Kahl, Brad S.

Introduction: PET/CT is the standard-of-care for staging and therapy response assessment in lymphoma. Fluorodeoxyglucose (FDG)-avidity in extranodal marginal zone lymphoma (EMZL) remains controversial with some variability by extranodal location. The current Lugano classification recommends the use of CT scans only in staging and follow-up for EMZL. However, emerging data from small studies have challenged this suggestion. In this study we aimed to determine the ability of PET/CT to detect FDG-avid EMZL during staging work-up. Methods: First, we retrospectively analyzed the University of Miami (UM) MZL database (period 2/2016-1/2023) searching for patients who underwent staging PET/CT. Images were reviewed by expert radiologists to ascertain avidity of tumor and not surrounding tissue, with specific attention to ocular and GI locations; if scans were not available (n=15), we retrieved data from reports (results presented in part at ICML2023). Next, we aimed to validate the initial UM results additionally analyzing data from imaging reports for patients prospectively enrolled in the Lymphoma Epidemiology of Outcomes (LEO) MZL cohort (period 7/2015-5/2020), excluding LEO patients from Miami to avoid overlap. Patients with high-grade transformation at diagnosis were excluded. For patients with >1 extranodal site, each location was counted independently. We considered FDG-avid disease if SUVmax was ≥2 as this value is commonly observed between mediastinal blood pool (BP) and liver background. To normalize data, we calculated ratios of lymphoma SUVmax versus both BP and liver background, as available. Patients without measurable disease were excluded from analysis. Results: Among 210 patients with EMZL in the UM cohort, 152 had staging PET/CT and were analyzed. Twenty-two patients demonstrated >1 extranodal site providing a total of 187 locations. The LEO cohort included 411 patients from 7 centers, with 235 having available imaging reports. Fifty-two patients in this cohort demonstrated >1 extranodal site providing a total of 306 locations. Disease distribution is depicted in Table 1. Among 187 EMZL locations in the UM cohort, the most common were gastric (n=33, 17.6%), ocular (n=31, 16.6%), lung (n=30, 16%), skin and soft tissue (n=16, 8.6%, each). Similarly, lung (n=63; 20.6%), soft tissue (n=46; 15%), gastric and ocular (n=34 each; 11%) were common locations in the LEO cohort. EMZL demonstrated FDG-avidity (SUVmax ≥2) across all locations with identical values in both cohorts (UM= 78.1% & LEO= 76.5%). FDG-avidity by location is shown in Table 1A & B with salivary gland (100% & 100%), lung (93.3% & 95.2%), soft tissue (93.8% & 100%), and airways (90.9% & 100%) demonstrating high avidity in both cohorts. Contrarily, skin was commonly non-FDG avid (93.8% & 81%). The median size of FDG-avid lesions was 2.4cm (range, 0.7-17.4) in UM and 2.9cm (range, 0.1-12) in LEO cohorts. In patients with >1 extranodal site FDG-avidity was nearly universal across sites (UM=93% & LEO=100%). We observed a significant correlation between lymphoma size and FDG-avidity for UM (r=0.33; P=0.001), and for LEO (r=0.55; P<0.0001). In patients with background FDG-avidity data in the UM cohort (n=150), a BP index and liver index ≥1 detected lymphoma in 79.3% & 71.5% cases, respectively. We were unable to calculate indexes in LEO cohort since only limited data on BP (n=26) and liver (n=19) background was available in imaging reports. Conclusions: This study represents the largest analysis evaluating accuracy of PET/CT to determine initial tumor burden in 387 patients with EMZL. We demonstrate that EMZL is largely an FDG-avid disease across two cohorts, and PET/CT should be included in the staging of these patients while acknowledging possible limited sensitivity in GI locations due to physiologic uptake. Furthermore, we observed that patients with multiple extranodal locations demonstrate uniform FDG-avidity across all sites except for skin involvement. Based on our results we recommend the incorporation of PET/CT into standard staging of EMZL in planned revised Lugano classification guidelines. In those demonstrating initial FDG-avidity, a lower SUVmax threshold of SUVmax ≥2, comparison to mediastinal BP rather than to liver background activity and evaluating for resolution of focal FDG-avidity should be considered to assess treatment response in routine care and clinical trials.

