IPI Score Research Articles

Assessment of Activities of Daily Living (ADL)Scale Can be Used to Predict Overall Survival after CAR-T Cell Therapy in Elderly Patient(over 70 years of age) with Refractory/Relapsed B-Cell Lymphoma

Background:The advent of chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape for refractory/relapsed B-cell lymphoma (r/r B-NHL). However, there are limited data on outcomes in older patients (age≥65 years) treated with CAR -T-cell therapy, particularly in patients older than 70 years. Objectives:Our objective was to evaluate the efficacy of CAR -T-cell therapy in elderly patients with r/r B-NHL, including response rates, progression-free survival (PFS), and overall survival (OS), as well as factors affecting survival. Methods:As of April 1, 2023, a total of 80 patients with r/r B-NHL in the age group 65-70 years (n=57) or older than 70 years (n=23) were included. Diagnoses included DLBCL NOS (n=58) ,HGBCL(n=6) ,TFL(n=6), Richter(n=4) and Other(n=6). Baseline characteristics are described in Table 1.All patients were heavily pretreated. 71/80 (88.75%) patients were at stage III-IV. The median IPI score was 3 (range 1-5). 8/96 (10%) patients failure of prior autologous hematopoietic stem cell transplantation (HSCT). The median assessment score of ADL scale was 95 for both the 65-70 and > 70 age groups, and 47.5% of patients received bridging therapy(BT) prior to CAR -T cell therapy. There were no significant differences in baseline data between age groups. Prior to the study, CD19/CD22 antigen expression in tumor tissue was confirmed by pathology, and the target was selected according to antigen expression. The kinetics and function of CAR -T cells were monitored by quantitative PCR and flow cytometry. Efficacy was assessed by PET-CT every 3 months after CAR -T therapy. All p-values were two-sided values. Survival curves were calculated by the Kaplan-Meier method. Results: The number of patients who chose a CD19 target or a CD19/CD22 dual target for CAR -T therapy was 67/80 (%) and 13/80 (%), respectively. The median CAR -T cells infused dose in the 65-70 and > 70 age groups was 1.3 (range, 0.0485-9.5) and 1.6 (range, 0.088-3.91) (×106/Kg), respectively (P=0.9618).(Table 2).There were no differences between the 2 age groups in the occurrence of cytokine release syndrome (CRS) grade 3 or higher(P=0.6221). The proportion of patients using glucocorticoid therapy for CRS was higher in the age group > 70 years than in the age group 65-70 years, but there was no statistically significant difference (P=0.0957). A response occurred in 35/57 (61.4%) of patients in the 65-70 years age group and in 14/23 (60.7%) of patients in the > 70 years age group (P=0.9646), with a complete response in 21/57 (36.8%) and 8/23 (34.8%), respectively (P=0.8623). At a median follow-up of 8.05 months (95% CI: 10.27-15.20), 12-month overall survival(OS) was 54.6% (95%CI: 39.3%-67.6%) vs 72.1% (95%CI:43.9%-87.8%) at ages 65-70 vs > 70,12-month progression-free survival (PFS) was 32.8% (95%CI: 19.8%-46.5%) vs 32.9% (95%CI: 13.5%-54%), and there was no significant difference in OS (p=0.0623) and PFS(p=0.6327) by age group. In contrast, patients aged > 70 with ADL < 95 showed significantly shorter 12-m OS (0) compared to patients aged 65-70 with ADL≥95(55.2%,95%CI:35.5%-71.1%) or ADL < 95(40.5%, 95%CI: 14.2%-59.9%), or > 70 with ADL≥95(85.6%, 95%CI:52.5%-96.3%), respectively (Figure 1: P= 0.0069). The three negative factors comprising the prognostic tool OS: low ADL scores (P=0.0124), high IPI scores (P=0.0029), and presence of extranodal lesions (P=0.0143). Conclusions: Our data suggest that the safety and efficacy of CAR -T-cell therapy in > 70-year-old patients is not significantly different from that in 65-70-year-olds. Elderly patients with ADL scores below 95 have poor survival after CAR -T therapy, especially those over 70 years of age. However, studies on curative approaches and long-term follow-up are needed.

CD10 -CD14 -hla-DR -CD45 +SSC ++ Neutrophils with G-MDSC-like Feature Relate to Progress and Poor Prognosis in Non-Hodgkins Lymphoma Patients

Objectives: To explore CD10-CD14-CD45+HLA-DR+SSC++ neutrophils (CD10- neus) frequency in non-Hodgkins lymphoma (NHL) patients, and their immunologic characteristics and clinical significance. Methods: 90 NHL patients were involved, 47 age and gender-matched volunteers recruited as healthy controls (HC). The CD10- neus frequency in peripheral blood from the HC and NHL patients was detected. Then the CD10- and CD10+ neutrophils were isolated, and their morphologic characterization was compared. CD3+ T cells were also sorted for culture alone or co-culture with the autologous CD10+ or CD10- neutrophils for 48h, then the proliferation and viability of T cells were determined. The levels of Arg-1 and ROS in CD10+ or CD10- neutrophils were examined. Results: Little Few CD10- neus were detected in HC (1.94% ± 1.76), but the level was significantly elevated in newly diagnosed (NDP) and relapsed NHL patients (RLP), 37.90% ± 23.34 and 45.38% ± 20.89 respectively, there was a decrease in the remission patients (RMP, 26.62% ± 16.54). In NDP, CD10- neus at advanced stages was significantly higher than that at limited stages (50.16% ± 27.82 vs. 25.21±12.51, P = 0.017); similarly, the CD10- neus in patients with higher IPI score (3 to 5 points) more than that with lower IPI score (-2) group (53.94% ± 29.09 vs. 30.33 ± 17.73, P = 0.0154). According to the median value of CD10- neus, we further divided the patients into CD10- neus high or low two subgroups, the remission rate after 2 - 4 times first-line treatments in NDP with high CD10- neuts significantly lower than that in patients with low CD10- neuts (12.5% vs 88.24%, P = 0.001); the relapse free survival (RFS) in RMP with high CD10- neus significantly shorter than that with low CD10- neus (11.5 vs. 33.5 months, P = 0.001); the overall survive (OS) in RLP with high CD10- neus also shorter than that with low CD10- neus (23 vs. 39.5 months, P = 0.001). The CD10- neus from NHL mainly consisted of immature neutrophils, strong inhibited T-cell proliferation and viability, Arg-1 and ROS in CD10- neutrophils neuts vastly increased comparing to that from HC. Conclusions: CD10- neus in NHL have the two main characteristics of MDSCs cells (immature and T cell inhibition), the increased may predict disease progression and poor prognosis.

