Diffuse Large B-cell Lymphoma Pts Research Articles

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.

Circulating Tumor DNA Analysis Associates with Progression-Free Survival (PFS) with Odronextamab Monotherapy in Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL): Identification of Minimal Residual Disease Status and High-Risk Subgroups from the Phase 2 ELM-2 Study

Background Molecular characterization of B-cell non-Hodgkin lymphoma (B-NHL), through circulating tumor DNA (ctDNA) assessment of minimal residual disease (MRD) has been proposed as a tool to predict clinical outcome. Odronextamab, a CD20×CD3 bispecific antibody, demonstrated deep and durable responses and a generally manageable safety profile in patients (pts) with R/R FL or DLBCL in the Phase 2 ELM-2 study (NCT03888105; Kim TM et al. and Kim WS et al. ASH. 2022). In the overall populations, 12-month PFS rates were 64% and 29%, respectively. Using ctDNA from ELM-2, we show that these assessments associate with clinical outcomes following odronextamab treatment. Methods In ELM-2, pts received IV odronextamab in 21-day cycles, with step-up dosing in Cycle (C) 1, 80 mg (FL)/160 mg (DLBCL) QW in C2-4, then 160 mg (FL)/320 mg (DLBCL) Q2W until disease progression or unacceptable toxicity. Baseline (BL) ctDNA and tumor biopsies were used for molecular profiling. BL and on-treatment ctDNA were used for MRD determination in the biomarker population (BP; pts required ≥1 available plasma biomarker sample to be included in the BP). The first post-BL ctDNA sample was collected on C5 Day (D) 1, at the time of positron emission tomography-computed tomography (PET-CT). A modified AVENIO ctDNA analysis workflow (Roche; research only) was used for next-generation sequencing, based on the cancer personalized profiling by deep sequencing technique (Kurtz et al. J Clin Oncol. 2018). Whole blood cell pellets were used to filter out germline allele variants. MRD negativity was reported when the P value for variant allele frequency was >0.005. Results The BP comprised 53 FL pts and 63 DLBCL pts; at BL, all FL pts and all but one DLBCL pt were MRD(+). Pts remaining on study until C5D1 had similar PFS regardless of whether they were in the BP or overall population (FL, n=111; DLBCL, n=83). Pts who were MRD(-) at C5D1 had significantly longer PFS vs. those who remained MRD(+) (FL: HR 0.27 [95% CI 0.09-0.84], P=0.024 [Fig. 1a]; DLBCL: HR 0.29 [95% CI 0.12-0.71], P=0.007). In pts with FL achieving complete response (CR) by PET-CT at C5D1, a trend for prolonged PFS was observed in those who were MRD(-) (n=26) at this timepoint vs. those who were MRD(+) (n=17; HR 0.29 [95% CI 0.07-1.1], P=0.072). Pts with DLBCL who were MRD(-) at C5D1 (n=20) had similar PFS benefit regardless of PET-CT CR status (HR 0.56 [95% CI 0.10-3.11], P=0.511). Four DLBCL pts who were MRD(-) and did not achieve CR by PET-CT at C5D1 (partial response, n=3; stable disease, n=1) went on to achieve PET-CT CR at a later timepoint. Mutational analyses of BL ctDNA identified TP53 as the most frequent mutation (FL, n=34/53 [64%] mutation-evaluable pts; DLBCL, n=44/58 [76%]). In FL pts, TP53 mutations were associated with MRD(+) status at C5D1 (Fisher's exact test, P=0.002) and predicted significantly shorter PFS (HR 3.57 [95% CI 1.01-12.69]; P=0.049); this association was not observed in DLBCL. LymphGen classification (Wright et al. Cancer Cell. 2020) of BL ctDNA in pts with DLBCL identified mostly MCD and EZB subtypes (MCD, n=15; EZB, n=14; ST2, n=1; BN2, n=1; other, n=26). EZB-subtype pts treated with odronextamab had significantly longer PFS compared with MCD-subtype pts (HR 0.23 [95% CI 0.07-0.83]; P=0.025 [Fig. 1b]). Using BL ctDNA, cell of origin was determined in 43/58 pts with DLBCL; odronextamab treatment led to similar PFS in higher-risk non-germinal-center B-cell-like (non-GCB, n=18 [42%]) pts vs. GCB pts (n=25 [58%]; HR 1.62 [95% CI 0.72-3.62]; P=0.244). Further molecular assessment focused on gene fusions in DLBCL pts in the BP (39 with local laboratory gene fusion and ctDNA analyses, 24 with only ctDNA analyses). Odronextamab led to similar PFS in pts with double-hit (n=15) or triple-hit (n=5) fusions compared to those without (n=43; P=0.343 and P=0.140, respectively). Conclusions This study is among the first to analyze ctDNA in pts with R/R FL and DLBCL in a pivotal trial. This non-invasive method allows molecular characterization of pts with no available tissue, enabling identification of high-risk subgroups. CtDNA MRD status at C5D1 of odronextamab treatment was highly associated with PFS in pts with FL and DLBCL and in the future could form the basis of response-directed treatment paradigms. Molecular characterization in tumor biopsies, including CD20, will be presented. Ongoing monitoring of ctDNA may serve as an important early progression marker in R/R FL and DLBCL.

Autologous Stem Cell Transplantation before Lymphocyte Apheresis for CAR-T Cells Therapy Negatively Impacts on T-Cells Fitness and NK Cell Levels in DLBCL Patients

Background Chimeric antigen receptor T (CAR-T) cells are an effective therapy in Diffuse large B-cell Lymphoma (DLBCL). However, more than half of patients (pts) still relapse. CAR-T cells from T-lymphocytes (T-Ly) enriched for early lineage T-cells have shown higher replicative potential and better efficacy. Recent studies have also shown that NK cells may enhance CAR-T cells antitumor efficacy by enhancing immune/tumor cells cluster formation and improving CAR-T cells fitness. In the BioCART BS study, we assessed the T-cell subpopulations and NK cells at Ly-apheresis evaluating the impact of previous treatments. Methods Since April 2021, 27 DLBCL pts underwent Ly-apheresis at our Center. In Italy, until now, DLBCL pts are eligible to CAR-T cells therapy if relapsed/refractory after at least two lines of treatments. Since cryopreservation of the apheresed Ly is allowed for Tisa-cel, DLBCL pts with poor prognostic risk factor (primary refractory; PET positivity before Autologous Stem Cell Transplantation [ASCT]; relapse within 12 months) were enrolled in a “pre-emptive” Ly-apheresis program, scheduling leukapheresis as soon as possible. Combinations of monoclonal antibodies were used by Flow Cytometry to evaluate the CD4/CD8 ratios and T-cell subset percentages and counts. In particular of CD45RA+CCR7+ Naïve (N), CD45RA-CCR7+ Central Memory (CM), CD45RA-CCR7- Effector Memory (EM), and CD45RA+CCR7- Terminally Differentiated (TD) cells. NK cells were defined as CD3-CD56+/CD3-CD16+ cells. CAR-T cells expansion was evaluated using specific CD19 CAR reagent. All stained samples were acquired on a Canto II (BD Bioscience) flow cytometer and analyzed using DIVA software version 9.0. The CAR-T cells therapy response was evaluated at 30 days post infusion by CT or PET scan. Results 12 out of the 27 (44.4%) DLBCL pts underwent pre-emptive Ly-apheresis: 3 pts were primary refractory, 7 had PET+ before ASCT, while 2 relapsed within 1 year from the end of treatment program. Conversely, 15 pts were enrolled in the standard program, after at least two lines of treatment. The latter have been divided into 2 groups: pts who had received ASCT (n=9) and those who did not (n=6). At baseline, no clinical differences have been observed between the three groups. The median age was 61 years (29-73), while most pts had IPI >2 (68%) and Ann Arbor score>2 (82%). Comparing T-cell subpopulations at Ly-apheresis, pts who previously underwent ASCT presented a more “exhausted” T-Ly profile (Figure 1). Indeed, they displayed lower CD4/CD8 ratios compared with both the pre-emptive (p 0.03) and standard group without a history of ASCT (p 0.003). In addition, ASCT results in lower CD4+ Naïve T cells, both as percentage of parental cells and as absolute count, compared to the other two groups (p 0.003 and 0.005 for the pre-emptive group, p 0.005 for the group without previous ASCT). Conversely, pts who underwent ASCT had higher percentages and absolute counts of CD4+ EM T-Ly than pts in the pre-emptive group (p 0.003 and 0.05, respectively). They had also lower CD8+ Naïve T cells compared with those pts in the standard group who did not receive ASCT, while they displayed a trend towards increased absolute counts of highly differentiated CD8+ cells. Considering the NK-cells, pts who underwent ASCT had lower percentages of NK cells compared with pts of the pre-emptive group, as well as the standard group not receiving ASCT (p 0.01 and 0.002, respectively). This may reduce the CAR-T cells antitumor efficacy and CAR-T cell fitness. Of note, the T-Ly fitness impacts both on CAR-T cells expansion and efficacy. Indeed, pts who previously underwent ASCT less frequently had an adequate CAR-T cells expansion (“expander” pts: 25% vs. 75%) and a lower peak of CAR+ cells (4.5% vs. 21.9% CAR+ cells). In addition, pts who previously underwent ASCT displayed a lower, although not significant, complete remission rate at 30-days response compared with those pts who did not received it (20% vs. 44.4%). Notably, 5 out of 12 (42%) pts in the pre-emptive group had already activated a CAR-T cell program, showing its feasibility. Conclusion ASCT before Ly-apheresis results in more “exhausted” T-Ly profile and lower NK cells proportion at the time of leukapheresis. Timely pre-ASCT Ly-apheresis, as well as the use of CAR-T in second line would help to collect more “fit” Ly enriched with NK cells, and this may result in higher CAR-T cells expansion and efficacy.