Background: Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell lymphomas that share pathologic features but differ in clinical presentation, outcome, and molecular features. The World Health Organization (WHO) and International Consensus Classification (ICC) classify ALCLs by presence or absence of ALK rearrangements (R) and clinical presentation (systemic, cutaneous [c], or breast implant-associated [BIA]). ICC, but not WHO, recognizes DUSP22-R as defining a new genetic subtype of ALK- ALCL. The classifications otherwise do not reflect additional molecular heterogeneity in genetics (e.g., TP63-R) or therapeutic vulnerabilities (e.g., JAK-STAT3 pathway activation). Methods: ALCLs (N=689) underwent expert consensus review (WHO/ICC) through the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). All cases also underwent genetic subtyping (ALK, DUSP22, TP63, and triple-negative [TN]) using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), as well as IHC for phospho-STAT3 Tyr705 (pSTAT3). RNAseq was performed and evaluable in 393 cases; the remaining cases had insufficient tissue, tumor content, RNA yield or quality, and/or sequencing data quality. Sequenced and non-sequenced sub-cohorts had similar demographics and subtype distribution. Results: Unsupervised gene expression profiling (GEP) identified 2 main molecular types of ALCL. Type I ALCLs predominantly included ALK+ ALCLs, BIA-ALCLs, and a subset of TN ALCLs (designated TN-I), whereas Type II ALCLs predominantly included ALCLs with DUSP22-R, TP63-R, or both (double-hit; DH), and the remaining TN ALCLs (TN-II). Type I ALCLs were strongly associated with pSTAT3 expression (74.2±26.4% positive malignant cells vs 9.9±22.7% for Type II; P<0.0001). An independently derived pSTAT3 staining threshold of 30% assigned Type I vs II with 91% accuracy. A third cluster of ALCLs, mostly cALCL, showed an epithelial GEP signature rather than a lymphoma signature; these cases were assigned to Types I or II based on pSTAT3 IHC. Distinct sub-signatures were identified for ALK+, DUSP22-R, TP63-R, and BIA ALCL (Fig. 1), but not ALK- ALCL or cALCL. Gene set enrichment analysis showed Type I ALCLs to be enriched for JAK-STAT3 signaling genes (normalized enrichment score [NES], 2.22; FDR<0.0001) and related pathways, such as TNFα-NFκB signaling (NES, 2.21; FDR<0.0001). In contrast, Type II ALCLs were enriched for cell cycle, DNA repair, epigenetic, and metabolic pathway genes, but not for major tyrosine kinase-mediated signaling pathway genes. Enriched epigenetic pathways included chromatin modifying enzymes (NES, -1.86; FDR=0.002) and histone methylation (NES, -1.71; FDR=0.002). EZH2 was the most overexpressed gene in Type II ALCLs (fold-change, 7.74; FDR=8.84×10 -306). At the protein level, EZH2 IHC H-scores were 275±45 in Type II and 168±70 in Type I ALCLs (P<0.0001); H3K27me3 H-scores were 170±81 and 76±63, respectively (P<0.001). The top metabolic gene set involved cholesterol biosynthesis (NES, -1.88; FDR=0.002). Overall survival (OS) data were available in 257 systemic ALCL patients (145 sequenced and 112 non-sequenced; cALCL and BIA-ALCL were excluded). Non-sequenced TN ALCLs were assigned to TN-I or TN-II using pSTAT3 IHC. The results supported earlier data indicating favorable prognosis of DUSP22-R ALCL (5 y OS, 95%) and ALK+ ALCL (87%), intermediate prognosis of TN ALCL (TN-I, 52% and TN-II, 38%; P=NS), and poor prognosis of TP63-R/DH ALCL (0%)(P<0.0001; Fig. 2). Conclusions: Two overarching molecular types of ALCL exist, predominantly associated with the presence (Type I) or absence (Type II) of the JAK-STAT3 signaling program. Distinct GEP signatures exist for ALK+ ALCL and BIA-ALCL (predominantly Type I), and DUSP22-R ALCL and TP63-R ALCL (predominantly Type II). TN ALCLs lacking ALK-R, DUSP22-R, and TP63-R can be stratified into TN-I and TN-II subtypes. pSTAT3 IHC has >90% accuracy as a surrogate for GEP-based subtyping. ALK- ALCL and cALCL cluster by molecular subtype rather than by defining GEP signatures. Type II ALCLs are enriched for targetable epigenetic and metabolic pathways, including EZH2/histone methylation and cholesterol biosynthesis. This molecular classification is diagnostically, prognostically, and potentially therapeutically relevant, and can be applied using FISH and IHC in routine practice and in the clinical trial setting.

Background: QOL can be affected by disease burden, side effects of treatment, and psychosocial effects of living with cancer. Although MZL is considered incurable, we previously found that patients diagnosed from 2002-2015 had a good QOL both at baseline (BL) and the first decade after diagnosis, regardless of treatment choice (Bommier et al., submitted). Here, we evaluate whether these findings can be extended to the 2015-2020 treatment era and a more diverse US cohort. Methods: Adults with newly diagnosed MZL from 8 academic centers were prospectively enrolled within 6 months of diagnosis from 2015-2020 in the LEO cohort (NCT02736357). Participants were actively followed for disease progression/relapse, retreatment and death. QOL was measured at BL, and at 1, 2, 3 and 5 years after diagnosis using the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) scale (range 0-164), which consists of the FACT-General (FACT-G, range 0-104) plus a lymphoma-specific scale (range 0-60). Total FACT-G measures 4 QOL domains (range): physical (0-28), social/family (0-28), emotional (0-24), and functional (0-28) well-being (WB). We also used the Trial Outcome Index (TOI; range 0-112), which consists of FACT-G physical and functional WB plus the lymphoma-specific scale and is commonly used as an endpoint in treatment trials. All MZL patients with both BL and at least one follow-up QOL questionnaire were eligible for analysis. Patients were grouped by initial management: active surveillance (observation), local/antibiotic therapy (radiation, surgery, or anti- H. pylori therapy), or systemic therapy (chemotherapy, targeted agents, or antibody therapy). Change in QOL scores over time was analyzed using mixed models for repeated measurements, and initial treatment groups were compared. Results: Of 384 patients, 60% were female, 91% were White, 6.6% were Black/African American, and 13% were Hispanic (all races). The median age was 64 years (range 19-94). For initial management, 28% (N=106) were observed, 31% (N=118) received local/antibiotic therapy, and 42% (N=160) received systemic