Prognostic Impact of Pre-Treatment Cell-Free DNA Concentration in Newly Diagnosed Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Although some risk factors associated with worse survival are known, there are no reliable predictive biomarkers of response. Considering the prognostic relevance of cell-free DNA (cfDNA) in B-cell lymphomas, in this work we aimed to explore its role in 75 patients (pts) enrolled in the PTCL13 prospective study (NCT02223208), including newly diagnosed Peripheral T-cell Lymphoma, Not Otherwise specified (PTCL-NOS, n=30), nodular T Follicular Helper Lymphoma (nTFHL, n=26) and Anaplastic Lymphoma Kinase negative Anaplastic Large Cell Lymphoma (ALK-ALCL, n=19). Cell-free DNA was extracted using the Maxwell® RSC LV ccfDNA Kit (Promega) from plasma samples. Pre-treatment cfDNA concentration had a median value of 19.1 ng/mL of plasma (range: 2.27-1082 ng/mL) and was significantly increased in the presence of high-risk clinical parameters, including disease-related risk factors (increased lactate dehydrogenase levels, p<0.0001; presence of extranodal disease p=0.04), prognostic scores used in PTCLs (International Prognostic Index >2, p<0.0001; Prognostic Index for T-cell lymphoma >1, p=0.0006), and patient condition (poor performance status, p=0.0003), compared with cfDNA concentration in low-risk categories. On the other hand, no association was detected between age, Ann Arbor stage, bone marrow involvement and cfDNA levels. In addition, higher baseline cfDNA concentration was found in pts who progressed compared with those who achieved a response at the end of 6 chemotherapy cycles (p= 0.0303). Importantly, pre-treatment cfDNA level had a negative impact on both progression-free survival (PFS, Univariate Cox linear model, p=0.0001) and overall survival (OS, Univariate Cox nonlinear model, p=0.0105). Multivariate analysis confirmed a significant influence of cfDNA on PFS [Multivariate Cox Model, HR 1.34, 95% Confidence Interval (CI) 1.14-1.58, p= 0.0004 and HR 1.28, 95% CI 1.11-1.48, p= 0.0006] greater than that of IPI and PIT scores, LDH, performance status, and extranodal disease. Furthermore, to identify a specific pre-treatment cfDNA concentration associated with a worse prognosis, an analysis by receiver operating characteristic (ROC) curve was performed by dividing the values according to the death event. In doing so, a cut-off of 42.78 ng/mL was identified (Youden's J statistics) above which PFS and OS are significantly reduced (log-rank test p= 0.0177 and < 0.0001, Figure 1 and 2 respectively). Among the 21 pts with cfDNA>42.78 ng/mL, 8 were PTCL-NOS, 4 nTFHL and 9 ALK- ALCL, with nTFHL being significantly less represented than ALK-ALCL (p=0.043). Multivariate analysis confirmed a significant effect on survival when cfDNA above or below 42.78 ng/mL were tested with IPI, LDH and ECOG (HR 2.76, 95% CI 1.24-6.16, p= 0.0128 for PFS; HR 9.45, 95% CI 3.10-28.81, p=0.0001 for OS). When tested together with PIT, ECOG and extranodal disease, both cfDNA and PIT score were associated with OS (HR 9.30, 95% CI 3.22-26.87, p<0.0001 and HR 0.34, 95% CI 0.12-0.94, p=0.037 respectively), while no significant correlations with PFS were found (cfDNA≥ vs <42.78 ng/mL, HR 1.83, 95% CI 0.86-3.91, p= 0.1178). Moreover, sequencing of cfDNA and diagnostic biopsy-extracted DNA was performed in an exploratory cohort of 25 pts using a target custom panel of 60 genes. We identified lymphoma mutations in 18 plasma samples (number of mutations in pts with at least a mutation: median=2, range 1-5) and in 20 biopsy samples (median=2, range 1-6). Mutations identified in biopsy were confirmed in coupled plasma samples in 74.4% cases. In conclusion, our data demonstrate that pre-treatment cfDNA concentration has a strong prognostic impact in PTCLs and represents a superior predictor of shorter survival, compared to canonical parameters. Despite the fact that sequencing is feasible as demonstrated in our preliminary analysis, and is crucial to identify molecular alterations, its applicability in routine clinical practice is limited. On the other hand, cfDNA concentration is an inexpensive biomarker that can quickly provide prognostic information in the real-world scenario. Its influence on survival in the context of a prospective study where PTCLs were homogeneously treated identifies cfDNA as an easily assessable biomarker that could become part of those to be measured in newly diagnosed PTCLs.

CAR T- Cell Therapy Provides an Opportunity for Further Consolidation Treatment for Relapsed or Refractory Adult Burkitt Lymphoma Patients

Background: Adult Relapsed and refractory Burkitt's progresses rapidly, and there is limited data on CART therapy. The available data also indicates poor survival rates. Aims: Exploring the efficacy of CAR-T therapy for adult relapsed/refractory Burkitt's lymphoma, and analyzing the factors affecting the efficacy and survival of CART treatment. Methods: This single-centre, retrospective study analysed patients with Burkitt's lymphoma who received CAR-T therapy at the Beijing GoBroad Boren Hospital between December 2018 and February 2023. The inclusion criteria were adult relapsed and refractory Burkitt's lymphoma. Nineteen patients were included: 13/19 (68%) male; Median age is 37 (19-56).6/18 (33%) patients get standard intense chemotherapy（not R-CHOP）.17/19 (89.4%) patients were at stage IV at the time of salvage therapy. 9/19 (47.4%) patients IPI score was ≧3 .9/19 (47.4%) patients had > 7.5 cm bulky disease. Midian Leukapheresis LDH is 547.9 U/L. Patients had received a median of 4 cycles (range 3-14) prior to treatment. 2/19 (10.5%) and 2/19 (10.5%) patients had failed prior autologous hematopoietic stem cell transplantation and prior allogeneic hematopoietic cell transplant, respectively. 17/19 (89.4%) patients received bridging therapy before CAR-T，which only have 1 patient CR and 1 patient achieve a PR. Analyzing whether a sequential consolidation treatment strategy for patients who respond to CART therapy can prolong survival. Results: The median CAR-T infusion dose is 1.46*10^6/kg（0.0126-7.22）. The median of CAR-T peak expansion is 89.5（3.84-710）*10^6/L , which occurred on day 7（7-11）after CAR-T cell therapy. 16/19（84.2%） of patients experienced CRS, with 3/19 (15.8%) of them classified as grade III-IV.Besides,5/19(15.8%) of patients experienced iCANS, with 3/19 (26.3%) of them classified as grade III-IV. The median follow-up time was 4.274 (0.2-43.4) months.Three months ORR and CRR were 31.6% and 21.1%. The best ORR and the best CRR were 47.4% and 26%, respectively. One-year progression free survival and overall survival were 15.8% and 21.1%. For individuals who achieved CR/PR to CART therapy in three months, their survival curves were significantly better than those of individuals with SD/PD. The univariate analysis of PFS showed that risk factors included the high LDH at the time of leukapheresis(p=0.0182,HR 1.001) ,three months response is SD/PD (p=0.0045,HR 20.8) and initial treatment with R-CHOP based chemotherapy(p=0.0319,HR 5.46) .Among the 19 patients, 12 patients continued to receive other treatments for consolidation or salvage, including 5 cases of other target CAR-T therapies, 5 cases of autologous transplants, and 2 cases of allogeneic transplants. However, only 4 of these all patients remained disease-free. Among them, 2 patients received allogeneic transplants, 1 patient received autologous transplant, and no subsequent other treatments in one patient. Summary/Conclusion: CAR-T therapy should be recommended as soon as possible after Burkitt becomes relapsed or refractory due to the ineffectiveness of multi-drug chemotherapy. Upon reaching remission, the transition to autologous or allogenic stem cell transplantation may be considered. Due to the small number of cases, further validation of our findings is still needed.

Treatment Intensity and Outcomes in Elderly Patients with DLBCL Receiving First Line Therapy