Risk of Central Nervous System Vs. Systemic Relapse in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP: What Should We Focus on?

Background: Clinical outcome of patients (pts) with diffuse large B-cell lymphoma (DLBCL) has improved during the last two decades. However, a significant proportion of DLBCL pts is still at risk of lymphoma relapse (REL)/progression or death due to progression. DLBCL pts with adverse clinical features, i.e., those with high IPI or CNS IPI scores are at the highest risk of lymphoma REL, systemic (S) or central nervous system (CNS) REL. CNS prophylaxis is questionable based on retrospective analyses. Moreover, the risk of S-REL should be discussed in those pts as well. However, the comparison of the risks of CNS vs S-REL within the different CNS IPI risk groups has not been shown. Methods: Using the prospective observational NiHiL project (NCT03199066), we identified pts ≥ 18 years of age with histologically confirmed DLBCL or high-grade B-cell lymphoma (diagnosed 2011-2021), who received R-CHOP as frontline treatment in 2 centres in Czech Republic. Pts with CNS involvement at diagnosis were excluded. Cumulative incidence of CNS (± S) REL was calculated using Kaplan-Meier statistics treating S-REL and death as competing events. Results: A total of 1242 pts were included; according to CNS IPI score (available in 1225 out of 1242 pts), 344 (28.1%), 539 (44.0%) and 342 (27.9%) pts were categorized as being at low (0-1, LR), intermediate (2-3, IR), and high risk (4-6, HiR) resp. Overall, 308 (24.8%) pts received CNS prophylaxis with either high-dose(HD) Methotrexate (MTX), HD-AraC, intrathecal chemotherapy or combination. By CNS IPI, 150 (43.9%) out of 342 pts with HiR CNS IPI received CNS prophylaxis. CNS prophylaxis was given less frequently in the IR (n 111[20.6%] out of 539 pts) or LR (n 45 [13.1%] out of 344 pts) CNS IPI groups. At a median follow up of 5.3 years (range; 0.1 - 13.3), 307 (24.7%) out of 1242 pts developed lymphoma REL, out of which 45 occurred in CNS (35 isolated CNS REL, 10 simultaneous CNS+S-REL) and 262 lymphoma RELs occurred systemically. CNS prophylaxis had no impact on the incidence of CNS REL in pts with HiR CNS IPI. Median time to CNS (± S) and S-REL was 11.5 months (range; 2.7-116.8) and 11.8 months (range; 0.8 - 144.3), resp. Occurrence of RELs within the first 6, 12 and 24 months after lymphoma diagnosis was as follows: 20%, 53.3% and 80% for CNS (± S) RELs and 21%, 50.4% and 67.2% for S-RELs. In the entire cohort, the 7-year cumulative incidence of CNS (± S) and S-REL were 4.4% and 23.7%, resp. Across all CNS IPI risk groups, there was significantly higher risk of S-REL as compared to CNS (± S) REL. The 7-year cumulative incidence of S-REL vs CNS (± S) REL and the respective HRs were 10.5% vs 1.9%, HR 6.2 (95% CI 3.4-11.2) in the LR-, 25.2% vs 2%, HR 11.7 (95% CI 8.3-16.6) in the IR-, and 35.8% vs. 12.4 %, HR 3.6 (95% CI 2.5-4.9) in the HiR CNS IPI ( Fig1), resp. At the time of analysis, 417 (33.6%) out of 1242 pts were dead. CNS (± S) REL was associated with shorter post-REL overall survival (OS) as compared to S-REL (HR 1.8, p=0.001, median OS 0.38 vs 1.04 years, resp). In the entire cohort, the 7-year cumulative incidence of death due to lymphoma was 19.3% (16.7% and 3.1% due to S-REL and CNS (± S) REL, resp). The 7-year cumulative incidence of death due to R-CHOP-related toxicity, unrelated to lymphoma and unknown causes were 2.5%, 4.2% and 9.8%, resp. In HiR CNS IPI, the 7-year cumulative incidence of death due to lymphoma was 34.9% (28.3% and 9.2% due to S-REL and CNS (± S) REL, resp), while the 7-year cumulative incidence of death due to R-CHOP-related toxicity, unrelated to lymphoma and unknown causes were 5.1%, 5.1% and 14.9%, resp ( Fig2). Conclusion: DLBCL pts are at significantly higher risk of S-REL as compared to CNS (± S) REL overall and across all CNS IPI risk groups. In addition, death due to S-REL is the leading cause of death overall and across all CNS IPI risk groups. However, CNS (± S) REL represents remarkable portion of all lymphoma RELs occurring in the HiR CNS IPI group and non-negligible cause of death in DLBCL. Our results support the conclusion that R-CHOP + HD MTX is not sufficient to reduce the risk of S-REL as well as CNS REL especially in pts with HiR CNS IPI. New 1 st line treatment options able to reduce simultaneously the risk of S-REL as well as CNS REL are needed to improve the outcome of DLBCL pts especially in the subgroup with HiR CNS IPI. Grant support: AZV NU23-03-00127, NU21-03-00411, Charles University Hematology-Oncology Cooperatio Program

Do the Control Cohorts of Phase III Randomized Trials Reflect the Real-World Results of DLBCL Patients?

Do the Control Cohorts of Phase III Randomized Trials Reflect the Real-World Results of DLBCL Patients?

Final Results of a Phase I/II Trial of Carfilzomib + R-CHOP for Frontline Treatment of Patients with Non-Germinal Center Diffuse Large B-Cell Lymphoma (DLBCL)

INTRODUCTION: Recent data from the REMoDL-B trial show that addition of the proteasome inhibitor bortezomib to R-CHOP improves progression free survival (PFS) of patients (Pts) with activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) compared to R-CHOP, but peripheral neuropathy limited dose intensity. Relative to bortezomib, carfilzomib (K) displays comparable clinical activity in plasma cell neoplasms but does not cause neurotoxicity. K has preferential clinical activity in relapsed non-germinal center (non-GC) DLBCL treated with chemotherapy (Torka, et al. Blood Adv. 2023). To explore the safety and efficacy of K in combination with R-CHOP (KR-CHOP), we performed a phase I trial to identify the recommended phase 2 dose (RP2D) in all DLBCL Pts followed by a phase II extension exclusively in non-GC DLBCL. METHODS: Between 2015-2020, Pts with untreated de novo or transformed DLBCL, adequate organ function and ECOG PS ≤ 3 were enrolled at 3 US academic medical centers. As previously reported [Hill, et al, Blood (2018), 132 (Supl.1):1692], during phase I dose escalation, the RP2D of K was 20 mg/m 2 on days (D) 1 & 2 of cycle 1 and 56 mg/m 2 on D1 & 2 of cycles 2-6. Rituximab was given on D2 and CHOP was given on D3. All Pts received pegfilgrastim and zoster prophylaxis. To assess the cardiac safety of combining K with anthracycline, we compared echocardiogram data at baseline and conclusion of therapy from study Pts and control NHL Pts treated with CHOP. To gauge for differential clinical activity of KR-CHOP vs R-CHOP, we compared PFS and overall survival (OS) rates for study Pts with non-GC DLBCL vs. Pts with non-GC DLBCL receiving standard of-care (SOC) R-CHOP at the Cleveland Clinic during the same period. The outcomes were also compared between propensity score (PS)-matched pairs, to account for differences in baseline demographics and clinical risk. RESULTS: 48 Pts were enrolled, and 47 treated; 18 in dose levels < RP2D and 29 at RP2D.Baseline demographics and treatment outcomes are shown in the Table. All-grade (G) hematologic adverse events (AEs) were: anemia, 35% (22% ≤ G2, 13% G3); thrombocytopenia, 24% (15% ≤ G2, 2% G3, 7% G4); febrile neutropenia, 9% (all G3/G4). Non-hematologic AEs included: nausea, 49% (47% ≤ G2, 2% G3); vomiting, 23% (21% ≤ G2, 2% G3), peripheral sensory neuropathy, 27% (all ≤ G2); dyspnea, 24% (all ≤G2). There was one case of G3 congestive heart failure. Echocardiograms from 42 study Pts who completed 6 cycles of KR-CHOP showed no statistically significant difference in change in ejection fraction from baseline compared to 39 control Pts [95% vs. 94%, respectively (P = 0.59)]. The overall response rate was 89% (70% CR, 19% PR). At a median follow-up of 31 months, 3-year Kaplan-Meier estimates of PFS and OS for the study population were 79% and 87%, respectively. There were 8 deaths in the study: 4 due to lymphoma; 2 due to infection; 2 due to other causes. Comparing outcomes of the 36 study Pts with non-GC DLBCL to 172 control Pts receiving R-CHOP as SOC, more control Pts had stage IV disease (54% vs 34%, p=0.03) and older age (median 67 vs 66 years old, p=0.03), but less frequently >1 extranodal site of disease (23% vs. 42%, P = 0.02). PS matching using logistic regression identified 25 case-control pairs of Pts with non-GC DLBCL according to gender, age, and other International Prognostic Index (IPI) elements (see Table). In analysis of PS-matched pairs of Pts with non-GC DLBCL, Pts treated with KR-CHOP had better 3-year PFS and OS relative to Pts treated with R-CHOP as SOC [96% vs. 50% (p=0.002) (see Figure) and 67% vs. 96% (p = 0.02), respectively]. In Cox univariate analysis, treatment with R-CHOP vs. KR-CHOP was associated with an increased risk of PFS and OS with hazard ratios (HR) of 6.15 [95% confidence interval (CI) 1.71 - 22.05, P = 0.002] and 3.19 [(95% CI, 1.01 -10.11), P = 0.02], respectively. CONCLUSION: KR-CHOP can be delivered safely, without excess cardiac toxicity or peripheral neuropathy. The superior PFS and OS rates for Pts with non-GC DLBCL vs. controls receiving R-CHOP are encouraging but should be interpreted with caution due to inherent selection bias in clinical trial populations. These data suggest that, like bortezomib, carfilzomib (K) may have preferential clinical activity in ABC DLBCL. Future randomized trials are justified using advanced molecular profiling to further investigate which Pts with DLBCL may benefit from addition of a proteasome inhibitor as part of frontline treatment.