therapy. Across treatment groups, there were no significant differences by age, gender, race, or performance status, while there were differences by Hispanic ethnicity (p=0.006), Ann Arbor stage (p<0.001) and MALT-IPI score (p<0.001) (Table). At BL, patients receiving systemic therapy had lower physical WB (p=0.008), emotional WB (p=0.04), functional WB (p=0.03), FACT-G total score (p=0.008), lymphoma subscale (p<0.001), FACT-Lym (p=0.001) and TOI (p<0.001) compared to observation and local/antibiotic therapy (Table). While FACT-G total scores were largely stable through 5 years after diagnosis, social/family WB declined from BL for patients initially receiving either local/antibiotic therapy (mean at 1-year -1.4, p<0.05; 2-year -2.1, p<0.05; 3-year -1.6, p<0.05; 5-year-2.9, p<0.05) or systemic therapy (mean at 2-year -1.2 , p<0.05; 3-year -1.4, p<0.05; and 5-year -1.2, p<0.05), while this was stable for observed patients. In patients receiving initial systemic therapy, there was a transient improvement in the lymphoma-specific scale (mean +1.7, p<0.05) and TOI (mean +3.7, p<0.05). Otherwise, QOL remained stable over time and global QoL (FACT-G, FACT-Lym), TOI, Lymphoma-specific scale (Figure), and the other FACT-G subscales (physical, emotional, or functional WB) did not differ by initial treatment strategy. Conclusions: In the diverse LEO cohort from the recent treatment era, we confirm our prior findings for newly diagnosed MZL patients that QOL is globally stable over the first 5 years after diagnosis; emotional WB is not associated with initial treatment type, providing evidence that being initially observed does not negatively impact emotional health; and there is a decline in social/family WB (support from friends and family, family acceptance of illness, family communication, close to partner), which supports the need to consider interventions for patients to address these unmet needs. In addition, this study extends these findings to the lymphoma-specific scale, FACT-Lym, and TOI, which all showing largely stable trends in the 5 years after diagnosis and suggest that recent MZL treatment strategies, including systemic therapies, neither impair nor improve QOL.

Background Peripheral T-cell lymphomas (PTCLs) comprise a rare, heterogeneous group of non-Hodgkin lymphomas of mature T-cell origin. Most systemic (s) PTCL subtypes typically have poor outcomes with conventional anthracycline-based chemotherapy. Biomarker-driven and subtype-specific treatments are promising but unmet needs. Few benchmark studies exist to characterize the current real-world landscape of clinical and pathologic practice. We report the patterns of care and updated outcome data for PTCL patients enrolled in the LEO-MER multi-center prospective cohort study (ClinicalTrials.gov NCT02736357). Methods Patients aged 18 years or older with newly diagnosed PTCL were prospectively enrolled in the University of Iowa/Mayo Clinic MER cohort (2002-2015) or the expanded LEO cohort (2015-2020). Clinical, pathology, treatment, and outcome data were abstracted from medical records using a standard protocol in both cohorts. Pathology underwent expert re-review based on WHO criteria. Overall survival (OS) was calculated from date of diagnosis to date of death or last follow-up. Event-free survival (EFS) was calculated from date of diagnosis to disease progression, initiation of 2 nd line therapy, or death from any cause. EFS and OS were evaluated using Cox model and Kaplan-Meier estimator. Log-rank test was used to test the significance of difference between groups. Results LEO-MER enrolled 1132 PTCL patients during the study period (462 MER and 670 LEO). Of these, 722 were sPTCLs (281 MER and 441 LEO), including PTCL-NOS (N=253, 35%), anaplastic large cell lymphoma (ALCL; N=180, 24.9% [74 ALK+, 106 ALK-]), angioimmunoblastic T-cell lymphoma (AITL, N=164, 22.7%), extranodal NK-TCL (N=50, 6.9%), adult T-cell leukemia/lymphoma (N=33, 4.6%), enteropathy-associated TCL (N=19, 2.6%), and hepatosplenic TCL (N=13, 1.8%) ( Table 1). Median age at diagnosis was 60 years. M:F ratio was 1.5. Comparing LEO to MER, African American population was 15.4% vs 0.7%, and Hispanic was 10% vs 2.2%. Clinical characteristics were comparable between MER and LEO overall: PS≥2, 20.9%; elevated LDH, 50.7%; stage III-IV, 67.6%; and IPI 2-5, 65.7%. The most common 1 st line chemotherapy regimens overall were CHOP-based (N=506, 70%), including 60% receiving CHOP-like chemotherapy in both MER and LEO cohorts (CHOP [N=268, 37%], CHOEP [N=91, 13%] or EPOCH [N=75, 10%]), and 16% with CHOP-like in combination with novel agents in LEO cohort (BV+ [N=41, 9.3%], azacitidine+ [N=11, 2.5%], pralatrexate+ [N=10, 2.3%], lenalidomide+ [N=8, 1.9%]) ( Table 1). More patients received etoposide in LEO (40.3%) than in MER (20.3%). 74 patients (10.3%) underwent consolidative SCT following induction chemotherapy (71 auto and 3 allo). 65 patients (11.2%) received frontline therapy on clinical trials. At a median follow-up of 9.4 years in MER and 4 years in LEO, 177 (MER) and 269 (LEO) events, and 150 (MER) and 206 (LEO) deaths were observed, respectively. The 3-year EFS and 4-year OS estimates for sPTCL were 46.3% and 59.1% in MER, and 40.4% and 51.3% in LEO. EFS and OS correlated with IPI scores and differed by sPTCL subtypes ( Figure 1). ALCL had superior survival, with 3-year EFS and 4-year OS of 78.2% and 90.5% for ALK+, and 65.9% and 76.9% for ALK-. Non-ALCL subtypes including PTCL-NOS and AITL had inferior outcomes, with 3-year EFS and 4-year OS of 31.4% and 42.8% for PTCL-NOS, and 33.4% and 50.7% for AITL. In subset analysis, the addition of etoposide to CHOP chemotherapy as either CHOEP or EPOCH was associated with improved OS for ALK- ALCL (p=0.038, log-rank), but not for ALK+ ALCL (p=0.75) or non-ALCL subtypes of PTCL-NOS and AITL (p=0.88). Conclusion The LEO-MER study is the largest prospective cohort study of PTCL to date. Patterns of care in the LEO cohort begin to incorporate novel agents in frontline therapy. Outcomes continue to mature with longitudinal follow-up and ongoing accrual, which poise to shape benchmarks in the contemporary era. The lack of benefit of etoposide adding to CHOP induction and poor overall survival of non-ALCL subtypes underscores the unmet need of therapeutic breakthrough for non-ALCL frontline treatment, particularly through clinical trials with biomarker-guided approaches incorporating novel agents.

