment with blinatumomab (disease progression, n = 1; infection, n = 1). 3/4 patients with PR and 4/4 patients with SD after R-chemotherapy achieved CR following blinatumomab. Consolidation with blinatumomab in patients with newly diagnosed, high-risk DLBCL who did not progress under R-chemotherapy was better tolerated than in previous studies where blinatumomab was used for treatment of patients with lymphoma.

PARK2 regulates eIF4B-driven lymphomagenesis.

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP); thus, treatment of this fatal disease remains an area of unmet medical need and requires identification of novel therapeutic approaches. Dysregulation of protein translation initiation has emerged as a common downstream node in several malignancies, including lymphoma. Ubiquitination, a prominent post-translational modification associated with substrate degradation, has recently been shown to be a key modulator of nascent peptide synthesis by limiting several translational initiation factors. While a few deubiquitinases have been identified, the E3-ligase responsible for the critical ubiquitination of these translational initiation factors is still unknown. In this study, using complementary cellular models along with clinical readouts, we establish that PARK2 ubiquitinates eIF4B and consequently regulates overall protein translational activity. The formation of this interaction depends on upstream signaling, which is negatively regulated at the protein level of PARK2. Through biochemical, mutational, and genetic studies, we identified PARK2 as a mTORC1 substrate. mTORC1 phosphorylates PARK2 at Ser127, which blocks its cellular ubiquitination activity, thereby hindering its tumor suppressor effect on eIF4B's stability. This resultant increase of eIF4B protein level helps drive enhanced overall protein translation. These data support a novel paradigm in which PARK2-generated eIF4B ubiquitination serves as an anti-oncogenic intracellular inhibitor of protein translation, attenuated by mTORC1 signaling. Implications: Our data implicates the FASN/mTOR-PARK2-eIF4B axis as a critical driver of enhanced oncogene expression contributing to lymphomagenesis.

Molecular features encoded in the ctDNA reveal heterogeneity and predict outcome in high-risk aggressive B-cell lymphoma

Inadequate molecular and clinical stratification of the patients with high-risk diffuse large B-cell lymphoma (DLBCL) is a clinical challenge hampering the establishment of personalized therapeutic options. We studied the translational significance of liquid biopsy in a uniformly treated trial cohort. Pretreatment circulating tumor DNA (ctDNA) revealed hidden clinical and biological heterogeneity, and high ctDNA burden determined increased risk of relapse and death independently of conventional risk factors. Genomic dissection of pretreatment ctDNA revealed translationally relevant phenotypic, molecular, and prognostic information that extended beyond diagnostic tissue biopsies. During therapy, chemorefractory lymphomas exhibited diverging ctDNA kinetics, whereas end-of-therapy negativity for minimal residual disease (MRD) characterized cured patients and resolved clinical enigmas, including false residual PET positivity. Furthermore, we discovered fragmentation disparities in the cell-free DNA that characterize lymphoma-derived ctDNA and, as a proof-of-concept for their clinical application, used machine learning to show that end-of-therapy fragmentation patterns predict outcome. Altogether, we have discovered novel molecular determinants in the liquid biopsy that can noninvasively guide treatment decisions.

Phase I Study of Novel SYK Inhibitor TAK-659 in Combination with R-CHOP for Front-Line Treatment of High Risk Diffuse Large B-Cell Lymphoma

Phase I Study of Novel SYK Inhibitor TAK-659 in Combination with R-CHOP for Front-Line Treatment of High Risk Diffuse Large B-Cell Lymphoma