Background: One-third of patients (pts) with newly diagnosed DLBCL are 70 and older. Although a standard of care for first-line (1L) DLBCL is anthracycline-based chemoimmunotherapy with R-CHOP, in elderly DLBCL pts treatment approaches vary and outcomes of these are poorly understood. In this study, we aimed to evaluate long-term outcomes among elderly pts with DLBCL across 1L regimens with a focus on those who received reduced dose (RD) R-CHOP, standard dose (SD) R-CHOP, and non-anthracycline alternative regimens (AR). Methods: We evaluated a cohort of pts from the Flatiron Health electronic health record (EHR)-derived, de-identified database with DLBCL diagnosis (dx) after 1/1/2011, age 70 or greater at dx, and with no evidence of prior indolent lymphoma or other malignancy within 2 years of 1L therapy. RD R-CHOP was defined as <80% SD doxorubicin or cyclophosphamide. Time-to-event analysis was performed with the Kaplan-Meier method and differences were evaluated using the log rank test. Real world overall survival (rwOS) was defined as the interval, in months (mos), from DLBCL dx to death or last follow-up. Real world progression free survival (rwPFS) was defined as the interval, in mos, from initiation of 1L therapy to progression, death, or last follow-up. Multiple imputation was performed (m = 50). Multivariate Cox regression analysis (MVA) was conducted within each imputed dataset and pooled. MVA was additionally performed across age strata. Results: There were 434 pts included in the complete cohort. Eighty-six percent (N=372) received 1L therapy and 62 pts (14%) had no therapy documented. Among treated pts, 47% were female, median age was 79 (IQR 75-82), and median CCI score 7 (IQR 6-9). Twenty-six percent and 47% had limited and advanced stage at dx, respectively; stage was unknown in 27%. Cell of origin was germinal center (GCB), non-GCB, and unknown in 34%, 24%, and 43%, respectively. Forty-eight percent of pts (N=212) received R-CHOP as 1L. Best real world response (rwR), defined as either complete response (CR) or partial response (PR) to 1L, was 89.0%, 89.5%, and 81.6% (p = 0.20) in pts who received SD R-CHOP, RD R-CHOP, and AR, respectively. CR rates were 78.0%, 58.1%, and 60.2% (p = 0.008) among these cohorts, respectively. Median rwOS and rwPFS among all treated pts was 39.0 mos (32.4-47.3) and 15.2 mos (12.3-23.4), respectively. Among patients who received SD R-CHOP, RD R-CHOP, and AR, median age (IQR) was 72 (71-77), 81 (79-83), and 80 (77-81), respectively (p<0.001). Median Charlson comorbidity index (CCI) score (IQR) was 6 (5-8), 8 (6-9), and 7 (6-9) across these groups, respectively (p<0.001). SD R-CHOP was associated with better rwPFS and rwOS in the entire treated cohort. Real world OS and rwPFS were 95.6 mos (67.0-NE) and 77.3 mos (40.3-NE) for SD R-CHOP, 37.6 mos (27.9-NE) and 15.8 mos (11.9-35.8) RD R-CHOP, and 25.7 mos (16.0-32.6) and 9.6 mos (8.1-12.0) for AR, respectively. When stratifying by age, pts 70-79 years had PFS of 77.3 mos (41.2-NE), 22.4 mos (9.86-NE), and 11.0 mos (8.6-23.4) with SD R-CHOP, RD R-CHOP, and AR, respectively (p <0.0001), whereas pts >=80 had PFS 6.14 mos (4.21-NE), 14.7 mos (8.87-NE), and 7.3 mos (4.47-12.0) with these regimens (p=0.03). In Cox regression MVA, CCI was associated with rwPFS in pts >=80 (HR 1.18, p=0.004). High-risk IPI score was associated with rwPFS (HR 2.13, p=0.05) and rwOS (HR 2.51, p=0.033), but only in pts age 70-79. When stratifying by age and adjusting for comorbidities, IPI, and MYC alteration, treatment with RD R-CHOP and AR were associated with inferior rwPFS and rwOS compared to SD R-CHOP among pts age 70-79, however, there was no association between treatment intensity and outcome among pts >=80 (Table). Conclusions: This study represents one of the largest real-world studies evaluating contemporary outcomes among elderly pts with DLBCL receiving 1L therapy. In MVA, SD R-CHOP is significantly associated with improved rwPFS and rwOS compared to RD-RCHOP and AR, but only among pts aged 70-79. There was no effect of treatment intensity or regimen on either rwPFS or rwOS among pts aged >=80. Other covariates significantly associated with outcome included CCI among pts >=80 and high-risk IPI in pts 70-79. These results suggest that pts aged 70-79 should receive SD R-CHOP whenever feasible, but that treatment intensity is not the primary determinant of outcomes among pts aged >=80. CCI should be part of routine evaluation in elderly DLBCL pts.

Efficacy and Safety of Reduced-Dose Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) in Patients over 80 with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

Background: The standard treatment for newly diagnosed DLBCL has been R-CHOP for many years. Recently, Pola-R-CHP using polatuzumab vedotin has been reported to have superior efficacy to R-CHOP and is available as first-line treatment for DLBCL. However, the patients in the phase 3 POLARIX trial were under 80, and the efficacy and safety for patients over 80 are not established. To investigate the efficacy and safety of Pola-R-CHP in the elderly, we conducted this study. Patients and Methods: From September 2022 to March 2023, we retrospectively analyzed patients with newly diagnosed DLBCL treated with Pola-R-CHP at Anjo Kosei Hospital. Patients previously treated for hematologic malignancies were excluded. The dosages of polatuzumab vedotin and rituximab were not reduced, and the dosages of cyclophosphamide, doxorubicin, and prednisone or treatment schedules were determined by the treating physician. The primary endpoint was the rate of treatment continuation without early termination, and secondary endpoints were efficacy, progression free survival (PFS), and safety. Results: A total of 29 patients (younger group: under 80, n = 21; elderly group: over 80, n = 8) were consecutively enrolled. The median age in the younger group was 64 (range 42-78) and in the elderly group was 82.5 (range 80-94). Patient characteristics, including history of malignancy (24% vs 13%, p=0.50), lifestyle diseases (43% vs 50%, P = 0.73), and sanctuary lesions (10% vs 25%, P = 0.28), were comparable in both groups. However, advanced disease was significantly higher in the younger group (76% vs 38%, P = 0.05). The Revised IPI scores were similar in both groups (Very good: 5% vs 0 %, Good: 29% vs 50%, Poor: 67% vs 50%, P = 0.50). Cyclophosphamide, doxorubicin, and prednisone were administered at full dose in 71% of the younger group, but were reduced in all patients in the elderly group (P = 0.001). Peg-GCSF was administered during treatment in all cases in the elderly group. The median days to the 6th cycle were 111 (range 105-126) in the younger group and 114.5 (range 107-124) in the elderly group, with no significant difference (P = 0.37). The rate of treatment continuation until the 6th cycle was 86% in the younger group and 100% in the elderly group, with no significant difference (P = 0.27, Fig A). Three patients in the younger group discontinued treatment due to deterioration of comorbidities (n=1), early death due to infection (n=1), and insufficient treatment effect leading to regimen change (n = 1). In the positron emission tomography (PET) / computer tomography (CT)-based response evaluation after treatment, complete metabolic response was observed in 48% of the younger group and 50% of the elderly group, and partial metabolic response was observed in 19% and 13% respectively (P = 0.90, Fig B). The CT based response were evaluated during the treatment. After 2 cycles of treatment, partial response was achieved 86% of patients in younger group and 75% of those in elderly group (P = 0.50). In the elderly group, complete response was confirmed in 75% of the patients at the end of cycle 6. The 6-month PFS after treatment initiation was 95% in the younger group (95% confidence interval, 71-99%) and 100% in the elderly group (p = 0.54). The incidence of grade 3 or higher non-hematologic toxicity was 28% in the younger group and 48% in the elderly group (P = 0.27). The incidence of febrile neutropenia or grade 3 or higher infection was 76% in the younger group and 75% in the elderly group (P = 0.95), and one case of grade 5 sepsis was observed in the younger group. There were no cases of cytomegalovirus reactivation or infection. Peripheral neuropathy occurred in 3 cases (14%) in the younger group but not in the elderly group. Conclusion: Pola-R-CHP is a feasible and effective treatment in clinical practice for patients over 80 with newly diagnosed DLBCL, with efficacy equivalent to that in younger patients. Further confirmation of long-term treatment effects and safety is necessary, but reduced-dose Pola-R-CHP is a reasonable choice as a standard treatment for newly diagnosed DLBCL in the elderly.

CD19/BCMA Dual-Targeting Fastcar-T GC012F for Patients with Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma: An Update