Background: Recently, large B-cell lymphomas (LBCLs) have undergone major shifts in classification and treatment paradigm, particularly with the advent of CD19-targeted chimeric antigen receptor T cell therapy (CAR-T). Initially approved as third-line treatment in LBCL in 2017, as of early 2022 CAR-T is indicated for second-line therapy (2L) in patients with relapsed or refractory (R/R) disease within 12 months of frontline treatment or who are not candidates for autologous stem cell transplant (ASCT). Given this quickly changing landscape, we aimed to describe disease characteristics, patterns of care, and survival outcomes in patients with R/R LBCL receiving two or more lines of systemic therapy across modern treatment eras. Methods: We developed a database of patients with R/R LBCL from 8 U.S. academic centers in the Lymphoma Epidemiology of Outcomes (LEO) Cohort study (NCT02736357) and Consortium for Real World Evidence (CReWE). Unlike the SCHOLAR-1 dataset (M Crump et al, Blood 2017), our cohort included any patient receiving 2L, regardless of timing of progression/relapse. For this analysis, eligible patients were aged ≥18 years and received 2L between 2002-2022. Patients with histologic transformation, post-transplant lymphoproliferative disorder, primary CNS lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma, or plasmablastic lymphoma were excluded. Prognostic factors, therapy details (including intent for ASCT and/or CAR-T), and outcomes, including treatment response, event-free survival (EFS), and overall survival (OS), were abstracted for all lines of therapy. Treatment eras were defined as pre-CAR-T (2002-2010), CAR-T available via clinical trial (2011-2017), and post-FDA approval of CAR-T (2018-2022). Results: Of 1760 patients initiating 2L for R/R disease, 1523 were eligible for analysis. Median age at start of 2L was 62 (interquartile range [IQR] 53-70), and 65% were male; 11% were non-White, and 8% were Hispanic. High-grade subtypes comprised 16% of all cases. IPI was available for 1013 patients at time of 2L therapy, with 54% having IPI 3-5. Median time from diagnosis to 2L was 8.7 months (IQR 5.6-18.5), with 834 patients not having achieved complete response (CR) to 1L, 285 patients relapsing <12 months after 1L, and 404 patients relapsing ≥12 months after 1L. The median number of total lines of therapy received was 4 (range 2-18), with 586 and 347 receiving ASCT and CAR-T, respectively, at any line of treatment. At a median follow-up of 48 months from the start of 2L, 926 patients (61%) had died. Progressive lymphoma was the primary cause of death in 75% of deceased patients, with 8% of reported deaths due to therapy. 2L was received at an academic medical center in 83% cases, and 209 patients (14%) received 2L on a clinical trial. ASCT and/or CAR-T was planned at 2L for 989 patients (65%), of whom 463 ultimately received ASCT, 88 received CAR-T, and 21 received allogeneic transplant at 2L. 494 patients were not considered for ASCT or CAR-T at 2L, and 40 were unknown for ASCT/CAR-T intent. Breakdown by treatment era (n = 1518 with available treatment start date) is shown in the Table. Median EFS from start of 2L was 4.2 months (95% confidence interval [CI]: 3.8-4.8). Median OS from start of 2L was 18 months (95% CI: 17-22), and 2- and 5-year OS estimates were 46% (95% CI: 44-49%) and 35% (95% CI: 33-38%), respectively. EFS and OS improved significantly for patients initiating 2L between 2011-2017 compared to 2002-2010. However, EFS and OS in the 2018-2022 era remained similar to 2011-2017 (Figure). Conclusions: To our knowledge, this study is the first-ever large-scale attempt to describe patterns of care and outcomes in LBCL 2L in the modern era, inclusive of all treatment approaches. The rich and unique LEO CReWE dataset captures evolving practice approaches over time in terms of both intent for and receipt of cellular therapies. Likely reflecting the rapid development of many novel immune effector cell products and bispecific antibodies, we observed increased enrollment on 2L clinical trials in the 2018-2022 period, including a substantial proportion of patients receiving CAR-T in 2L. Importantly, survival increased in treatment eras during which CAR-T was available. Ongoing analyses of factors associated with improved survival will be presented at the meeting.