Disease Control Affects Outcomes of Patients with Relapsed Diffuse Large B Cell Lymphoma Treated with CD19 Directed CAR T-Cell Therapy

Introduction: CAR T-cell therapy against CD19 (CART-19) has become the standard of care for pts with primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL) in the second and third line settings. The use of CART-19 therapy improves clinical outcomes compared to standard chemotherapy-based salvage regimens. However, DLBCL pts with disease progression following CART-19 therapy have poor overall survival (OS). Identifying biomarkers associated with improved outcomes can inform the optimal timing for CART-19 implementation. We report the impact of disease control at the time of CART-19 therapy on clinical outcomes. Methods: We conducted a retrospective study of relapsed/refractory (r/r) DLBCL treated at our institution with commercial CART-19 products between 4/2018 and 2/2023. Clinical, pathologic, and pharmacologic (type of bridging, lymphodepletion) characteristics were collected. PET/CT imaging prior to CART-19 therapy was used to determine pretreatment disease status (CR, PR or chemo-resistant disease). Treatment outcomes included best response to CART-19 therapy, frequency and severity of adverse events (CRS or ICANS), PFS and OS. Associations with clinical outcomes were evaluated using logistic regression models by Firth's method. Odds ratios [OR] and 95% CI were obtained. OS and PFS were summarized via Kaplan-Meier method; estimates of median 6- and 12-m rates were obtained with 95% CI. Associations with OS and PFS were evaluated using Cox regression models. Analyses were conducted in SAS v9.4; significance level 0.05. Results: 94 pts were included in this study. Median age was 64 yrs [range 22-81]; 66% were male; 90% Caucasian. Comorbidity index [assessed by HCT-CI] was 2+ in 51.7% pts. Median time from CART-19 discussion to re-infusion was 3.1 m [range 0.2-80 m]. Based on PET/CT scan assessment prior to CART-19 therapy, 9.6% pts achieved CR to bridging, 19% had PR, 64% were resistant (SD or PD). High risk IPI score was present in 23.4%. 14.9% pts had prior ASCT. FluCy lymphodepletion was given in 83% pts. Best response to CART-19 therapy: CR 45.7%, PR 12.8%. PD and SD observed in 28.7% and 3.2% of pts respectively. At median follow up of 36.5 m, median PFS was 6.7 m [95% CI 3.8-18.4]; median OS was 16.0 m [95% CI 9.8-30.6]. Any grade CRS occurred in 61.7%; Grade 3+ CRS 8.5%. Any grade ICANS occurred in 45.7%; Grade 3+ ICANS 16%. Second cancers occurred in 9.6%; 4 pts developed MDS. Adequate disease control at the time of CART-19 therapy was associated with improved ORR (P=0.028). Lack of disease control determined by PET/CT at the time of CART-19 infusion correlated unfavorably with OS and PFS. Pts with chemoresistant disease at the time of CART-19 therapy had a median survival of 7.2 m [HR 2.07 (0.74-5.79)] compared to pts in CR or PR at the time of CART-19 (median survival 27.9 m and 26.8 m respectively, p=0.023). Any grade ICANS [HR 2.46 (1.43-4.23) p=0.001], and ICANS grade 3+ [HR 3.38 (1.82-6.26) p=<0.001] were associated with an increased risk of death. On analysis of associations with PFS, lack of response to CART-19 therapy [SD/NR HR 15.05 (3.92-57.74) p=<0.001], any grade ICANS [HR 1.74 (1.06-2.87) p=0.029], and ICANS grade 3+ [HR 2.52 (1.38-4.59) p=0.003] were associated with increased risk for progression. Grade 3+ ICANS was adversely correlated with PFS in CR pts [HR 3.81 (1.22-11.90) p=0.021] and CR + PR pts. Several factors were associated with increased risk for toxicities. Lack of disease control at the time of CART-19 therapy, [OR 3.30 (0.79-13.79) p=0.003], development of ICANS, any grade [OR 4.08 (1.64-10.14) P=0.003] or grade 3+ ICANS [OR 7.71 (1.28-46.27) p=0.025] correlated with the development of any grade CRS. ICANS of any grade [OR 6.92 (1.12-42.79) p=0.037] and ICANS grade 3+ [OR 6.57 (1.50-28.77) p=0.013] correlated with Grade 3+ CRS. Lack of disease control status [OR 4.18 (0.85-20.55) p=0.011], any grade CRS [OR 4.08 (1.64-10.15) p=0.003], and grade 3+ CRS [OR 6.92 (1.03-46.64) p=0.047] were associated with an increased incidence and severity of ICANS. Conclusions: Disease control assessed by functional imaging at the time of CART-19 therapy for r/r DLBCL may be an independent predictor of CART-19 therapy outcomes. In this cohort, adequate disease control prior to CART-19 therapy was associated with improved ORR, PFS and OS. Optimizing disease control prior to cellular therapy may ultimately improve clinical outcomes while mitigating cellular therapy related toxicity.

Odronextamab Demonstrates Durable Complete Responses in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Progressing after CAR-T Therapy: Outcomes from the ELM-1 Study

Background Chimeric antigen receptor (CAR) T-cell therapies have recently been established as an important option for the management of relapsed/refractory (R/R) DLBCL. However, real-world studies suggest that approximately half of all patients (pts) receiving commercial CAR-T therapies will relapse within 6 months. These pts have a poor prognosis, with estimated overall survival (OS) of only 5 months, indicating a significant unmet need. Odronextamab is a novel, off-the-shelf, CD20×CD3 bispecific antibody that has demonstrated activity in both R/R follicular lymphoma and R/R DLBCL. We have previously reported encouraging results with odronextamab from the Phase 1 ELM-1 study (NCT02290951) in pts with R/R DLBCL post CAR-T therapy (Bannerji R, et al. Lancet Haematol. 2022). These results were consistent with the antitumor activity seen in pts with R/R DLBCL from the Phase 2 ELM-2 study (Kim WS, et al. ASH 2022). Here, we present an updated analysis of outcomes in a prespecified cohort of post CAR-T patients from ELM-1. Methods Intravenous odronextamab was administered weekly in 21-day cycles during Cycles (C) 1-4. Revisions to the step-up regimen were reported previously (Bannerji R, et al. Lancet Haematol. 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 160 mg on Days (D) 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg every 2 weeks until disease progression or unacceptable toxicity. Those pts who achieved a complete response (CR) that was durable for ≥9 months transitioned to dosing with 320 mg every 4 weeks. The primary endpoint was objective response rate (ORR), assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included duration of response (DoR), progression-free survival (PFS), and OS. Immune biomarker assessment was an exploratory endpoint. Results As of Dec 20, 2022, 46 pts were treated (safety-evaluable), with 44 pts evaluable for efficacy. For safety-evaluable pts, median age was 63 years (range 27-82), 67% male, 74% Ann Arbor stage III-IV, and 72% were refractory to CAR-T therapy administered in any prior line. 44 pts were evaluable for efficacy after 4.9 months median duration of follow-up. The ORR and CR rate by ICR were 48% (21/44) and 30% (13/44), respectively. Responses were durable, and both median DoR and median duration of CR were not reached. The probability of maintaining a response for 12 months was 62% and the probability of maintaining a CR for 9 months was 86%.A responder analysis of the subgroup of pts who achieved a CR will be presented. The CAR-T treated pts with DLBCL who were evaluable for biomarker analysis (n=10) had lower T-cell counts at baseline compared with CAR-T naive DLBCL pts (n=41 comparable pts who received odronextamab in ELM-2), yet the fold-change of T-cell expansion at C4D15 was greater in CAR-T treated pts versus CAR-T naive pts. T-cell dynamics, such as changes in activation, exhaustion, and memory subsets, will be presented. Safety was generally consistent with that previously reported. Six (13%) pts permanently discontinued odronextamab due to a treatment-emergent AE (device-related infection, pneumonia, dysphagia, gait disturbance, leukemia, and encephalopathy [n=1 each]). The most common treatment-emergent AE was CRS (any grade, 52%). The highest grade of CRS reported was Grade 2, and low-grade CRS events occurred in 46% of pts with the 0.7/4/20 mg step-up regimen. No cases of ICANS were reported in pts with the 0.7/4/20 mg regimen. Grade ≥3 infections occurred in 10 (22%) pts, with no Grade 5 events. No cases of tumor flare were reported. Conclusions Odronextamab monotherapy demonstrates encouraging antitumor activity in heavily pretreated pts who have progressed after CAR-T therapy, with a generally manageable safety profile. Durable CRs were achieved in this difficult-to-treat setting. These data support the potential role of odronextamab in the treatment paradigm for R/R DLBCL. Further studies to evaluate the optimal sequencing and combinations of odronextamab with CAR-T therapy are warranted.