Background CD19-directed CAR-T cell therapy is a valuable treatment option for relapsed/refractory B-cell non-Hodgkin's lymphoma (r/r B-NHL). It has been shown that a significant percentage of B-NHL clinical samples also express B cell maturation antigen (BCMA). To further improve safety and efficacy, we have been exploring utility of a CD19 and BCMA dual-targeting CAR-T, GC012F, manufactured through a novel next-day FasTCAR-T process, for treatment of r/r B-NHL. Here, we present updated results of this ongoing IIT trial with more patients and longer follow-up. Methods From October 2021 to June 2023, nine eligible refractory/ relapsed defuse large B cell lymphoma (r/r DLBCL) patients (pts) were enrolled in this study and treated with a single infusion of GC012F in escalating dosing cohorts after a standard lymphodepletion regimen over 3 days (20 - 30 mg/m 2/day Flu, 250 - 300 mg/m 2/day Cy). The primary objectives of this study were safety and tolerability assessment; the secondary objectives were pharmacokinetics and efficacy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by ASBMT 2019, and adverse effects were evaluated according to CTCAE 5.0. Efficacy assessment of GC012F was based on the Lugano criteria. Expansion of CAR-T cells and CAR copy numbers were analyzed by flow cytometry and qPCR, respectively. Results As of data cut-off of June 30 th, 2023, with a median of 372 days (range 131 - 625) of follow-up, all nine patients received single GC012F infusions at dose levels from 3.7×10 4 to 3×10 5 CAR-T/kg, and completed 3 months or longer time follow-up evaluations. The median age was 52 years (range 18 - 60). Among the enrolled patients, eight pts were Ann Arbor stage III/IV disease, one patient with double hit, and four pts had IPI score of 3. The lymphoma samples of all patient expressed CD19, and 7 out of 8 expressed various levels of BCMA. The median SPD was 2690.81 mm 2 (408.3 - 13325.96 mm 2). Patients received a median of 2 prior lines (range 2 - 3) of therapy including rituximab and anthracyclines. Two patients received prior auto-HSCT. All patients responded to GC012F treatments, 100% (9/9) pts achieved ORR at month 3 post GC012F infusion; 77.8% (7/9) CR at month 3, 66.7% (6/9) CR at month 6 and 62.5% (5/8) CR at month 9, respectively. Up to date, the longest duration of remission was 20.8 months. No dose-limiting toxicities were observed. Five patients experienced grade 1 CRS, and one patient in the highest dose group (3×10 5 CAR-T/kg) had grade 3 CRS within 2 days. No ICANS were observed. Of the nine treated patients, grade ≥ 3 hematologic toxicities were neutropenia (9/9), leukopenia (8/9), lymphocytopenia (8/9), and thrombocytopenia (7/9). All TEAEs were resolved after treatment with standard of care and supportive care. The median peak copy number of CAR-T cells in the peripheral blood was 71,000 copies/μg DNA (range 9263 - 185,039), and the median peak time was 14 days (range 9 - 21d). CAR-T geometric mean AUC 0-28 for patients was 658,538 copies/μg DNA × day (319,104 - 1,359,031; 95% CI). CAR-T cells were also detected in tumor biopsies from all five patients tested. Conclusion This first-in-human trial of GC012F, a CD19-BCMA dual targeting CAR-T product, for the treatment of r/r B-NHL showed a manageable safety profile and promising clinical responses. The ORR was 100% at month 3 with 77.8% (7/9) achieving CR. GC012F CAR-T cells were detected in the tumor biopsies, indicating the infiltration of CAR-T cells into the tumor lesions. Overall, based on the safety and efficacy results, CD19-BCMA dual targeting CAR-T product GC012F is a promising therapy for patients with refractory/ relapsed DLBCL.

This Is a Title in Title Case: A Retrospective Study for 14 R/R DLBCL Patients

This study retrospectively analyzed 14 R/R DLBCL patients who received combined treatment of obutenib in Fujian Medical University Union Hospital from July 2021 to April 2023. Except for four patients using Orelabrutinib as post-second line treatment, all the other patients received 1 to 8 course Orelabrutinib as second line treatment. The combined chemotherapy regiments include R-EPOCH and R-DHAP. Among them, there were 8 males (57.1%) and 6 females (42.9%), with a median age of 56/57 (39-79) years. The median follow-up time was 11 (3-27) months. At the time of diagnosis, there were 12 cases (85.7%) in the Ann Arbor stage III-IV, 7 cases (50.0%) with an IPI score of 3-5, 6 cases (42.9%) with non GCB type, 8 cases (57.1%) with double expression, 2 cases (14.3%) with primary central nervous system lymphoma, and 6 cases (42.9%) with secondary central nervous system lymphoma. All patients had extranodal involvement, with 10 cases (71.4%) with ≥ 2 extranodal lesions and 8 cases (57.1%) with elevated LDH. At the end of treatment, the ORR and DCR were 42.9% and 28.6%, respectively, with a median PFS of 7 (95% Cl: 4-12) months and a median OS not achieved. Among them, the ORR and DCR of central nervous system lymphoma were 75.0% and 50.0%, respectively, with a median PFS of 9.5 (95% Cl: 6-22) months, and the median OS was not reached. Neutropenia (n=2, 14.3%) is the most common level 3/4 adverse event. No patient died due to adverse reactions.This study suggests that the combination of Orelabrutinib and chemotherapy has an excellent therapeutic effect in R/R DLBCL, especially in CNSL.

End-of-Treatment Response Assessment after Frontline Therapy for Aggressive B-Cell Lymphoma: Landmark Comparison of a Singular PET/CT Scan Versus Ultrasensitive Circulating Tumor DNA

Background : Lymphoma response criteria rely on PET/CT scans at end of therapy (EOT) to determine complete response (CR), which is necessary for cure. ~25% of patients achieve <CR by response criteria, but PET/CT scans have imperfect specificity and the positive predictive value of a single PET/CT scan at EOT is only ~50% (Kostakoglu 2021). To overcome this limitation, clinicians use additional tests including tissue biopsies or repeat PET/CT scans prior to salvage therapy to adjudicate positive results, but it remains unclear how often this occurs. Circulating tumor DNA (ctDNA) has improved tumor specificity that may reduce reliance on additional tests. We addressed these questions within a clinical trial delivering 1L therapy to pts with aggressive B-cell lymphoma. Methods : Pts were enrolled in a phase 2 study of DA-EPOCH-R or R-CHOP +/- acalabrutinib for treatment naïve DLBCL or high-grade B-cell lymphoma (HGBCL) [NCT04002947]. All pts were >18yrs old, stage II-IV, with adequate organ function. Pts completing induction therapy with available EOT PET/CT scans and EOT plasma samples were studied. PET/CT scans were interpreted by 2 nuclear medicine (NM) radiologists blinded to clinical outcomes using the 5-point Deauville Score (DS) with DS4/5 considered positive. Tissue biopsies and unplanned PET scans after the EOT PET/CT scan to determine remission status were recorded. Measurable residual disease (MRD) in plasma cfDNA was evaluated by Phased Variant Enrichment & Detection Sequencing (PhasED-Seq) at Foresight Diagnostics blinded to clinical outcomes. Tumor derived Phased Variants (PVs) were identified from baseline pretreatment plasma samples or baseline tumor tissue, with matched constitutional DNA from paired PBMCs used to censor germline variants and CHIP. PVs were used to assess EOT MRD. Results were reported as MRD positive when ctDNA levels exceeded an analytical detection threshold (~1:10 6 cfDNA molecules) corresponding to 98% specificity. The prognostic utility of MRD was compared to standardized PET/CT scan at EOT to freedom-from-progression (FFP) and progression-free survival (PFS). Results : 55 enrolled pts completing planned therapy had EOT PET/CT and MRD analyzed. 54 (98%) pts were successfully genotyped and comprised the study population. Median age was 61 (range 26-85), including 22 (41%) female, 44 (81%) with advanced stage, and 26 (48%) with IPI score ³3. Pathologic subtypes included 24 (44%) GCB, 21 (39%) non-GCB, 8 (15%) HGBL-DH, and 1 (2%) THRLBCL. 43 (80%) pts received DA-EPOCH-R and 11 (20%) pts received R-CHOP. Twenty-six (48%) pts received acalabrutinib with R-chemotherapy. After 26 months median follow-up, the 2-year FFP and PFS of the cohort was 89% and 84%. Fourteen (26%) pts had a positive EOT PET/CT scan and 40 (74%) were negative. The concordance rate between the 2 NM radiologists on positive scans was 100%. Only 2 of 14 patients with a positive EOT PET/CT had clinical progression requiring salvage therapy (14% PPV). Nine (64%) of these pts required additional tests to determine remission status including 5 repeat PET/CT scans and 4 tissue biopsies. The 2-year PFS for pts with a positive vs negative EOT PET/CT was 66% vs 90% (p=0.08, Fig.A). Twelve (22%) pts had detectable EOT MRD and 42 (78%) were undetectable. 7 pts with detectable EOT MRD had clinical progression requiring salvage therapy or have died. While no pt with undetectable EOT MRD progressed, 1 (2%) died in remission of sudden cardiac death. Of 14 pts with positive EOT PET/CT, 7 (50%) had undetectable ctDNA and none progressed, suggesting MRD testing could have potentially rendered additional tests unnecessary. Conversely, patients with positive PET/CTs who progressed invariably had detectable ctDNA at EOT, suggesting utility of MRD for adjudicating PET/CT results. The 2-yr PFS for pts with detectable vs undetectable EOT MRD was 33% vs 98% (p<0.0001, Fig.B). At EOT, the PFS hazard ratio for MRD was 35.7, as compared with 3.1 for PET/CT. Conclusions : Response evaluations relying on PET/CT scans often require additional tests and procedures to assess remission status in aggressive B-cell lymphomas. Initiation of salvage therapy without adjudication in patients not achieving CR by EOT PET/CT scans will result in overtreatment. Given the higher specificity and PPV of EOT MRD, we propose an integrated response evaluation strategy combining these methods to reduce unnecessary additional tests and overtreatment.