Introduction: DH/THL also classified as high-grade B cell lymphomas (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements have higher risk of progression after initial treatment and poor response to salvage therapies compared to diffuse large B cell lymphoma (DLBCL), NOS. Recently, CART cell therapy has shown encouraging responses in treatment of relapsed refractory (R/R) DLBCL. In this retrospective study, we evaluated whether survival of (R/R) DH/THL is improved in the CART era. Methods: In this multicenter retrospective study, adult pts (pts) with R/R DH/THL after anthracycline-based therapy were included. Demographic and clinical variables were obtained from electronic health records. Study objectives was overall survival (OS) at 2 year landmark. We utilized full propensity score matching to compare progression free survival (PFS) and OS of CART with 2 nd line chemoimmunotherapy. Results: 278 DH/THL pts treated between 2010-2020 were included. Median age was 63 years (range 52-74), 163 (58%) were male, 119 (43%) were classified as DLBCL and 116 (42%) as HGBCL; 40 (14%) were transformed from follicular lymphoma. 225 (82%) had advanced stage, 161 (67%) had elevated LDH, 85 (33%) had bulky disease, 74 (59%) had B symptoms. 105 (38%) pts treated for relapsed disease before 2018 were included in the pre-CART era cohort. 168 (60%) pts treated from 2018 onwards were included in the CART era cohort. 102 (60%) pts in CART cell era received CART cells, 40 (14%) received polatuzumab vedotin (pola), 10 (3.5%) received loncastuximab tesirine, tafasitamab and bispecific antibody each. Characteristics at relapse were similar in both groups. Median follow up was 8.9 (0.2-146) months. 2-year OS estimate was 36% (CI 95: 30-42%) in entire population. Patients treated in CART cell era had significantly higher OS (2 yr OS: 43% [CI 95: 35-53]) compared to pts treated in pre-CART cells era (2-year OS: 24% [CI 95: 16-34], p=0.0006) (Figure 1). In multivariable analyses, increasing age (HR = 1.02 (CI 95: 1.01, 1.04), p=0.003), extranodal disease (HR = 1.41 (CI 95: 1.00, 1.99), p<0.001), elevated LDH (HR = 1.57 (CI 95: 1.11, 2.24), p=0.01) were associated with inferior OS. Increasing time to relapse (HR = 0.98 (CI 95: 0.97, 0.99), p<0.001) was associated with superior OS. BCL6 rearrangement did not affect OS. When adjusted for these factors, treatment with CART cells was associated with higher 2 yr OS (HR = 0.33 (CI 95: 0.22, 0.49), p<0.001). Treatment with polatuzumab (HR = 1.07 (CI 95: 0.71, 1.6), p=0.07) was not significantly associated with OS in univariable analysis. 102 pts underwent CART cell therapy at any point for relapse; 94 (93%) were refractory to prior chemotherapy. 62 (60%) responded and 52 (50%) had CR after CART cells. 2-year PFS and OS after CART cell therapy were 28% (CI 95: 19-40) and 40% (CI 95: 30-53), respectively. Increasing time to CART was associated with inferior OS (HR: 1.02 (CI 95: 1.0-1.03, p=0.03) but not PFS (HR: 1.02 (CI 95: 0.99-1.04), p=0.2). 219 (79%) pts received curative intent salvage chemotherapy for 2 nd line. 2-year PFS and OS were 15% (CI 95: 11-20) and 38% (CI 95: 31-45), respectively. 21 pts received CART cell therapy for 2 nd line. 2 year PFS and OS in this small number of pts were 52% (CI 95: 35-79) and 70% (CI 95: 52-94), respectively. Due in part to the small number of pts who received CART cells in 2 nd line, we utilized full propensity score matched analysis to compare each patient in CART cell group to all possible matched controls in salvage chemotherapy group. Variables matched were age, LDH, extra nodal disease and time to relapse. In propensity score matched analysis, pts who received CART cells had significantly higher 2 year PFS (HR: 10.5 (CI 95: 3.4-17.5), p=002) and 2 year OS (HR: 7.5 (CI 95: 1.4-13), p=0.01). Conclusions: Survival of r/r DH/THL appears to have improved in the era of CART cell therapy. About 2/3 of pts refractory to chemotherapy respond to CART cells, and in multivariable analysis, receipt of CART cells was associated with improved OS. Increasing time to CART cells was associated with inferior survival. In a propensity score matched analysis utilizing full matching, CART cell therapy in 2 nd line was associated with significantly higher 2 year PFS and OS compared to curative intent salvage therapy. Other CD 19 and CD 20 targeting agents approved after CART cell therapy might contribute to favorable survival, effect of these agents could not be assessed because of small numbers.