EXPLORING DIFFERENTIAL MUTATIONAL DISTRIBUTION BY TARGETED SEQUENCING IN A R‐CHOP TREATED COHORT OF DIFFUSE LARGE B‐CELL LYMPHOMA PATIENTS

Background: Diffuse large B-cell lymphoma (DLBCL) harbors striking clinical and molecular heterogeneity, which continues to encumber risk stratification with a consequently high rate of refractory/relapsed patients (pts). Though the genomic landscape of DLBCL has been comprehensively uncovered, the search for eligible molecular biomarkers continues. Exploratively, we set out to retrospectively evaluate differential mutational distributions in a DLBCL cohort using targeted sequencing. Patients and method: A cohort of 105 de novo DLBCL pts, uniformly treated with first-line R-CHOP, were studied. Thirty pts relapsed, of which 70% had early relapses (<2 years after completing therapy), while 30% had late relapses (≥2 years). Targeted next-generation sequencing (90 gene panel) was applied on archival paraffin-embedded diagnostic samples and, if available, first relapse samples. Results: In total, 118 samples were sequenced, each displaying a median of 12 (range 1–46) putative somatic protein-coding mutations. Germinal center B-cell (GCB) DLBCL (n = 60) displayed a differential somatic signature with enrichment of EZH2, TNFRSF14, BCL2, ACTB, SOCS1, and FAS mutations (Fisher's Exact, p < 10-4), whereas mutations in CDKN2A, PRDM1, MYD88, and CD79B were significantly enriched in non-GCB pts (p < 10-4, n = 44). Survival analysis confirmed inferior overall survival (OS) in non-GCB DLBCL (5-year OS, log-rank (Mantel-Cox), p = 0.01, hazard ratio (HR) 1.7). Pts with double-hit biology (DHB), defined as either MYC and BCL2 and/or BCL6 fluorescent in situ hybridized positive and/or with MYC and BCL2 immunohistochemical double expression (n = 32), did not display a significant mutational signature or differential OS. However, a subgroup of DHB pts characterized by mutations in MYC, PRDM1, or IRF4 (n = 15) had markedly inferior OS (5-year OS, log-rank, p = 0.0003, HR 3.34) compared to negative non-DHB pts (n = 55) or negative non-DHB/DHB pts (p = 0.0017, HR 2.7, n = 72). Noticeably, ACTB mutations were only present in non-DHB pts. The mutational distribution at diagnosis did not differ between pts with relapse and in sustained remission. However, in the relapse group, GNA13 mutation at diagnosis was more frequent in early relapses than late relapses (43% vs. 0%, Fisher’s Exact without correction, p = 0.03). The presence of GNA13 in the entire cohort showed a trend towards inferior survival. Conclusion: Differential distribution with significant mutational signatures were expectedly found in GCB versus non-GCB, but not in subgroups with DHB or relapse. Interestingly, mutations in MYC, PRDM1 or IRF4 identified a distinct subset of DHB pts with inferior survival. Furthermore, GNA13 mutations were significantly enriched in early relapse pts. These preliminary findings call for validation of GNA13 as a potential marker of early relapse as well as the prognostic value of MYC, PRDM1 and IRF4 mutations in DHB DLBCL. The research was funded by: The Danish Cancer Society and The Vissing Foundation Keywords: aggressive B-cell non-Hodgkin lymphoma, genomics, epigenomics, and other -omics, tumor biology and heterogeneity Conflicts of interests pertinent to the abstract T. S. Larsen Consultant or advisory role Roche, Gilead, Novartis, Celgene/BMS Research funding: Genentech

Feasibility of CAR-T in very old patients with relapsed/refractory diffuse large B-cell lymphoma.

e19521 Background: Chimeric antigen receptor T-cell therapy (CAR-T) has shown great efficacy in older relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) patients (pts). Pivotal trials have shown similar progression free survival (PFS) and overall survival (OS) between older and younger pts, and no difference in the incidence of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), or grade 3-4 hematologic and non-hematologic toxicities. Nevertheless, there are limited reports in the literature concerning very old pts (≥75 years) receiving CAR-T for R/R DLBCL, and especially real world data in correlation with co-morbidities. Methods: We conducted a retrospective, single center analysis, including R/R DLBCL pts who underwent apheresis for CAR-T at 75 and older. We assessed co-morbidities by Cumulative Illness Rating Scale (CIRS-G) tool which set a score of 0-4 on all organ systems according to severity, and polypharmacy at time of apheresis, defined as ≥5 medications per day. We analyzed baseline characteristics, response rates, toxicity, and survival outcomes (PFS and OS). Results: A total of 47 pts were referred for CAR-T treatment. Median age at apheresis was 76.6 (75-86) years. Most of these pts received first-line treatment with full or attenuated dose R-CHOP (89%). However, 20 pts (42.5%) had refractory disease, and those achieving PR/CR had a median time to relapse of 13 months. Thirty-two pts (68%) were referred for CAR-T with refractory disease. Six pts died before receiving the CAR-T infusion due to PD. Characteristics of 41 pts receiving CAR-T infusion divided into subgroups of pts with CIRS-G categories 3-4 and pts with polypharmacy are shown in the table. Conclusions: CAR-T in very old (≥ 75 years) R/R DLBCL is feasible with no increased toxicity. While efficacy is important, the preliminary survival analysis seems suboptimal. At 1-year follow-up only a third of pts are alive. Severe co-morbidities or polypharmacy did not impact response or survival. Most deaths were due to disease progression, these outcomes might be attributed to the high rate of refractory disease. [Table: see text]

Serum Level Kinetic of Key Cytokines in Newly Diagnosed Lymphoma Patients during First Line Treatment: Correlation with PET/CT Scan Results and Treatment Outcome

Background: Cytokines are soluble proteins that play a key role in mediating and regulating inflammation and immune responses. Further, they are involved in lymphoid development and differentiation, as well as in lymphoid tumorigenesis. Aim of the present study was to verify if the serum-cytokine levels could be an early marker of treatment response. With this purpose, we analyzed the serum concentration kinetic of key cytokines in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin lymphoma (HL) pts comparing it with PET/CT scan results and treatment outcome. Patients and Methods: After Ethic Committee approval, we start to enroll lymphoma pts treated at Modena Cancer Center. Until now, 29 patients entered the study, including 12 pts with DLBCL, 11 with FL, and 6 with HL. DLBCL lymphoma were treated with R-CHOP and FL patients with R-CVP or R-Benda or R-CHOP, while HL patients with ABVD + ABVD or BEACOP following indications of intermediate PET. A panel of eight serum cytokines/chemokines (IL6, IL2, IL8, IL10, IFNγ, TNFα, CXCL10/IPI10, CCL17/TARC) was analyzed using the Simple Plex system (Protein Simple, San Jose, CA, USA) according to the manufacturer's recommendations. Serum samples were collected at the day of staging (PET-0), at the day of intermediate PET (I-PET) and at the day of end treatment PET (EOT-PET). Samples were analyzed in duplicate. Continuous variables were compared by Mann-Whitney test and categorical variables by Chi2 test. Matched data were analyzed by paired Wilcoxon or Friedman test. Statistical significance was defined as p < 0.05. Results: The median age of all 29 pts was 60 yr (range 21-86), and 65 % were male. Patients with HL were younger (50 yr) than pts with FL (61 yr) and DLBCL (68 yr). In all 29 pts, median concentration of IL10, IL6, TNFα at EOT-PET decreased in comparison with the levels at PET-0, while IFNγ and IPI10 increased. IL8 increased in DLBCL and in HL, while decreased in FL. IL2 levels did not show relevant changes. No statistically significant differences were found between the concentrations of these cytokines at PET-0 and EOT-PET. The mean serum TARC level at PET-0 were 854 pg/mL (range 130-5829), 1209 pg/mL (range 134-6903) and 8327 pg/mL (range 6488-10885) in DLBC, FL and HL pts, respectively. At EOT-PET the mean concentration of TARC were 562 pg/mL (range 130-854) (p=0.49), 989 pg/mL (range 134-6903) (p=0.74), 591 pg/mL (range 353-932) (p=0.03 ) in DLBCL, FL and HL pts, respectively. In HL patients, TARC values were significantly lower at I-PET with a mean of 525 pg/mL (range 210-1062) compared to PET-0 (p=0.016), with a p value along the 3 timepoint =0.009. EOT-PET and I-PET, evaluated by Deauville score shows that almost all patients achieved CR at the end of treatment: 11 out of 12 DLBCL pts have a Deauville score between 1 and 3, as well as all FL and HL pts. Only 1 DLBCL patient had a Deauville score of 4 at the end of treatment, achieving CR after further radiotherapy. Conclusion: Our study, despite the limitations due to the small number of pts enrolled to date, shows that the concentrations of cytokines/chemokines, with the exception of TARC, do not undergo significant changes, before and after first-line therapy. The TARC values, on the other hand, correlate well with the results of PET/CT and therefore also with the response to therapy in all subtypes of lymphoma. This correlation is statistically significant in pts with HL. TARC assessment could therefore become a useful, inexpensive and easy to determine predictive marker of response to therapy and may be important for determining treatment strategy in lymphoma patients. Further, the TARC levels assessed during the follow-up could be early markers of relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1 Study of Plamotamab, an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma: Recommended Dose Safety/Efficacy Update and Escalation Exposure-Response Analysis