Development and validation of CT‑based radiomics model of PET-negative residual CT masses: apotential biomarker forpredicting relapse‑free survival innon-Hodgkin lymphoma patients showing complete metabolic response.

PET-negative residual CT masses (PnRCMs) are usually dismissed as nonviable post-treatment lesions in non-Hodgkin lymphoma (NHL) patients showing complete metabolic response (CMR). We aimed to develop and validate computed tomography (CT)-based radiomics model of PET-negative residual CT mass (PnRCM) for predicting relapse-free survival (RFS) in NHL patients showing CMR. A total of 224 patients who showed CMR after completing first-line chemotherapy for PET-avid NHL were recruited for model development. Patients with PnRCM were selected in accordance with the Lugano classification. Three-dimensional segmentation was done by two readers. Radiomic scores (RS) were constructed using features extracted using the Least-absolute shrinkage and selection operator analysis among radiomics features of PnRCMs showing more than substantial interobserver agreement (> 0.6). Cox regression analysis was performed with clinical and radiologic features. The performance of the model was evaluated using area under the curve (AUC). For validation, 153 patients from an outside hospital were recruited and analyzed in the same way. In the model development cohort, 68 (30.4%) patients had PnRCM. Kaplan-Meier analysis showed that patients with PnRCM had significantly (p = 0.005) shorter RFS than those without PnRCM. In Kaplan-Meier analysis, the high RS group showed significantly (p = 0.038) shorter RFS than the low-scoring group. Multivariate Cox regression analysis showed that high IPI score [hazard ratio (HR) 2.46; p = 0.02], treatment without rituximab (HR 3.821; p = 0.019) were factors associated with shorter RFS. In estimating RFS, combined model in both development and validation cohort showed AUC values of 0.81. The combined model that incorporated both clinical parameters and CT-based RS showed good performance in predicting relapse in NHL patients with PnRCM.

Outcomes and Toxicities in Patients with Diffuse Large B-Cell Lymphoma of the Gastrointestinal Tract.

Diffuse large B-cell lymphoma (DLBCL) involving the gastrointestinal (GI) tract is rare and long-term outcomes are not well defined. Combined modality therapy (CMT) with radiotherapy (RT) in addition to systemic therapy in this setting is not commonly pursued. We aim to characterize outcomes in patients with GI DLBCL treated with systemic therapy, with or without RT. Patients diagnosed with DLBCL of the GI tract (with or without mesenteric involvement) treated at a single institution from 1988-2022 were retrospectively reviewed on an IRB-approved protocol. Clinical and treatment data were collected including adverse events (AE; acute vs late defined as before or 4 weeks after therapy end). Kaplan-Meier and Cox regression models were used to estimate survival. Of 207 patients, 62% were male and median age at diagnosis was 63 (IQR 52-73). Gastric involvement was most common (n = 130, 63%), followed by small intestines (n = 48, 23%) and colon/rectum (n = 24, 12%). Most presented with early-stage disease (n = 124, 60%), with a median IPI score of 1. All patients received chemotherapy. Of 182 treated with CHOP/EPOCH, 36 (20%) were treated in the pre-rituximab era while 146 (80%) received rituximab. 66 patients (32%) were treated with RT, 89% as part of first line CMT. 50 cases (76%) received consolidative RT, while 10 (15%) targeted residual gross disease and 4 (6%) targeted distant sites. Median dose and fractionation were 36Gy (IQR 30.6-39.6) in 18 fractions (IQR 17-22). Over half (n = 132, 64%) developed grade 3+ acute chemotherapy AEs, and the most common were anemia (n = 64), febrile neutropenia (n = 40), and neutropenia (n = 20). Grade 3+ late chemotherapy AEs occurred in 14 patients (7%). Acute grade 3+ radiation AEs were uncommon (n = 2, 3%; colitis, emesis). No grade 3+ late radiation AEs were noted. Median follow-up was 46 months (IQR 16-97). 169 (81.6%) had a complete response (CR), with 154 (91%) after first line chemotherapy, 9 (5%) after second line, and 6 (4%) after RT. CR was defined by PET (62%), endoscopy (22%), CT (9%), or other methods (7%). The 5-year progression-free survival for those treated with one line of chemotherapy with or without RT was 95%. Median overall survival (OS) was not reached. Improved OS was associated with early-stage disease (p = 0.003), low IPI (p = 0.001), fewer chemotherapy lines (p<0.001), and CR (p<0.001). OS did not differ by gender, age, immunophenotype, GI site, SUVmax, or RT. Patients with early stage DLBCL treated with RT in the post-rituximab era received fewer chemotherapy cycles compared to those treated without RT (p = 0.02; median of 4 (IQR 3-6) vs 6 cycles (IQR 4-6)), with no OS difference. GI DLBCL patients have favorable outcomes after CMT with minimal late toxicity. CMT with RT to the GI tract is well tolerated with no OS difference compared to chemotherapy alone, and may mitigate risks from additional chemotherapy cycles for selected early-stage patients.

Comparison of Ki67 Proliferation Index in Gastrointestinal Non-Hodgkin Large B-Cell Lymphomas: The Conventional Method of Evaluation or AI Evaluation?

The most common NHL subtype in SEEU is DLBCL (39%), and it manifests with a variety of cellular morphologies and a high proliferation index. Also, the GI tract is the most common site of extranodal NHLs, and most NHLs involving the GI tract are of B-cell lineage, of which diffuse large B-cell lymphoma is the most common subtype, irrespective of location. The last few years have seen digital pathology as a vital technology that has a positive impact on diagnostics, but studies on the use of DP for lymphoma identification, however, are still restricted to only determining whether a tumor is present or absent. Using the example of cases of malignant NHL, we aim to investigate the diagnostic utility of DP using QuPath software in evaluating the proliferation index and the prognostic significance and to show that improved visualization and analysis contribute to the convergence of these complementary diagnostic modalities for lymphomas. The average proliferation index (Ki67) was 58.33% with values between 10% and 85%. After the stratification of the cases, an increased proliferation index was observed in the majority of cases (53.33%), and this aspect was associated with the advanced age of the patients (p = 0.045). Visual assessment provides lower Ki67 values than automated digital image analysis. However, the agreement coefficient between the conventional method and the AI method indicates an excellent level of reliability (ICC1-0.970, ICC2-0.990). The multivariate analysis revealed that in the cases where the proliferation index Ki67 is high (˃70%), the IPI score represents an important risk factor predicting mortality (HR = 10.597, p = 0.033).

The association of Hypoxia-Inducible Factor-2α (HIF-2α) overexpression score with Germinal Center B-Cell Like (GCB) and Non-Germinal Center B-Cell Like (Non-GCB) subtypes of Diffuse Large B-cell Lymphoma (DLBCL)