Background: We previously reported thatearly events in follicular lymphoma (FL), defined as progression of disease within 24 months (POD24) or early transformation to a more aggressive histology, are significantly associated with increased risk of lymphoma related death. To refine clinical management, the FLIPI24 prognostic model was developed to predict the risk of early events after starting immunochemotherapy (IC) (Maurer et al, 2022). The FLIPI24 model was found to be significantly superior to standard clinical models for prediction of both event-free survival at 24 months (EFS24) and overall survival (OS) in internal and external validation sets of patients receiving IC. We sought to evaluate the prognostic ability of the FLIPI24 model in patients with FL not receiving IC. Methods: The cohort consists of prospectively enrolled patients in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and the multicenter Lymphoma Epidemiology of Outcomes (LEO) Cohorts. Data were collected from medical records by standard protocol with all events verified by medical record review. Eligible patients were those diagnosed with grades 1-3A FL and initiated observation, rituximab monotherapy, radiation, or other non-IC therapy. The FLIPI24 model utilizes 5 continuous variables: age (linear 60-90 years with inflection at age 75), HGB (linear 8-17 g/dL), WBC (linear 4-11x10 9/L), LDH/ULN (linear 0.5-5), and B2M (linear 1-10 mg/L). FLIPI24 risk is grouped as follows: low risk (≤10%], low-average risk (10-15%], average risk (15-20%], high risk (20-40%], very high risk (>40%) for an early event. EFS was defined as time from diagnosis to progression, relapse, (re)treatment, histologic transformation, or death due to any cause. OS was defined as the time from diagnosis until death from any cause. Cox models and Kaplan Meier curves were used to evaluate association between FLIPI24 and EFS or OS. Results: 1542 patients initiating non-IC management approaches at diagnosis from 2002-2020 were identified. 51% were >60 years (IQR 52-70), and 49% were male. Most patients (86%) had FL grade 1-2. 61% of patients met any criteria for high tumor burden per GELF, BLNI, or GITMO based on available variables. Treatment approaches were 833 observation (54%), 315 rituximab monotherapy (20%), 186 radiation (12%), and 208 other non-IC approaches (14%). At median follow-up of 58 months, EFS24 was 73.8% (95% CI: 71.6%, 76.1%), 5-year OS was 90.9% (95% CI: 89.3%, 92.5%) and 253 (16%) patients died. The FLIPI24 score identified poor outcomes among patients with high/very high-risk score (FLIPI24 >20%), with median EFS of 1.8 years (95% CI, 1.3, 3.28) and 5 year OS of 65.1% (95% CI: 55.9-75.8) (Figure 1). When evaluating patient subsets, for patients with high tumor burden (defined based on available variables) and high/very high-risk score, median EFS was 1.6 years and 5 year OS was 64.6% (95% CI: 54.9%-76.1%). Among patients with low tumor burden FL and high/very high-risk score, median EFS was 2.0 years (95% CI: 0.84-NA) and 5 year OS was 66.2% (95% CI: 42.4%-100%). Patients undergoing observation with high/very high-risk score similarly had shortened median EFS of 1.53 years (95% CI: 1.25-NA) and 5 year OS of 68.9% (95% CI: 56.4%-84.1%). The FLIPI24 had superior concordance for OS (c=0.726) compared to the FLIPI (c=0.646) when evaluated in patients not treated with IC. Results were comparable in the subsets of patients observed (c=0.706 vs 0.596) and receiving rituximab monotherapy (c=0.764 vs 0.721). Conclusion: The FLIPI24 model has been previously validated to provide an individual risk score at diagnosis for the likelihood of experiencing an event within 24 months from starting IC. Here we demonstrate that a high FLIPI24 score predicts for poorer outcomes following non-IC strategies including observation, treatment with radiation, and rituximab monotherapy. The FLIPI24 has better prognostic performance for OS than FLIPI in this non-IC population. High FLIPI24 in patients not treated with IC identifies a patient population who should be considered for IC and/or novel frontline therapies when feasible.