Introduction: Plamotamab is a humanized bispecific antibody that binds both CD20 and CD3 and recruits cytotoxic T cells to kill CD20-expressing malignant cells. In the dose-escalation phase of an ongoing first-in-human (FIH) Ph 1 study (XmAb13676-01; NCT02924402), plamotamab was well tolerated with manageable cytokine release syndrome (CRS) and demonstrated evidence of clinical activity in heavily pretreated patients (pts) with relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL) (Patel; ASH 2021). Here, exposure-response (ER) analyses of the dose-escalation cohorts from the same study are reported. Safety and efficacy results from the follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) escalation (Part C) and expansion cohorts at the proposed recommended dosing regimen (RD) are also reported. Methods: The study is an FIH, multi-center, open-label Ph 1 dose-escalation study in R/R NHL pts. The dose-escalation phase has 3 Parts: Parts A and B using weight-based dosing; Part C using flat step-up doses (SUD). An IV RD was identified from Part C, which was used to expand into FL and DLBCL. Treatment was continued for ≥2 cycles if therapeutic benefit was evident. ER analysis was conducted based on exposure metrics calculated using population pharmacokinetic (popPK) model for plamotamab vs. observed responses related to efficacy/safety from Parts A, B, and C. Results: At data cut-off for RD safety/efficacy evaluation (25July2022), 36 pts were enrolled on or before 01April2022 (median age: 67 years, range: 36-86; 61% male). At baseline, 11.1% had stage III disease and 69.4% had stage IV disease. Median number of prior lines of therapy was 4 (range: 2-10), with 50% pts receiving CAR-T as a prior therapy (16 pts with DLBCL, 2 pts from other NHL subtypes, and no pts with FL). After last therapy, 91.7% of all pts had relapsed/progressed. In the RD safety population (n=36), CRS was the most common adverse event (AE; 72.2%). CRS was mostly confined to Cycle 1 and no Grade (Gr)≥3 CRS was reported. Treatment-emergent AEs (≥25%) included anemia (44.4%), pyrexia and nausea (38.9% each), asthenia (27.8%), and aspartate aminotransferase increase, diarrhea, and hypophosphatemia (25.0% each). Gr≥3 AEs (≥10%; 77.8% overall) were anemia (19.4%), neutropenia and neutrophil count decreased (16.7% each) and thrombocytopenia (11.1%). SAEs (≥5%; 55.6% overall) were CRS (25.0%), COVID-19 (8.3%), pneumonia and sepsis (5.6% each). AEs leading to plamotamab discontinuation occurred in 5 pts (13.9%). Overall, 25 pts were evaluable for efficacy at the RD. DLBCL pts at the RD (n=19) had an objective response (OR) rate of 47.4% (9/19 pts) and CMR/CR rate of 26.3% (5/19 pts); DLBCL pts with prior CAR-T had an OR rate of 46.2% (6/13 pts) and CMR/CR rate of 30.8% (4/13 pts). In FL pts at the RD (n=6), OR rate was 100% (6/6 pts) and CMR/CR rate was 50% (3/6 pts). The median time to initial response was 54 days for DLBCL and 56.5 days for FL. At data cut-off for ER analysis (10Nov2021) of Parts A, B and C only, exposure data were available from 55 pts who received at least 1 dose of plamotamab in the second cycle, were evaluable for CRS and for efficacy and safety at the target dose. For the first "priming” dose, plamotamab exposure correlated significantly with peak IL6 levels as well as incidence of Gr≥2 CRS events. At subsequent SUD, Postdose-Cmax / Predose-Ctrough ratio, indicative of the fold-change with each SUD, was the best predictor of any grade CRS events. At the target dose, no significant relationship exists between plamotamab exposure vs. all Gr≥3 AEs. A positive relationship exists for best OR, which is further improved by accounting for the impact of residual rituximab on plamotamab binding to CD20 using a competitive binding model. Conclusion: Plamotamab demonstrated evidence of clinical activity in heavily pretreated pts with DLBCL and FL with promising responses in pts with prior CAR-T therapy. CRS was generally manageable with premedication. Safety and efficacy evaluation of pts at the RD is currently ongoing, and updated results will be provided. Taken together, popPK/PD analysis of plamotamab exposure with IL6 levels, CRS incidence, high-grade AEs and OR rate provide guidance for RDs to be studied in future trials. A novel exposure metric was proposed to inform step-up dose increases that minimize the risk of CRS, while impact of rituximab on drug efficacy was captured as has been described in the literature. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Odronextamab in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): Results from a Prespecified Analysis of the Pivotal Phase II Study ELM-2

Background Odronextamab is a hinge-stabilized, human IgG4-based CD20×CD3 bispecific antibody (Ab) that binds CD20 on B cells and CD3 on T cells, triggering T-cell-mediated cytotoxicity of malignant B cells. In ELM-1 (Ph1, NCT02290951), odronextamab demonstrated encouraging activity in pts with DLBCL receiving ≥2 prior lines of therapy (LOT). DLBCL pts treated with odronextamab at doses ≥80 mg had an ORR of 53% and a CR rate of 53%. Responses were durable with 88% probability of an ongoing response at 12 mos (Bannerji R. et al. Lancet Haematol. 2022). The R2PD for R/R DLBCL was determined as 160 mg weekly. Here, we present for the first time, results from a prespecified analysis of the 160 mg DLBCL cohort from the pivotal ELM-2 study (Ph2, NCT03888105), which incorporated an optimized step-up regimen designed to maintain efficacy while minimizing acute toxicity including cytokine release syndrome (CRS). Methods ELM-2 is a global, multicenter study enrolling pts at 91 sites in 13 countries. Adult pts with DLBCL who had relapsed or were refractory to ≥2 prior LOT including an anti-CD20 Ab and an alkylator were enrolled. IV odronextamab was administered in 21-day cycles with steroid prophylaxis and weekly step-up dosing during Cycle (C) 1 to mitigate risk of acute toxicity. The initial step-up regimen was 1 mg split over C1 Day (D) 1 and C1D2, and 20 mg split over C1D8 and C1D9, followed by the 160 mg full dose on C1D15 (1/20 regimen). The 1/20 regimen was revised during the study to further mitigate CRS risk by adding an intermediary step-up dose. The modified regimen consisted of 0.7 mg split over C1D1 (0.2 mg) and C1D2 (0.5 mg), 4 mg split over C1D8 and C1D9, and 20 mg split over C1D15 and C1D16, followed by the 160 mg full dose on C2D1 (0.7/4/20 regimen). 160 mg weekly continued until the end of C4. After C4, maintenance treatment was 320 mg odronextamab every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by independent central review (ICR) according to Lugano 2014 criteria. CRS was assessed using 2019 ASTCT criteria. Results As of April 20, 2022, 121 pts with DLBCL were evaluable for safety; 90 for efficacy. Median age 67 y (range 24-88), 60% male, 80% Ann Arbor stage III-IV, 58% IPI score ≥3, median prior LOT 2 (range 2-8), and 56% were primary refractory. 65% were double refractory to anti-CD20 Ab and alkylator in any LOT. Median duration of study follow-up was 17.1 mos. ORR and CR rate by ICR were 53% (48/90) and 37% (33/90), respectively, and were consistent across high-risk subgroups and in the subgroup treated with the 0.7/4/20 step-up regimen. CRs were durable; median duration of CR was not reached (95% CI: 10.2 mos-not estimable) and the probability of an ongoing CR at 9 mos was 73%. TEAEs occurred in 117 (97%) pts, considered treatment related in 102 (84%). In the overall safety-evaluable population, the most common TEAEs (>30% all grades) were CRS (53%), pyrexia (41%), and anemia (34%). Following implementation of the 0.7/4/20 step-up regimen in C1, no Grade ≥3 CRS events were observed. Only Grades 1 and 2 CRS were observed in 35% and 13% of DLBCL pts, respectively. All CRS events resolved with supportive measures; 20% of pts received tocilizumab and none required vasopressors or mechanical ventilation for CRS management. ICANS was reported in only 2 pts (4%) following revisions to step-up dosing, and both were low grade; ICANS occurred in 6% of pts with the 1/20 regimen. Treatment-related Grade 5 AEs occurred in 2 pts (2%), and treatment-related AEs led to odronextamab discontinuation in 8 pts (7%). Conclusions In the first results from a pivotal Ph 2 trial, odronextamab demonstrated clinically meaningful efficacy, durable CRs, and manageable safety with only low grade ICANS reported with the 0.7/4/20 regimen. The results of this study confirm the preliminary odronextamab activity observed in ELM-1, and collectively show odronextamab efficacy both before and after CAR T therapy in hard-to-treat, highly aggressive R/R DLBCL, while at the same time demonstrating a manageable safety profile. The 0.7/4/20 odronextamab step-up dose regimen for C1 mitigates the risk of high-grade CRS, which has been observed consistently with other bispecifics and CAR T therapies and may present an important future option for the management of pts with R/R DLBCL. Updated safety and efficacy data will be presented.

Safety, Tolerability, Pharmacokinetics (PK) and Preliminary Antitumor Activity of the Cyclin-Dependent Kinase-9 (CDK9) Inhibitor AZD4573 in Relapsed/Refractory Hematological Malignancies: A Phase 1 First-in-Human Study