Link of Video Abstract: https://www.youtube.com/watch?v=KF58IGGdWmc Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. It is classified into homogeneous subtypes, namely Germinal Center B-Cell Like (GCB) and Non-Germinal Center B-Cell Like (GCB), with the latter associated with worse survival outcomes. Increased expression of Hypoxia-Inducible Factor-2α (HIF-2α) is often observed in DLBCL and has been correlated with enhanced angiogenesis, suggesting its potential as a prognostic factor in managing DLBCL. The study evaluates the association between HIF-2α overexpression and the GCB and non-GCB subtypes of DLBCL. Methods: This cross-sectional study utilized samples from DLBCL patients at Dr. Kariadi Semarang Hospital between January and December 2021. Immunohistochemistry was performed on the samples to determine the DLBCL subtypes and assess the presence of HIF-2α. HIF-2α was evaluated by immunohistochemistry based on its distribution and intensity. The Kruskal-Wallis test was used to find the association between HIF-2α expression and the GCB and non-GCB subtypes of DLBCL. Furthermore, Spearman's rank correlation test explored the correlation between all numeric variables. Results: A total of 30 subjects were included in this study, with 7 samples of GCB subtype (23.3%) and 23 samples of non-GCB subtype (76.6%). Kruskal-Wallis test showed no association between HIF-2α expression and the subtypes of DLBCL (p=0.812). Spearman's rho correlation test indicated no correlation between HIF-2α overexpression score with NCCN IPI score in GCB (r=0.219; p=0.637) and non-GCB (r=-0.194; p=0.386). Conclusion: There was no association between HIF-2α expression and GCB and non-GCB subtypes of DLBCL. Additionally, no correlation was found between HIF-2α overexpression and NCCN IPI score.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: DLBCL patients treated with R-CHOP regimen have prolonged survival, but 20%–40% of patients survive less than 5 years. Autoantibodies (AAbs) have the advantages of easy specimen acquisition and dynamic real-time monitoring. Blood-based autoantibodies have stratified lymphoma patients outcomes in previous studies, such as anti-ALK autoantibody titers were found to predict anaplastic large B-cell lymphoma (ALCL) recurrence risk stratification. This study was designed to find prognostic AAbs biomarkers for early progression, PFS, and OS in DLBCL patients treated with R-CHOP by utilizing a proteomic test based on autoantibodies. Patients and methods: Plasma samples from 325 DLBCL patients and FFPE samples from 37 DLBCL patients with biopsy confirmation were retrospectively collected between 2006 and 2020. All patients were previously untreated and collected before first-line R-CHOP and had complete clinical data. Patients were divided into relapse and non-relapse groups based on EFS24. There were three cohorts in this study. In the discovery phase, 20 samples were conducted comprehensively high-throughput protein microarray (∼20 K proteins, HuProtTM). In the verification phase, 181 samples were conducted low-density focused array (200 proteins). And in the validation phase, 135 samples were conducted for ELISA detection. Besides, exploratory analyses revealed the expression difference of prognostic AAbs target proteins in DLBCL FFPE samples. Results: Global autoantibody profiling of DLBCL patients were observed. Four autoantibodies were significantly different in relapse and non-relapse patients (p < 0.05) and associated with superior survival outcomes (PFS and OS) both in the verification phase (n = 181) and validation phase (n = 135). Based on the AUC for EFS24, 2 AAbs were chosen for the riskscore model conduction. 2 AAbs signature riskscore model was predictive of PFS with AUC of 0.72, 0.76 and 0.82 at 1, 3 and 5 years independent of IPI score in validation phase. Combining with the IPI score, 2 AAbs signature riskscore identified a more poor prognosis group (5-year PFS rate: 17.86%) versus IPI score high group (33.3%), a mediate group(56.49%) versus IPI score high_inter/low_inter group (46.3% and 48.2%) and a more favorable group (89%) versus IPI score low group (85.78%). Furthermore, 2 AAbs target proteins were also higher in DLBCL patients with superior outcomes (p < 0.05). Conclusions: We have demonstrated the extensive profiling of autoantibodies in DLBCL patients, and identified a novel prognostic AAbs panel and it can also contribute to improving the prognostic stratification ability of IPI score. Keywords: autoantibody, biomarker, diffuse large b-cell lymphoma, protein microarray Encore Abstract - previously submitted to regional or national meetings (up to <1000 attendees), EBMT 2023, AACR 2023, ASCO 2023, EHA 2023 The research was funded by: China National Major Project for New Drug Innovation (2017ZX09304015, 2019ZX09201-002) Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, risk models No conflicts of interests pertinent to the abstract.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: High dose chemotherapy/autologous stem cell transplantation (ASCT) and CD19-directed chimeric antigen receptor-modified T cells (CART19) are potentially-curative treatment options for patients (pt) diagnosed with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBL). Analysis of a large series of pt receiving ASCT and/or CART19 has not been performed and may reveal differences in treatment failure (TF) which could inform efforts to optimize pt selection for these therapies. Methods: Included pt were age ≤75 years who received ASCT and/or CART19 for R/R DLBCL/HGBL at the University of Pennsylvania between 3/1/13 and 3/1/21. All ASCT pt demonstrated either partial or complete metabolic response to salvage immunochemotherapy (IC). Freedom from TF (FFTF) was defined as the interval between receipt of cell infusion and proven/suspected relapse of lymphoma (DLBCL/HGBL for ASCT pt or any lymphoma for CART19 pt) or last follow-up (f/u) in remission. Data were censored on 3/1/23. Results: Characteristics at the time of relapse preceding ASCT or CART19 are listed in the Table. Minimum prior LOT was 1 for ASCT and 2 for CART19 pt. With a median length of f/u of 62.7 months (mo) for ASCT pt and 37.6 mo for CART19 pt, the estimated (est) rate of FFTF at 36 mo were 59% and 24%, respectively. Cox regression analysis of characteristics predictive of TF at 36 mo revealed history of tIL (hazard ratio [HR] 0.23, P = 0.016) for ASCT pt, and history of tIL (HR 0.48, P = 0.004) as well as IPI score ≥3 (HR 2.7, P < 0.001) for CART19 pt. As depicted in the Figure, ASCT pt experienced significantly higher est rates of FFTF at 36 mo if achieving actual FFTF at 3 mo (64% vs. 38%, P = 0.002), 6 mo (76% vs. 52%, P = 0.02), 12 mo (84% vs. 62%, P = 0.03) and 24 mo (95% vs. 78%, P = 0.03) post-infusion as compared to CART19 pt. For characteristics which predict for TF at 36 mo (no history of tIL and IPI score ≥3), the incidence was either similar or significantly lower for CART19 versus ASCT pt who achieved actual FFTF at 3, 6, 12 and 24 mo. Keyword: Aggressive B-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. D. J. Landsburg Consultant or advisory role: Morphosys, Epizyme, Calithera, ADC Therapeutics, Karyopharm Research funding: Curis, Calithera, Epizyme Educational grants: Novartis S. D. Nasta Research funding: Pharmacyclics, Roche, Rafael, FortySeven J. Svoboda Consultant or advisory role: SEAGEN, Pharmacyclics, Incyte, Genmab, BMS, Atara, Astra Zeneca, Adaptive, ADCT Research funding: TG, SEAGEN, Pharmacyclics, Merck, Incyte, BMS, Astra Zeneca J. N. Gerson Consultant or advisory role: Genentech, Abbvie Research funding: Loxo S. J. Schuster Consultant or advisory role: Novartis, Regeneron, Nordic, Morphosys, MustangBio, Incyte, Genentech/Roche, Janssen, Legend Biotech, Loxo, Acerta, BiGene, Celgene, Nanovecter Research funding: Novartis, Pharmacyclics, Merck, DTRM, Juno Therapeutics, Abbvie, Adaptive Biotechnologies, Incyte, Genentech/Roche, Celgene, TG Therapeutics S. K. Barta Consultant or advisory role: Daiichi Sankyo, Kyowa Kirin, Janssen, Affimed Honoraria: Acrotech, Seagen, Kyowa Kirin E. A. Chong Honoraria: Juno/BMS, Novartis, Beigene, KITE, Tessa A. L. Garfall Consultant or advisory role: Jannsen, GlaxoSmithKline, Bristol-Myers Squibb Research funding: Novartis, Tmunity Therapeutics, Janssen, Crispr Therapeutics E. A. Stadtmauer Research funding: BMS, Celgene, Abbvie, Sorrento N. V. Frey Consultant or advisory role: Sana Biotechnology, Kite Pharma, Syndax Pharmaceuticals Research funding: Research Funding D. L. Porter Consultant or advisory role: Novartis, Kite/Gilead, Incyte, Janssen, Jazz, DeCart, BMS, Bluebird Bio, Angiocrine, Mirror Biologics, Capstan Therapeutics, Instill Bio Research funding: Novartis

Impact of neighborhood deprivation on disability free survival in patients with aggressive B cell non-Hodgkin lymphoma.