Introduction Survival rates for people with mantle cell lymphoma (MCL) have improved in recent years. Among the potential factors accounting for this improvement is the approval of multiple new therapies over the past two decades, including bortezomib, bendamustine, ibrutinib, lenalidomide, acalabrutinib, and zanubrutinib. We hypothesized that the availability of multiple agents with non-overlapping mechanisms of action would result in significant improvements in overall survival following first-line therapy. Methods Patients diagnosed with MCL between 2002 and 2017 were identified using the SEER-Medicare linked database. Selected patients were >65 years of age at the time of diagnosis with MCL. Lines of therapy were determined using billing codes, with inpatient/outpatient claims used for traditional agents and Medicare Part D dataset used for oral agents. Next lines of therapy were defined based on claims for new anticancer agents separated from the end of the prior line by some certain number of days. Sensitivity analyses were performed varying the number of days between therapies. Overall survival (OS) was defined as initiation of initial therapy to death, while OS2 was defined as time from initiation of second-line therapy to death. Time to next therapy 1 (TTNT1) was defined as time from start of first-line therapy to death or start of second-line therapy, whichever came first. Cox models and Kaplan-Meier (KM) survival curves were generated for time-to-event analyses. Analyses were stratified by categories of years of first- and second-line therapies corresponding to eras of key drug approvals (e.g., 2002-2005, 2006-2009, 2010-2013, >2013). Results In total, 4,832 patients were included, among whom 3,840 patients (79.5%) had claims for first-line regimens and 1,648 (34.1% of total and 42.9% of patients with first-line regimens) had second-line regimens. Of the 4,832 patients, the majority were male (67.4%), White (94.6%), and non-Hispanic (94.7%), with good performance status (74.8%) and a Charlson Comorbidity Index <2 (64.8%). The median age at diagnosis was 75 (IQR 70-81). Patients with first- and/or second-line regimens did not differ significantly from the entire population of 4,832 patients with MCL in terms of baseline characteristics. In the first-line setting, use of bendamustine-rituximab (BR) increased from 2.3% of patients treated in 2006-2009 to 49.5% in 2014-2017. Similarly, use of single-agent BTK-inhibitors (BTKi) increased from nonexistent in patients treated in 2010-2013 to 13.8% in 2014-2017. In the second-line setting, use of single-agent BTKi similarly increased from 2.6% of those treated in 2010-2013 to 44.9% in 2014-2017. Median OS for the 3,840 patients with fist-line regimens was 4.4 years (95% CI, 4.1-4.5); median OS for those receiving first-line therapy in 2002-2005 was 3.5 years (3.1-3.9), compared to 3.7 (3.4-4.0), 4.5 (4.2-5.0), and not reached (4.8-NR) among those treated in 2006-2009, 2010-2013, and 2014-2017, respectively. Patients treated in 2014-2017 had significantly improved OS compared with those in 2002-2005 (log rank p<0.0001). Median TTNT1 overall was 2.5 years (2.4-2.6); median TTNT1 was 3.2 years (2.9-3.5) vs 2.3 years (2.1-2.6) for patients who received first-line therapy in 2014-2017 compared to 2002-2005 (log rank p<0.0001) ( Figure A). In addition, there was a significant difference across KM curves for OS2 stratified by categories of years of second-line therapy, with median OS2 of 2.5 (2.0-3.2) in patients treated in 2014-2017 compared to median OS2 of 2.1 (1.7-2.5) in 2010-2013 ( Figure B). Discussion In this analysis, we observed improvements survival of MCL patients over time, along with similar improvements in outcomes following first-line therapy, which may correlate with increased BR and BTKi use as first-line agents. Unexpectedly, improvements in survival following first-line therapy were considerably more modest. Potential explanations include lack of data from recent years during which we expect continued increased utilization of oral therapies vs unique impact of repeated therapies in the elderly. Overall, these data support the need for ongoing development of first- and subsequent-line therapies in MCL.

Background: We previously reported that treatment with the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) in combination with the checkpoint inhibitors targeting CTLA-4 and/or PD-1 (ipilimumab (I) and nivolumab (N)) led to high overall response rates (ORR) and complete response (CR) rates in relapsed/refractory (R/R) Hodgkin's lymphoma patients in a Phase 1 ECOG-ACRIN sponsored clinical trial. As previously presented in the Phase 1 component of NCT01896999 (E4412), the ORR for the treatment arms were: BV+I 76%, BV+N 89%, and BV+I+N 82%, with CR rates of 57%, 61%, and 73% across the groups, respectively. This suggested that not all patients who responded derived equal benefit. Moreover, with a median follow-up of 2.24 years, the PFS of 1.1 year, NR, and 2.49 years across the groups suggest that even some patients who achieved CR progressed on or subsequent to treatment. Currently biomarkers have no ability to predict which patients will maximally benefit from these therapies. We investigated blood-based immune biomarkers mechanistically across all cohorts which may explain differential responses and guide future treatment decisions for R/R HL patients. Methods: Peripheral blood plasma for 54 of 61 (89%) patients evaluable for response was collected at up to 4 time points and tested for 92 immuno-oncology soluble analytes with Olink proximity extension assay and for antibody titers to 20 known tumor antigens by ELISA. Matching peripheral blood mononuclear cells (PBMC) were analyzed by CyTOF mass cytometry for major immune cell subsets and marker surface expression, and for T cell receptor diversity by Immunoseq®. Mixed effect linear models were used to identify significantly associated changes (P<0.05) related to treatment longitudinally within groups and to ORR between groups. Results: Analysis of plasma demonstrated durable increase in soluble plasma PD-1 and decreases in CCL17, ANGPT2, MMP12, IL13, and CXCL13 in N-containing regimens, and higher GZMA and CAIX in BV+I (P<0.05). Despite baseline heterogeneity in PBMC composition, we found durable increases in plasmacytoid dendritic cells (pDC) after N-containing treatments, and transient increases