Introduction: CDK9, a serine/threonine kinase, regulates transcription elongation by phosphorylating RNA polymerase II at serine 2 (pSer2). Transient inhibition of CDK9 modulates expression of genes with short-lived transcripts and labile proteins, providing a potential therapeutic opportunity in tumors dependent upon oncogenes fitting these criteria. AZD4573 is a highly potent and selective CDK9 inhibitor that rapidly and preferentially decreases BCL2 family anti-apoptotic proteins MCL-1, BFL-1 as well as the oncogene MYC, inducing apoptosis in a broad range of human hematological malignant cell lines. AZD4573 monotherapy has shown antitumor effects associated with transient CDK9 inhibition in leukemia and lymphoma preclinical models. This multicenter, nonrandomized, open-label, phase 1 study (NCT03263637) was conducted to assess safety, tolerability, PK, pharmacodynamics (PD) and preliminary antitumor activity of AZD4573 in patients (pts) with relapsed or refractory hematological malignancies. Methods: The study comprised two parallel dose-escalation arms using a 3+3 design. Arm A included pts with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, or multiple myeloma. Arm B included pts with acute myeloid/lymphocytic leukemia, chronic myelomonocytic/lymphocytic leukemia, or hairy cell leukemia. Pts must have received at least 2 prior lines of therapy for the current histology. In each arm, pts received AZD4573 IV on an 8-week cycle using an intra-patient ramp up starting at 6 mg and increasing in 3 mg increments to a target dose of 18 mg (cohort 1) or 12 mg (cohort 2). The initial dosing regimen was 2 days on/12 days off but was changed to once weekly (QW) in cohort 1. Pts in Cohort 3 received AZD4573 9 mg QW on a 4-week cycle including intra-patient ramp up (3 mg, 6 mg, 9 mg). The primary objectives were to assess safety and to determine the biologically effective dose/maximum tolerated dose (MTD). Adverse events (AE) were assessed using CTCAE v4.03. Secondary/exploratory endpoints included PK, PD, and antitumor efficacy. Results: Overall, 44 pts were treated and evaluated for safety and efficacy: 22 each in Arms A and B. Median age was 69.0 years (range, 26.0 - 84.0), 65.9% were male, and median number of prior lines of therapy was 3 (range, 1-11). At data cutoff (Sept 30, 2021), all pts had discontinued treatment, mainly due to disease progression (47.7%) or AEs (22.7%). All pts had treatment-emergent adverse events (TEAEs) which were serious in 88.6%. The most common TEAEs were diarrhea (59.1%), pyrexia (52.3%) and nausea (50.0%). The most common TEAE that led to discontinuation was pneumonia (4.5%). Treatment-related AEs (TRAEs) occurred in 93.2% of pts and were serious in 59.1%, but none led to death. The most common TRAEs were diarrhea (50%), nausea (47.7%) and tumor lysis syndrome (TLS, 40.9%: laboratory TLS, 38.6%; clinical TLS, 6.8%) (Table 1). Elevated liver enzymes were transient and resolved spontaneously. These increases were assumed to be mainly due to down-modulation of hepatic transporter proteins and reduced enzyme clearance rather than direct hepatocellular cytotoxicity (based on clinical, in-vitro and in-silico assessments). Regarding MTD, the 18 mg dose was not tolerated in either arm (clinical TLS and acute kidney injury in Arm A; hypotension and liver injury in Arm B). AZD4573 12 mg was tolerated in Arm A, but not tolerated in Arm B due to clinical TLS (n=2). The recommended Phase 2 dose (RP2D) was 12 mg QW in Arm A and 9 mg QW in Arm B. AZD4573 showed dose-proportional increases in AUC and Cmax, with moderate PK variability (~30-60% CV), and a t1/2 of ~5 hrs. Furthermore, AZD4573 led to dose-dependent reduction in pSer2 (>75%) and MCL-1 (>70%) in peripheral blood as evidence of target engagement and mechanism of action. Median duration of exposure was 10.1 wks in Arm A (range, 1.0-130.1) and 5.2 wks in Arm B (range, 1.0-35.7). In Arm A, there was 1 complete and 1 partial response in 17 DLBCL pts. Median overall survival was not reached in Arm A and was 8.8 months in Arm B, with 7 (31.8%) deaths in each. Conclusion: AZD4573 had manageable safety and a PK profile suitable for QW dosing in a broad range of hematologic malignancies including lymphoma and leukemia. The reduction in pSer2 and MCL-1 supports the RP2D of 12 mg for lymphoma and 9 mg for leukemia. A combination study of AZD4573 and acalabrutinib (NCT04630756) is ongoing to further examine the DLBCL response signal seen in this study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PET-Driven Radiotherapy (RT) in Patients with Low Risk Diffuse Large B-Cell Lymphoma (DLBCL): 5-Year Results of the DLCL10 Multicenter Phase 2 Trial By Fondazione Italiana Linfomi (FIL)

Background Recent data show that RT on PET-negative sites after chemo-immunotherapy in early stage DLBCL can be avoided. Nevertheless, bulky sites at diagnosis are still irradiated after rituximab-chemotherapy (R-CT), whereas residual uptake area (RUA at other sites are considered as failure. As PET negativity is mandatory to define complete remission (CR), we hypothesized that PET-neg areas after R-CT do not need consolidation RT independently from their size at onset Aims: To assess the role of RT in PET-neg and in PET-pos low-risk DLBCL patients after R-CT Methods: The DLCL10 protocol was a phase II study of patients (pts) >=18 years with low risk DLBCL according to the MiNT trial, (aa IPI 0 and bulky, aa IPI 1 +/- bulky) conducted in 19 FIL centers. Pts were treated with 6 courses of RCHOP and final response was evaluated with FDG-PET. Both pre and post treatment PET scans were centrally reviewed through the Widen web platform by a panel of 5 nuclear medicine experts. Positive scans were those centrally classified with Deauville score 3-4-5 by the first 2 concordant reviewers. Pts with one RUA received RT, 36 Gy involved-site, regardless of bulky disease at onset, while those with multiple RUA were shifted to salvage systemic therapy. Primary aim was to obtain a 2-year PFS of at least 85% for post R-CT PET-neg pts. Secondary endpoints were OS and response. Results: From January 2012 to December 2017, 115 consecutive pts were screened, and 110 were evaluable. Median age 58 years (47-65); M:F 61 /49; DLBCL de novo 90%, aa IPI 0 16 , aa IPI 1 94 (20% with bulky mass), bulky disease in the whole series 35 pts ; RCHOP-14 /RCHOP-21 73/37. At the time of the present analysis median follow-up was 63 months and 13 pts died (3 lymphoma, 2 acute toxicitiy, 2 late toxicity, 2 secondary neoplasm, 2 complication from allo-transplant, 1 other causes, 1 unknown). A total of 105 pts completed the R-CT program, while five were discontinuated for lymphoma progression (1), toxicity (2, both died), histological review (1) and patient dispersion (1). At end of treatment, 83 patients had PET-neg, whereas 17 had single RUA and received involved -site RT. In PET-neg patients, PFS was 90.6% (95% CI 81.1-95.4) at 2 years and 82.48% (95% CI 78.4-94.3) at 5 years. OS was 96.37% (95% CI 89.17-98.81) at 2 years and 87.81% (95% CI 77.62-93.54) at 5 years. After RT, 15 pts reached CR, one PR and one was not evaluable. None of them relapsed. Thus, all patients with positive focal RUA after R-CT were cured with involved-site RT. Concerning the 35 pts with bulky disease, 21 reached PET-neg and 14 had single RUA after R-CT and were thus irradiated (1 PD). There were two relapses in the PET-neg/not irradiated group, but only one in previously bulky site. In the PET-pos /RT group no relapse occurred. In the total population, 5 -year PFS and OS are 80.9% (95%, CI 79.28-92.18) and 87.1% (95%, CI 78.66- 92.38), respectively. Conclusion: Our data suggest that irradiating only sites of unique PET RUA, regardless of bulky at onset, can be considered as a reasonable strategy for low risk DLBCL pts. In cases with bulky disease, PET-driven RT allowed RT sparing in approximately half of patients in this small series. Moreover, consolidation RT in those with focal residual PET positivity, guaranteed excellent prognosis (17/17 cured) and can be considered as a valid option Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictors for Survival and Relapse in Patients (pts) with Diffuse Large b-Cell Lymphoma (DLBCL) Treated with Anti-CD19 CAR T-Cell Therapy: A Case for Early Intervention in High-Risks Pts Assessed By Day 30