7564 Background: Advancements in treatment over the last decade have greatly improved survival in B cell non-Hodgkin’s lymphoma (NHL), yet not all patients (pts) benefit the same. Non-Hispanic Black (NHB), uninsured and lower socioeconomic status pts continue to suffer worse survival. However, the impact of neighborhood deprivation on disability has not been explored. We aimed to assess the association between neighborhood deprivation and disability free survival (DFS) in NHL pts. Methods: 258 aggressive NHL pts treated between 2005-2020 were included. Pts without documented follow up were excluded. Race/ethnicity was categorized as non-Hispanic white (NHW), Hispanic, NHB and other. Primary outcomes included progression free survival (PFS), overall survival (OS) and DFS. DFS was defined as time to needing any rehabilitative, home-health or skilled nursing services immediately following induction therapy, indicating disability and lack of functional independence. Neighborhood deprivation was assigned using the national Area Deprivation Index (ADI), a validated measure classifying neighborhood adversity. Pts were categorized into high (67-99), intermediate (34-66) or low (1-33) ADI scores, with least disadvantaged designated by lower scores. Kaplan-Meier analyses were used to compare PFS, OS and DFS. Results: Demographic data is shown in the table; 45% were female, 65% were NHW, 10% were NHB, 8% were Hispanic and 10% were other. Median age at diagnosis was 57 years. There was no difference in PFS or OS between racial/ethnic groups (p=0.91 and p=0.23 respectively). Payor source influenced both PFS and OS (p&lt;0.001 and p&lt;0.001 respectively), with self-pay associated with worse PFS and OS. Neighborhood deprivation based on ADI did not influence PFS (p=0.33) or OS (p=0.76). High ADI score was associated with worse DFS compared to lower ADI scores (p=0.03). ADI score differed significantly based on race/ethnicity (p&lt;0.0001), with more NHB pts residing in areas of high ADI scores (40% vs 5% NHW vs 10% Hispanic). There was no association between ADI score and a pt’s ECOG performance status, IPI score or albumin at diagnosis (p=0.87, p=0.78 and p=0.59 respectively). Conclusions: NHL pts with higher neighborhood adversity experience more disability after treatment despite similar survival. Further work is needed to better understand how neighborhood factors are contributing to disability before community-level strategies for improvement can be developed. [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Allogeneic stem cell transplantation (alloSCT) was the only curative option for younger patients (pts) with relapsed/ refractory (r/ r) LBCL (DLBCL, tFL, PMBCL). Anti-CD19 CAR T-cells (CART) entered the clinical arena around 5 years ago now being considered standard of care for such patients. As >50% of LBCL pts progress or relapse after CART treatment we were interested in identifying prognostic factors for both modalities and their relative role in the treatment of advanced r/r LBCL. Methods: Pts registered with the EBMT database from 1/2016 to 5/2021 having received either a first alloSCT or commercially available CART therapy (Yescarta® or Kymriah ®) as ≥3rd therapy of LBCL were analyzed. To correct for imbalances in patient characteristics we did propensity score analyses considering only pts with complete information on IPI including LDH at the time of cell therapy. We performed multivariate analyses in patients with either low- or high-risk r/r LBCL according to LDH level at cell therapy in pts treated with alloSCT or CART. Results: We identified 515 pts with full information on IPI at cell therapy (212 alloSCT and 303 CART). Patient groups differed significantly in median age, IPI score, and disease status at cell therapy. Median follow up was 46.3 months after alloSCT and 22.1 months after CART treatment. In univariate analysis, type of cell therapy, disease status, and IPI at cell therapy had a significant impact on OS. Amongst IPI risk factors LDH, performance status, and number of extranodal sites had a significant impact on OS, PFS an RI. At 24 months, OS was 41% after allo SCT and 49% after CART. In a propensity score analysis using all IPI factors as covariates, CART was superior to alloSCT in terms of OS (HR 0.62, 95% CI: 45–0.84, p = 0.0193) but not PFS, RI or NRM. In multivariate analysis patients with IPI (o-2) low risk at cell therapy show better OS (HR 0.81, 95% CI 0.59–1.1, p < 0.0001) and PFS (HR 0.62, CI: 0.46–0.83, p = 0.00145), comparable RI and lower NRM (HR 0.21 CI: 0.11–0.42, p = 0.00001) with CART compared to allo SCT. In IPI (3–5) high-risk patients, CART showed significantly higher RI (HR 1.45, CI: 1.03–2.04, p = 0.03549) but lower NRM (HR 0.21, CI: 0.11–0.42), p = 0.00001) compared to allo SCT. OS and PFS did not significantly differ. Refractory disease was an independent adverse prognostic factor for OS (HR 1.74, CI: 1.3–2.33, p = 0.0002), PFS (HR 1.61 CI: 1.23–2.1, p = 0.0006) and RI (HR 1.79 CI: 1.29–2.49, p = 0.0006) but not for NRM. Results at 2 years are given in Table 1. Conclusion: IPI assessed at cell therapy is of prognostic impact for both CART and allo SCT. Overall, pts given CART for ≥3rd line treatment of DLBCL showed better OS than pts treated with alloSCT. In patients with high intermediate/high IPI results of CART must be improved and allogeneic SCT remains a valuable treatment strategy due to its high anti-lymphoma activity. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. B. Glass Consultant or advisory role: Kite, BMS, Novartis, Milteneyi, Roche, Janssen, Jazz, Abbvie Honoraria: Kite, BMS, Novartis, Milteneyi, Roche, Janssen, Jazz, Abbvie Research funding: Roche, Riemser A. Sureda Consultant or advisory role: Takeda, MSD, BMS, Novartis, Janssen, Roche, Sanofi, Gilead P. Dreger Consultant or advisory role: Kite, Novartis P. Corradini Honoraria: Abbvie, Amgen, Celgene, Giled, Incyte, Janssen, Takeda, R. Ram Honoraria: Novartis, Gilead, Takeda, BMS G. Wulf Consultant or advisory role: Gilead, Novartis A. M. García-Sancho Consultant or advisory role: Roche, BMS, Kyowa Kirin, Clinigen, Eusa Pharma, Novartis, Kite Gilead, Servier, Incyte, Lilly, Takeda, ADC Therapeutics America, Miltenyi, Kern M. Stelljes Consultant or advisory role: Medac, Pfizer, Jazz, Novartis, MSD, Amgen, BMS, Kite D. Blaise Consultant or advisory role: Jazz E. Forcade Consultant or advisory role: Gilead, Jazz, Novartis, GSK, Sanofi, MSD I. Hilgendorf Consultant or advisory role: Novartis, Abbvie J. A. Perez-Simon Consultant or advisory role: Novartis, Janssen, Gilead, Jazz, Alexion, Abbvie, Pfizer W. Bethge Consultant or advisory role: Gilead, Novartis, Miltenyi, Janssen, Celgene N. Schmitz Consultant or advisory role: Allogene Stock ownership: BMS Honoraria: Allogene Research funding: Janssen, Roche Educational grants: Allogene, Milteneyi