in plasmablasts and memory B cells, as well as early decreases in naïve CD4+ T cells and neutrophils across treatments. Treatment with BV+I+N demonstrated late increases in neutrophils, and changes in memory B cell markers. Clinical benefit analyses revealed that elevated soluble CD5, ADA, CXCL13, and CCL17 at baseline or after two treatment cycles were associated with worse ORR (P<0.05), and that a module of co-regulated soluble analytes at baseline, including MUC16, was associated with worse progression free survival (PFS) (P<0.05). NY-ESO-1 autoantibodies were more frequent in non-responders, and the top 10% of expanded TCR clonotypes were increased in responders after one treatment cycle (P<0.05). Conclusion: This data reveals differential immune activation based on treatment modality for patients with R/R HL receiving checkpoint-based regimens in combination with an ADC. Our data highlights potential tumor- and immune-derived predictive and pharmacodynamic biomarker candidates of response and resistance. These novel findings have relevance for R/R HL patients receiving immunotherapy and other immunotherapy combinations such as immuno-chemotherapy platforms. Prospective evaluation of these biomarkers in the Phase II component of this study, a randomized comparison of BV+N vs. BV+N+I which has completed adult accrual, is planned. Figure Legend Clinical responders and non-responder patient samples were analyzed using ELISA (auto antibodies), CyTOF (Cell populations), TCRseq (T cell clonality) and Olink (proteomics). The results showed that pDCs, Neutrophils and B-Plasmablasts increased with specific drug combinations independently of clinical response. While T Cell expansion was associated with clinical response, the increase of auto antibodies against NY-ESO-1 and circulating proteins CD5, ADA, MUC16, CXCL13, CXCL9 and CCL17 were associated with worse prognosis

Introduction: AutoHCT is an effective therapy for patients (pts) with DLBCL who are refractory or relapse following first-line chemotherapy, but long term outcomes remain suboptimal. The BTK inhibitor ibrutinib has shown promising activity in pts with ABC-DLBCL (Wilson et al, Nat Med 2015). In 2016 we launched a randomized phase III clinical trial to evaluate the addition of ibrutinib to AutoHCT as part of conditioning and as consolidation therapy for pts with relapsed/refractory ABC-DLBCL. Patients and Methods: Following assessment of open-label treatment in a safety cohort of 6 pts, we randomly assigned pts with chemotherapy-sensitive persistent or relapsed ABC-DLBCL to receive ibrutinib 560 mg [Arm A] or placebo [Arm B] concurrently with conditioning on days -6 to -1 of AutoHCT (Cycle 1). Following count recovery and resolution of acute toxicities, pts continued ibrutinib 560 mg in Arm A or placebo in Arm B for 12 additional 28-day cycles. Crossover to Arm A using single agent ibrutinib was allowed for pts progressing on Arm B. Central pathology review was performed for disease confirmation and subtype assignment. Initially, ABC subtype assignment was performed using the Nanostring Lymphoma Subtyping Test (LST) but the study was amended to use the IHC-based Hans classifier for non-GCB on 8/15/19. Other key eligibility criteria included receipt of no more than 3 prior regimens, no active CNS involvement, no need for long-term anticoagulation, and no prior progression on Ibrutinib. Pts were stratified by time to relapse (<=12 mos vs >12 mos), type of conditioning (BEAM or CBV) and prior ibrutinib use. The original design required 296 patients with 82% power to detect a difference in 2-year progression-free survival (PFS) rates of 67% vs. 50% with a two-sided alpha of 0.05. A revised statistical design allowed an interim futility analysis to be conducted after 40 pts were enrolled and followed for 2 years. Even though the study met criteria to continue accrual to a target of 160 pts, we decided to close it early due to declining accrual on 12/20/2022. We hereby present the primary analysis of the evaluable patients enrolled (data as of 07/17/2023). Results: Between 2/6/17 and 8/24/18, we screened 255 pts but enrolled only 34 (13%) largely due to long assay turnaround times and performance characteristics with the LST. Following the switch to the IHC-based Hans classifier (after 8/15/19), 60 out of 110 pts screened were enrolled (54%) in line with our a priori expectation. In total, 45 pts were randomized to Arm A vs. 43 to Arm B, with 39 and 38, respectively, being evaluable for the primary endpoint at this time. Median age was 61 years (range 20-75 years), median number of prior lines of therapy was 2, 46% of the pts were female, 21% were refractory or had early relapse, 94% were planned to receive BEAM conditioning. Overall, 87% of pts in Arm A and 88% in Arm B underwent conditioning while 70% and 67% respectively, started maintenance therapy. The median number of cycles received was 6 in Arm A vs. 5 in Arm B. The primary endpoint of 2-year PFS was 57.6% (95% CI: 42.1%, 78.8%) in Arm A vs. 40.8% (95% CI: 26.5, 62.8%) in Arm B (HR=0.54; 95% CI: 0.26, 1.10; log-rank p = 0.087). Median PFS was 26.5 months (95% CI: 10.2, not reached [NR]) in Arm A vs. 8.1 months (95% CI: 5.4, NR) in Arm B. Only one pt crossed over to Arm A after progression on Arm B. The most common grade 3-4 AEs in each of the arms were: neutropenia (A: 14%, B: 14%), febrile neutropenia (A: 11%, B: 9%), and thrombocytopenia (A: 11%, B: 7%). Rates of any grade atrial fibrillation were similar between arms (12.8% in Arm A vs. 10.5% in Arm B); one patient had grade 3 and one patient had grade 4 atrial fibrillation, both in Arm B. Six pts had reported grade 5 events (Arm A: 2 sepsis, 1 COVID-19, 1 respiratory failure and 1 disease progression and Arm B: 1 disease progression) but only one grade 5 event (sepsis, Arm A) was deemed probably related to treatment. Conclusions: Despite an early high rate of screen failures and declining accruals due to competition with CAR-T cell therapy, the primary analysis suggests that ibrutinib with and following AutoHCT in relapsed/refractory ABC-DLBCL is well-tolerated and may improve PFS in this high-risk patient population. This trial was supported by: U10CA180821, U10CA180882, U24CA196171; U10CA180820, UG1CA233234 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG) ClinicalTrials.gov Identifier: NCT02443077 https://acknowledgments.alliancefound.org