Purpose: Despite the success of CAR T-cell therapy in pts with relapsed/refractory (R/R) DLBCL, some pts still fail treatment, and their prognosis is dismal. Our aim is to elucidate factors that govern the clinical performance of CAR T therapy given as standard of care (SOC) for R/R DLBCL at a single institution and to recognize the group of pts who are at risk for relapse after CAR T as early intervention may help improve the outcomes. Methods: We performed a retrospective study of R/R DLBCL pts treated with CAR T-cell as SOC at our center between Jan 2018 and Feb 2021. Disease characteristics, ferritin and CRP levels were collected pre-treatment initiation; CBC data were collected at time of apheresis. The study was IRB-approved at our center. Results: Characteristics of the pts at pre-conditioning for CAR T are listed in Table 1. Of 201pts, 190 (94.5%) received axicabtagene ciloleucel, and 11 (5.5%) received tisagenlecleucel. Median time from apheresis to infusion was 29 days (range, 20-111). Regarding adverse events of special interest, 6% had cytokine release syndrome of > grade 3 and 38.8% had neurotoxicity > grade 3. Day 30 death rate was 4.5%. Nine (4.68%) pts developed AML/MDS and 3 (1.56%) additional pts had prolonged pancytopenia. Sixty (29.8%) pts died post Day 30 [42 of progressive disease (PD); PD/AML =3; PD/Infection =2; PD/Toxicity =2; Infection =9; unknown=2). Four pts lost follow-up after PD. With a median follow-up from infusion of 16.86 (0.92-38.7) months, the 12-months overall survival (OS) rate was 55.48 %(95%CI:49-63); 12-months relapse-free survival (RFS) was 34.57% (95% CI: 28-42). In multivariate analysis, the factors with independent influence on both RFS and OS were serum ferritin, > 2 extra-nodal sites of disease involvement, glomerular filtration rate pre-conditioning and Hb level at apheresis (Table 2, Figure 1a). Salvage therapies were received by 38 pts with PD after CAR T (median 1, range 1-6 lines of therapies), including 9 pts who received an allogeneic stem cell transplant. Only 5 (13%) of these 38 pts achieved CR. Therefore, we assessed response by day 30 to predict which pts were at risk for relapse prior experiencing an actual progression. We found a significant difference in OS and RFS in patients who were in CR vs PR/SD after CAR T. The 12-months OS rates were 75.52% and 54.38%, respectively (P<0.001). The RFS rates were 65.4% vs 16.56%, respectively (P<0.001, Figure 1b). In multivariate analysis, the factors with independent influence on RFS in Day 30 PR/SD pts were serum ferritin level pre-conditioning, histology (primary mediastinal vs DLBCL), and WBC at apheresis (figure 1c). Conclusions: Predictors of outcomes after CAR T cell therapy are multifactorial. However, we found that simple clinical tools by Day 30 (pts not achieving CR by imaging, ferritin level pre-CAR T infusion, WBC at apheresis) are associated with outcomes. Studies are needed to study whether integration of CAR T with innovative therapies in such high-risk patients may improve survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Polatuzumab Vedotin Combined with R-ICE (PolaR-ICE) As Second-Line Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Introduction: Currently, the standard of care for patients (pts) with relapsed/refractory (RR) diffuse large B-cell lymphoma (DLBCL) who relapse > 1 year after frontline treatment is salvage chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) in appropriately selected, chemosensitive pts. Following first-line therapy (tx) with a rituximab-containing anthracycline-based regimen in the modern era, response rates to platinum-based chemoimmunotherapy are suboptimal. More effective salvage regimens for RR DLBCL remain an unmet need. Polatuzumab vedotin (Pola) is an antibody-drug conjugate directed against CD79b that is safe and effective when combined with chemotherapy in frontline and relapsed, transplant-ineligible DLBCL pts [Tilly NEJM 2022, Sehn, JCO 2020]. We evaluated the safety and efficacy of Pola combined with rituximab, ifosfamide, carboplatin, and etoposide (RICE) as second-line tx in RR DLBCL in a multicenter phase 2 study. Methods: Adult transplant-eligible pts with ECOG ≤ 2 who had biopsy-proven RR DLBCL following frontline CD20-directed anthracycline-based chemoimmunotherapy were eligible. Pts with DLBCL not otherwise specified (NOS), transformed indolent lymphoma, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma (HGBCL) NOS, and HGBCL with MYC and BCL2 rearrangements were eligible. Pts with central nervous system lymphoma, peripheral neuropathy (PN) ≥ grade (gr) 2 or prior tx of RR DLBCL were excluded. Participants received PolaR-ICE: 1.8mg/kg Pola day (d) 1, rituximab 375mg/m2 d1, etoposide 100 mg/m2 IV d1-3, carboplatin AUC 5 (750 mg max) IV d2, ifosfamide IV 5000 mg/m2 d2 (inpatient) or divided between d1-3 (outpatient) every 21d for 2 cycles followed by PET-CT. G-CSF prophylaxis was mandatory. Pts in CR were eligible to proceed directly to ASCT or could receive a 3rd cycle of PolaR-ICE at investigator's discretion. Pts with partial response (PR) [or stable disease, MD discretion] received a 3rd cycle of PolaR-ICE. After ASCT, pts in ongoing response who had recovered from ASCT toxicities were eligible to receive Pola consolidation (1.8mg/kg) in 21d cycles starting d+30-60 to complete a cumulative 6 doses of Pola. A safety lead-in of up to 8 pts were enrolled according to the IQ rolling 6 design, with a de-escalation dose available (Pola 1.4mg/kg). Following the lead-in, a 2-stage design was employed with 20 pts enrolled (including lead-in) and since 8+ CRs were observed, the study proceeded to enroll a total of 40 pts. The co-primary endpoints were safety and CR rate according to 2014 Lugano classification. ORR, PFS and overall survival were secondary endpoints. Results: 41 pts were enrolled; baseline characteristics are shown in Table 1. 37 pts were evaluable for response: 1 pt died prior to response assessment, 1 pt was inevaluable for response and replaced, 1 pt had clinical progressive disease (PD) and counted in ORR evaluation as PD, and 1 pt is pending response evaluation. 40 pts have toxicity data available, including 22 pts who received 3 cycles of PolaR-ICE, 16 treated with 2 cycles to date, and 2 pts who received 1 cycle to date. Of 38 pts (37 evaluable + 1 clinical PD), 35 had an objective response after 2 cycles of PolaR-ICE for an ORR of 92%, 21 (55%) had a CR, 14 (37%) had a PR, 1 had stable disease and 2 had PD. The end of salvage (PolaR-ICE x 2 or 3) ORR was 89% and CR rate 61% (1 PR became PD and 2 PR converted to CR with a 3rd cycle). To date, 21 pts proceeded to ASCT and 13 pts received consolidation Pola. The most common treatment-emergent adverse events (TEAE, all gr) related to PolaR-ICE were anemia (78%), nausea (70%), thrombocytopenia (70%), leukopenia (50%), fatigue (48%), neutropenia (48%), lymphopenia (38%), constipation (35%), hypertension (30%), and hypophosphatemia (28%). The most common gr ≥ 3 TEAEs were anemia (43%), thrombocytopenia (43%), neutropenia (43%), and no other non-hematologic TEAE occurred in more than 2 (5%) pts. 1 pt underwent Pola dose reduction due to gr 4 cytopenias, gr 2 nausea. Gr ≥ 3 infection/febrile neutropenia/sepsis occurred in 3 (8%) pts. 1 pt had a study treatment-related gr 5 AE due to sepsis. PN occurred in 10 (25%) pts, all gr 1 except one gr 2 event. Conclusion: PolaR-ICE produced a high ORR with CR in a majority of pts and the safety profile was similar to RICE, without added toxicity due to Pola. Longer follow-up is needed to assess the durability of responses and outcomes following ASCT/Pola consolidation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Waveline-001: Updated Results from a Phase 1 Dose Escalation and Cohort Expansion Study of Zilovertamab Vedotin (MK-2140) in Non-Hodgkin Lymphoma

Background: Zilovertamab vedotin (ZV) is a receptor tyrosine kinase-like orphan receptor 1 (ROR1) targeting antibody-drug conjugate comprising zilovertamab, a proteolytically cleavable linker, and the antimicrotubule agent monomethyl auristatin E. ROR1 is a transmembrane protein absent in mature tissues but highly expressed in certain hematologic malignancies, making it an attractive therapeutic target. Safety and efficacy of ZV are being investigated in the phase 1 WAVELINE-001 study (NCT03833180), which is a dose escalation and cohort expansion analysis in patients (pts) with relapsed and/or refractory (R/R) hematologic malignancies. Initial results showed ZV had a tolerable safety profile and promising antitumor activity in R/R non-Hodgkin lymphoma (NHL; Wang M, et al. NEJM Evid. 2021;1[1]). Updated results, including PFS and OS for mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Richter transformation (RT), are presented. Methods: Eligible pts aged ≥18 years of age, with a histological diagnosis of MCL, DLBCL, or RT; had ECOG PS 0-2; and progression during or relapsed after prior systemic therapy, were included. WAVELINE-001 included 3 dosing schedules. Data from Schedule 1 are presented; Schedules 2 and 3 are ongoing. In Schedule 1, pts received ZV IV at a starting dose of 0.5 mg/kg on day 1 Q3W, increasing to 2.5 mg/kg using an accelerated plus 3 + 3 dose escalation design. Primary end point was determination of the maximum tolerated dose and/or recommended dosing regimen (RDR). Secondary end points included safety, ORR, DOR, PFS, and OS. Results: A total of 54 pts were enrolled in Schedule 1, of which 30 pts were treated at the established RDR of 2.5 mg/kg. At data cutoff (May 18, 2022), median follow-up was 15.3 months (range, 0.5-37.8). Median age was 70.0 yrs, 57% of pts were male, 48% had an ECOG PS of 0, 65% had received ≥3 prior therapies, 80% had NHL (FL, n=3; DLBCL, n=15; MCL, n=17; MZL, n=1; RT, n=7), and 20% had other disease (AML, n=3; CLL/SLL, n=7; mixed histology, n=1). MCL pts had received a median (range) of 4 (1-9) prior lines of therapy. All MCL pts received prior BTKi therapy, and none had prior CAR-T or CAR-NK therapy. 59% of MCL pts were Ann Arbor stage IV. DLBCL pts received a median (range) of 4 (1-7) prior lines of therapy, 67% of pts had received prior CAR-T or CAR-NK therapy; 47% of pts were GCB, and 33% were ABC subtype. Five pts (71%) with RT had the DLBCL subtype. No pts with RT received autologous stem cell transplant and received a median (range) of 3 (1-10) prior therapies. Any-cause adverse events (AEs) occurred in 52 (96%) pts. Any-grade treatment-related AEs (TRAEs) occurred in 40 pts (74%); most common (≥20%) were peripheral neuropathy (46%), neutrophil count decreased (35%), fatigue (35%), nausea (28%), and diarrhea (20%). Decreases in hemoglobin and platelet count occurred in 13% and 11% of pts, respectively. Grade 3-4 TRAEs occurred in 28 pts (52%), most commonly neutrophil count decreased (33%), platelet count decreased (11%), and peripheral neuropathy (7%). AEs of special interest regardless of causality occurred in 76% of pts; most common were hematopoietic cytopenia (56%) and peripheral neuropathy (48%). For pts experiencing peripheral neuropathy, most cases were grade 1/2 (41%); 7% were grade 3. Median (range) time to onset of first peripheral neuropathy was 49 (1-162) days. No incidences of tumor lysis syndrome or infusion reactions occurred and no grade 5 TRAEs occurred. AEs led to ZV discontinuation in 12 pts (22%) and interruption or reduction in 24 (44%). ORR was 33% (5/15; 95% CI, 12-62; 3 CR/2 PR) in DLBCL, 53% (9/17; 95% CI, 28-77; 2 CR/7 PR) in MCL, and 57% (4/7; 95% CI, 18-90; 1 CR/3 PR) in RT. No responses were seen among the other indications treated. Median DOR (range) was 4.6 months (2.9-21.5) for DLBCL, 10.0 (0-20.3) for MCL, and 2.8 (0-2.8) for RT. Median PFS (95% CI) was 3.9 months (0.5-7.0) for DLBCL, 11.4 (4.0-NE) for MCL, and 4.7 (0.7-NE) for RT. Median OS (95% CI) was 9.1 months (1.0-NE) for DLBCL, 18.0 (7.1-NE) for MCL, and 24.0 (2.7-NE) for RT. Among 12 pts with NHL (10 DLBCL and 2 RT) who had undergone prior CAR-T/CAR-NK therapy, ORR was 33% (4/12; 95% CI, 10-65). Conclusions: Updated results from WAVELINE-001 support prior analyses showing ZV had a tolerable safety profile and promising response rates, and favorable PFS and OS among heavily pre-treated pts with DLBCL, MCL, and RT, including pts who had received prior CAR-T/CAR-NK therapy.