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Richter's transformation (RT) is characterized by transformation of chronic lymphocytic leukemia to an aggressive lymphoma, most commonly CD20+ large B-cell lymphoma (LBCL). Prognosis for patients (pts) with RT is poor and no standard of care exists; there remains a major unmet medical need. Glofitamab is a T-cell engaging bispecific antibody (Ab) with a novel 2:1 (CD20:CD3) format. In a Phase I/II study (NCT03075696), fixed-duration glofitamab monotherapy demonstrated durable responses and a manageable safety profile in pts with relapsed/refractory LBCL (Dickinson et al. 2022). We report the efficacy and safety of glofitamab monotherapy in pts with RT after a median follow-up of 40.6 months (range: 0.3–53.9). Methods: All pts had RT and had received ≥1 prior regimen including ≥1 anti-(a) CD20 Ab. Pts received obinutuzumab pretreatment (1000 or 2000mg) 7 days before the first glofitamab dose and intravenous glofitamab at a fixed dose (0.6, 16, or 25mg) or with step-up dosing (SUD) in Cycle 1 (target dose 16 or 30mg) every 3 weeks for up to 12 cycles. Responses were assessed using Lugano 2014 criteria. Cytokine release syndrome (CRS) events were graded by ASTCT criteria. Results: As of 10 October 2022, 11 pts had received glofitamab at a fixed dose (0.6–25 mg, n = 5) or with SUD (2.5/10/16 mg, n = 3; 2.5/10/30 mg, n = 3). Median age was 71 years (range: 48–76); six pts were aged >70 years. Overall, 91.0% of pts had Ann Arbor stage III–IV disease and 45.5% had an IPI score ≥3. Median number of prior therapies was 3 (range: 1–4) and 54.6% of pts had ≥3 prior therapies. Most pts were refractory to a prior aCD20 Ab-containing regimen (90.9%) and all to their most recent regimen (100%); 54.5% of pts were refractory to their initial therapy. Investigator-assessed overall response rate and complete response (CR) rate were 63.6% and 45.5%, respectively. Median time to CR was 3 months (95% CI: 2.5–not estimable [NE]). Complete responses were durable and most (4/5; 80%) had been ongoing for ≥24.9 months at data cut (Figure). CRS occurred in 72.7% of pts, was primarily associated with the initial doses, and was mostly Grade (Gr) 1 (27.3%) or Gr 2 (27.3%); Gr 3 (9.1%, n = 1) or Gr 4 (9.1%, n = 1) events were uncommon. Glofitamab-related neurologic adverse events (AEs) potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 5 pts (Gr 3, n = 1 [syncope]; Gr 1, n = 4). No glofitamab-related Gr 5 (fatal) AEs or glofitamab-related AEs leading to discontinuation were reported. The research was funded by: NCT03075696 is sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing assistance, under the direction of all authors, was provided by Dikeledi Matlebjane, MSc of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd. Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract C. Carlo-Stella Employment or leadership position: Humanitas University Consultant or advisory role: Sanofi, ADC Therapeutics, Karyopharm Tx, Celgene/BMS, Roche, Merck Sharp & Dohme, Scenic Biotech, Novartis Honoraria: Celgene/BMS, Incyte, Roche, Janssen Oncology, Merck Sharp & Dohme, Astra-Zeneca, Gilead Research funding: Sanofi, ADC Therapeutics, Roche Other remuneration: Travel, accommodation, expenses - Takeda, Janssen Oncology M. Hutchings Consultant or advisory role: Takeda, Roche, Genmab, Janssen, Abbvie Research funding: Celgene, Genmab, Roche, Takeda, Novartis, Janssen, Merck, Abbvie, AstraZeneca E. Mulvihill Employment or leadership position: F. Hoffmann-La Roche Stock ownership: F. Hoffmann-La Roche Other remuneration: Travel, accommodation, expenses - F. Hoffmann-La Roche J. Relf Employment or leadership position: Roche Products Limited Stock ownership: Roche, F-Star Therapeutics and Harpoon Therapeutics B. Byrne Employment or leadership position: Roche Products Ltd, Welwyn Garden City, United Kingdom Stock ownership: Roche Products Ltd, Welwyn Garden City, United Kingdom L. Lundberg Employment or leadership position: F. Hoffmann-La Roche Stock ownership: F. Hoffmann-La Roche Other remuneration: Patent with F. Hoffmann-La Roche M. Dickinson Consultant or advisory role: Novartis, BMS, Gilead, Roche, Janssen, Abbvie, Genmab Honoraria: Roche, Amgen, MSD, Janssen, BMS, Novartis, Gilead, Abbvie Research funding: Novartis, Roche, Takeda, Celgene, MSD, Abbvie, Lilly Other remuneration: Travel, accommodation, expenses - Roche

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: Axi-cel was approved by NMPA to treat R/R LBCL adult patients who had received 2 or more prior treatments in 2021 June. For better understanding the efficacy and safety of commercial Axi-cel in Chinese R/R NHL patients in real world setting, we conducted this multi-center, non-interventional study (ChiCTR2100047990). The accrual goal is 200 patients, and the primary endpoint is median OS. Here we made an interim analysis and reported clinical outcomes of Chinese patients treated by commercial CAR-T products in real world for the first time. Methods: R/R NHL patients treated with commercial Axi-cel in 17 authorized treatment centers from 11/2021 to 02/2023 were included. All patients signed written informed consents. We reported best objective response rate (bORR), best complete response (bCR) rate and adverse events. Results: A total of 101 R/R NHL patients were efficacy-evaluable. The median age was 56.8 years old, and 25 (24.8%) patients were ≥65 years. Fifty-nine patients were male. Baseline characteristics, including 80 (79.2%) with DLBCL, 4 (4.0%) with PMBCL, and 6 (5.9%) with high grade B-cell lymphoma. Forty-two (44.2%) patients had IPI ≥3 and 18 (24.3%) patients ECOG PS were ≥2. The median prior lines of therapy was 2, including 36 (35.6%) patients got ≥3 previous treatments and 10 patients had history of ASCT. Eighty-four patients were resistant to previous therapy, and the primary refractory subgroup reached 47 (46.5%). Bridging therapy was given in 56 (55.4%) patients, while combination therapy in 29 (28.7%) patients. The median follow-up was 9.2 months. The bORR and bCR was 83.2% (95% CI, 74.4 to 89.9) and 58.4% (95% CI, 48.2 to 68.1) respectively (Figure 1A). Response rates were consistent across key covariates, including disease type, disease stage, IPI score, cell-of-origin subtype, etc. Patients ≥65 years had favorable ORR [92.0% (95% CI, 74.0–99.0)] and CR rate [80.0% (95% CI, 59.3–93.2)]. Median PFS was 12.0 months (95% CI, 7.3 to NA). The median DOR and OS were not reached. No new safety signal was observed in Chinese patients. The most common ≥ grade 3AE were white-cell count decreased (in 87.6% of the patients), neutropenia (in 82.9%), pyrexia (in 73.3%). Eighty-one patients experienced cytokine release syndrome (CRS) of any grade, and 16 (15.2%) patients occurred grade 3 or higher. Any grade of neurologic events (NE) occurred in 17 (16.2%) patients, and only 1 (1.0%) patients were grade 4. No grade 5 CRS or NE appeared (Figure 1B-C). Fifty-five percent received tocilizumab and 52% received glucocorticoids to manage CRS and/or NE. The median cumulative cortisone-equivalent corticosteroid dose was 2000 mg, which was similar to ZUMA-1 cohort6 and much smaller than ZUMA-1 cohort1+2. The research was funded by: The research was funded by Fosun Kite Biotechnology Co., Ltd., Shanghai, China. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies No conflicts of interests pertinent to the abstract.

CNS RELAPSE OF DIFFUSE LARGE B‐CELL LYMPHOMA AND ROLE OF UPFRONT PROPHYLAXIS: A 10‐YEAR SINGLE CENTER EXPERIENCE

Introduction: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare event, occurring in about 5% of patients (pts) and correlating with a very dismal prognosis. Much debate has surrounded the use of strategies to avert CNS disease recurrence. Nowadays, CNS prophylaxis is mostly based on high-dose intravenous (iv) methotrexate (HD-MTX), but its effectiveness is controversial. Our study focuses on pts with CNS relapse of DLBCL in order to evaluate their clinical and biological features, the validity of known prognostic scores, the efficacy of CNS prophylaxis, prognosis and treatment at the time of relapse. Methods: All pts with DLBCL diagnosed between January 2010 and December 2021 at AOU Città della Salute e della Scienza di Torino and treated with curative intent were selected: 498 cases with at least 12 months of follow-up were identified. Pts with primary mediastinal lymphoma, primary testicular lymphoma or CNS disease at diagnosis were excluded. Results: The case series included 406 pts. Mean age was 67 years, 56/400 had ECOG PS ≥ 2 (14%), 231/400 elevated LDH levels (58%), 251/404 were stage IV (62%), 192/374 IPI score ≥ 3 (51%), 189/373 CNS-IPI 2–3 (51%), 91/373 CNS-IPI 4–6 (24%). 95/397 pts received CNS prophylaxis (24%): 59 by intrathecal (IT) route only (15%) (n 26 CNS-IPI 2-3; n 29 CNS-IPI 4-6), 25 by iv MTX only (6%) (n 17 HD-MTX ≥3 g/mq; n 6 CNS-IPI 2-3; n 16 CNS-IPI 4-6), and 11 by combined route (3%) (n 5 CNS-IPI 2-3, n 6 CNS-IPI 3–6). 12 pts experienced CNS relapse; 8/12 exclusively CNS and 4/12 along with systemic recurrence. The cumulative incidence at 3 years was 2.8%. In univariate analysis CNS relapse risk was significantly influenced by ECOG PS and elevated LDH levels, while the use of prophylaxis was not shown to impact the risk of CNS recurrence. However, none of the pts who received systemic MTX prophylaxis had subsequent CNS disease, while 2/59 pts who received exclusive IT prophylaxis had CNS relapse with an incidence superimposable to the whole cohort (3.3%). In multivariate analysis, only ECOG PS confirmed significant correlation with the risk of such disease recurrence (Figure 1). With a mean follow-up of 36 months, the 3-year overall survival for pts with SNC recurrence was 30%. Encore Abstract—previously submitted to EHA 2023 Keyword: aggressive B-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.