Impact of a Validated Composite Comorbidity Score on Outcomes in Patients Treated with CAR T-Cell Therapy for Diffuse Large B Cell Lymphoma (DLBCL): A Multicenter Real-World Evidence (RWE) Study

Introduction: Chimeric Antigen Receptor T-cell therapy (CART) has dramatically improved outcomes for patients (pts) with relapsed/refractory (r/r) DLBCL, but the majority of pts still have poor outcomes due to progressive disease and toxicities. Tools quantifying frailty and comorbidities have not been verified in large patient cohorts. The Cumulative Illness Rating Scale (CIRS) is a comprehensive tool that has been found to predict outcomes in various B cell malignancies. We used a machine learning algorithm to rank the prognostic impact of specific comorbidities measured by CIRS on progression-free survival (PFS) in DLBCL pts undergoing leukapheresis for CART in a multicenter learning cohort (LC; Shouse et al, ASH 2021). In this study, we establish that these comorbidities also predict overall survival (OS) and verify their prognostic significance in a separate validation cohort (VC). Methods: We conducted a retrospective RWE analysis of pts with r/r DLBCL who underwent leukapheresis for CART at 10 academic centers. CIRS was assessed at the time of T-cell collection and calculated per Salvi (2008). High comorbidity burden was defined using a published cutoff of CIRS score ≥7. PFS and OS were measured from T-cell collection. Random survival forest (RSF) modeling of PFS and OS was repeatedly applied to random subsets of the LC to determine the most important CIRS categories and comorbidity levels in the presence of known prognostic factors (IPI at diagnosis, concurrent indolent lymphoma, age, ECOG performance status, number of prior therapies, prior transplant, number of medications, cell of origin subtype, complex karyotype, MYC rearrangement by FISH, and MYC+BCL2/BCL6 rearrangement). Cox proportional hazards models were fit to quantify the association between survival and significant pt features. Associations between comorbidities and CART adverse events were evaluated with Fisher's exact test. Results: We analyzed data from 577 pts. The median CIRS score was 7 (range, 0-25) with 54% (n=309) having CIRS ≥7. The median PFS was 11 months (95% CI: 8 - 15) and OS 30 months (95% CI: 23 - NA), with a median follow-up of 20 months. Although CIRS ≥7 was significantly associated with inferior PFS (HR=1.26) and OS (HR=1.35) in univariable analysis, it did not remain significant in multivariable models. According to RSF variable importance and node splits, key CIRS categories which adversely impacted OS were respiratory, upper GI, renal, and hepatic. 9% of pts had a score of ≥3 in at least one of the above comorbidities, which we designated Severe4. When accounting for other significant variables, Severe4 was independently associated with inferior PFS (HR=2.45, p<0.001) and OS (HR=2.30, p<0.001) in the LC. This finding was recapitulated in a single-center VC of 218 patients. In this cohort, median follow-up was 35 months, median age 61 years, median 3 prior therapies, ECOG 0-1 in 74%. As in the LC, axicabtagene ciloleucel was the predominant CART (93%). A CIRS comorbidity score of ≥3 in any of the Severe4 categories was found in 16% of pts. Severe4 remained independently associated with inferior PFS (HR=1.84, p=0.003) and OS (HR=1.82, p=0.007) in the VC (Figure). Pts with Severe4 also had a higher rate of grade ≥3 CRS (16% vs 6%; p=0.013), while development of grade ≥3 ICANS was associated with CIRS ≥7 (26% vs 12%; p<0.001). Conclusions: In this large RWE study, we demonstrate that the presence of comorbidity within the Severe4 composite index had prognostic significance for OS in CART recipients for r/r DLBCL. Importantly, Severe4 was validated in a separate cohort. Severe4 is predictive of severe CRS and CIRS ≥7 is predictive of severe ICANS. The underlying mechanism leading to this observation is an area of active investigation. Given these results, CIRS evaluation and Severe4 should be calculated prior to CART in DLBCL to identify those at highest risk for morbidity and mortality and to counsel pts about their expected risk. These results may be product specific given the enrichment of axi-cel patients and may need additional verification with other products. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase 1 Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide in Combination with Polatuzumab (ViPOR-P) in Relapsed/Refractory B-Cell Lymphoma: Preliminary Analysis of Safety and Efficacy

Background: Diffuse large B-cell lymphoma (DLBCL) is often curable with frontline chemotherapy; however, pts with relapsed/refractory (R/R) disease and those who fail CAR-T therapy have poor overall outcome. Oral small molecule targeted agents can disrupt key survival pathways in DLBCL, but fail to induce deep or durable responses as monotherapy. We have previously shown that ViPOR is safe and active in DLBCL, with preferential activity in non-GCB DLBCL and HGBCL-DH (Melani et al. Blood. 2020). Synergistic activity has also been demonstrated with MMAE, the chemotherapy payload of Polatuzumab (Pola), with ViPOR in pre-clinical DLBCL cell lines (unpublished data). We hypothesized that additional genotoxic stress with Pola will further leverage efficacy and time-limited, cyclic dosing will limit the hematologic toxicity of the regimen. Methods: R/R aggressive B-cell lymphoma pts with adequate organ function were eligible. In phase 1, a 3+3 design was used to determine the maximum tolerated dose (MTD) of 3 dose-levels (DLs) of Pola IV D2 and venetoclax (Ven) PO D2-14 (DL1: 1.4mg/kg + 600mg, DL2: 1.8mg/kg + 600mg, and DL3: 1.8mg/kg + 800mg) in combination with fixed-dose ibrutinib 560mg PO D1-14, prednisone 100mg PO D1-7, obinutuzumab 1000mg IV D1-2, and lenalidomide 15mg PO D1-14. An expansion cohort was included at the MTD for further analysis of safety and efficacy. ViPOR-P q21d x 6 cycles (C) was given without maintenance or planned consolidation. All pts received TLS, PCP, HSV, and G-CSF prophylaxis (ppx) with VTE ppx per investigator discretion. Baseline CT, PET, BM, and tumor biopsy were performed with CT scans after C2, 4, and 6 and PET after C6 or at time of suspected complete response (CR). Surveillance CT was performed q3m for 1y, q4m x 1y, q6m x 1y, then annually x 2y. Results: 15 pts were enrolled and treated in the dose-escalation cohort; 3 at DL1, 6 at DL2, and 6 at DL3. Lymphoma subtypes included DLBCL NOS (60%) and HGBCL-DH (40%). In 9 DLBCL NOS pts, 11% were GCB and 89% non-GCB subtype by IHC. Three (20%) pts had transformed disease. Median age was 51y (range 39-83), with stage III/IV disease in 80%, elevated LDH in 80%, and >2 extranodal sites of disease in 67%. Nine (60%) pts had high-intermediate/high-risk IPI. Median prior therapies were 2 (range 1-6), with prior BTKi in 27%, Pola in 7%, and CAR-T in 20%. Ten (67%) pts were primary refractory (i.e., <CR to frontline tx) and 8 (53%) of pts were refractory (i.e., <PR) to last tx. One dose-limiting toxicity (DLT) of prolonged G4 thrombocytopenia occurred at DL3, but no other DLTs were noted. Pola 1.8mg/kg and Ven 800mg were identified as the MTD and safe doses for use in the expansion cohort. Heme AEs were most common and included G3-4 (% cycles) thrombocytopenia (17%), anemia (7%), and neutropenia (5%). No cases of febrile neutropenia occurred across 58 cycles. The only non-heme G3-4 AE occurring in >10% pts was hypokalemia (29%), with all pts experiencing any grade hypokalemia requiring replacement. Other common non-heme AEs (% pts) included diarrhea (71%), increased LFTs (64%), nausea (50%), hypomagnesemia (43%), and rash (43%). VTE occurred in 7% with no a.fib or major bleeding observed. No events of TLS or treatment-related mortality occurred. Dose reductions and delays occurred in 3% and 5% of cycles, respectively. Of 12 pts off-tx, 7 completed all 6C, 3 experienced disease progression, and 1 each came off-tx per investigator discretion or unacceptable AE. Of 15 enrolled pts, 14 are evaluable for response with an overall response rate (ORR) and CR rate of 64% (9/14) and 36% (5/14), respectively (Fig 1A). With a median potential f/u of 7.4m, median TTR in responding pts was 1.35m, with 8 (89%) of 9 total responses ongoing (Fig 1B). One HGBCL-DH pt relapsed by imaging at 10.6m, 2 PR pts received consolidative XRT with allo-HSCT, and 2 PR pts remain on-tx. PFS and OS at 6m was 69.8% and 75%, respectively. Conclusion: ViPOR-P is safe without significant additional toxicity compared to ViPOR, and Pola 1.8mg/kg and Ven 800mg were taken forward in the ongoing expansion cohort. Most common G3-4 AEs were hematologic with no febrile neutropenia observed with the use of G-CSF ppx. Fixed-duration ViPOR-P x 6C without maintenance led to CR in 5 (42%) of 12 off-tx DLBCL pts with 80% CRs ongoing from 3.7-9.3m. A randomized phase 2 trial is planned to further elucidate the safety and efficacy of Pola in combination with ViPOR across R/R DLBCL and within pre-defined molecular and genetic subtypes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal