Evens, Andrew M.

Introduction: Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) Prognosis is highly variable due to underlying biological and molecular heterogeneity. The first-line (1L) treatment paradigm for MCL continues to evolve with increasing use of bruton tyrosine kinase inhibitors (BTKi) and decreasing use of autologous stem cell transplant (ASCT). TP53 alterations are associated with inferior outcomes in MCL. The aim of this retrospective study is to determine treatment strategies and clinical outcomes in MCL patients based on TP53 gene mutation status. Methods: Retrospective data were collected from 19 institutions in the United States from 1/1993 to 1/2024. We examined treatment patterns and outcomes among MCL patients >18 years of age with known TP53 mutation status by sequencing. Patients who did not receive treatment were excluded. The analysis was stratified based on presence of TP53 mutations. Systemic therapies were categorized as chemo-immunotherapy (CIT), non-chemotherapy (including monoclonal antibodies, lenalidomide, venetoclax, and novel agents on clinical trial), and regimens containing BTKi. The primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS) and time to next treatment (TTNT). OS and PFS were estimated with the Kaplan-Meier method and log-rank tests were used to compare groups. Results: 645 patients were included in the study, with 468 men (72.6%) and median age was 64 years (range 30-89). 230/645 patients (35.7%) had a TP53 mutation, of which 182 (79%) were identified prior to 1L. While the male/female distribution was the same between the mutated and unmutated groups, median age at diagnosis and MIPI risk score was higher in the TP53 mutated group (age 65.9 vs 63.1 yrs, p= 0.015; MIPI 6.4 vs 6.1, p<0.001). TP53 unmutated patients had a median of 1 line of therapy vs. 2 for the mutated group (p<0.001, range 1-8). Blastoid histology and higher ki67 were also associated with the TP53 mutated group (p=0.045, 0.01 respectively) The median OS was 14.2 years for TP53 unmutated and 8.3 years for TP53 mutated patients (p<0.0001). PFS in 1L was 0.95 years in TP53 mutated compared to 2.02 years in TP53 unmutated group (p<0.0001). Selection of 1L therapeutic strategy was not associated with presence of TP53 mutation (Χ2 p= 0.21) although more patients in the TP53 unmutated group underwent ASCT (119/415 vs 38/230; Χ2 p=0.0006) TP53 mutation was associated with inferior survival compared to TP53 unmutated patients for CIT in 1L but the difference did not reach statistical significance when non-chemotherapy regimens and regimens containing BTKi were used. For CIT in 1L, 5 year OS was 78% [71-84%] for unmutated compared to 58% [48-67%] for the mutated group (p=0.0001 ). For non-chemotherapy regimens, 5 year OS for unmutated patients was 73% [52- 86%] compared to 52% [25-73%] for the mutated group (p=0.09). For regimens containing BTKi, 5 year OS for unmutated was 93% [81-97%] compared to 57% [28-78%] for mutated (p=0.07). Within the TP53 mutated group, there were no differences in any clinical outcomes between those receiving CIT, non-chemotherapy, or BTKi in 1L. While median OS appeared numerically longer in the BTKi group (14.4 yrs vs 8.8 yrs for CIT and 6.8 yrs for non-chemotherapy), the difference did not reach statistical significance (p=0.58). In contrast,TP53 unmutated patients who received CIT in 1L had better TTNT (p=0.0039) compared to those in non-chemotherapy and BTKi groups. There was no improvement in PFS (p=0.79) or OS (p=0.47). Conclusions To our knowledge this is the largest retrospective real world dataset of MCL treatment outcomes stratified by TP53 mutation. As in prior studies, TP53 mutation portends a worse prognosis in MCL compared to TP53 unmutated patients, but outcomes are better than historically reported. CIT in 1L was not associated with improved OS in either group. Irrespective of TP53 mutation status, incorporation of BTKi in first line was not associated with improved clinical outcomes. The gap in OS between TP53 mutated and unmutated MCL may be narrowing as treatment paradigms shift away from intensive induction chemotherapy and ASCT, and due to an increasing number of effective therapies for relapsed patients. Clinical trials of novel agents are needed to further improve the OS of TP53 mutated MCL patients.

Background: Although advanced stage cHL typically has excellent disease outcomes, 20-30% of patients (pts) experience treatment failure. In addition, decision-making is challenging given varying treatment options and incomplete prognostic data across the disease course. Pre-treatment factors, such as those incorporated into the Advanced Stage Hodgkin Lymphoma International Prognostication Index (A-HIPI), predict 5 year (y) overall survival (OS) and progression-free survival (PFS) (Rodday JCO 2023). Other than interim PET (iPET) results, it is unknown what factors influence cHL disease states mid-therapy. Using multistate modeling (MSM) and individual pt data from the HoLISTIC Consortium, we refined prognostication across the cHL disease course, specifically assessing the relationships between A-HIPI, iPET and end of treatment (EOT) response, and whether the A-HIPI and iPET provide independent prognostic information. Methods: We analyzed 1240 pts aged 18-65y with newly diagnosed Stage IIB, III or IV cHL treated on 2 advanced stage PET-adapted trials (RATHL, SWOG0816). All pts first received 2 cycles of ABVD; those with a negative iPET (Deauville score (DS) ≤3) received ABVD or AVD, and those with a positive iPET (DS >3) received BEACOPP. In contrast to other methods, MSMs incorporate multiple disease states into one model, account for censoring and competing risks, and estimate transitions between disease states using different covariates. Our MSM had 6 states: diagnosis, negative iPET, positive iPET, EOT non-progression (e.g., DS ≤ 3), treatment failure, and death. Treatment failure included progression or relapse. All pts start at the diagnosis state and can transition to other states without return to prior states. Transition states with <5 events were excluded. The MSM was estimated using a multivariable Cox model with censoring at 5y. Covariates were the 5y PFS A-HIPI (comprised of stage and continuous age, lymphocyte count and albumin), which was included for all transitions, and iPET, which was included for transitions from EOT non-progression and from treatment failure. Higher scores on the 5y PFS A-HIPI indicate lower risk of progression or death; the A-HIPI was modeled for a 1 standard deviation (SD) increase. We calculated probabilities of 5y treatment failure for 4 sample pts based on low (70) and high (85) A-HIPI scores, positive and negative iPET, and EOT non-progression. Results: Median age was 33y (Q1=25, Q3=45), 56% were male, 23% were stage IIB, 40% III and 37% IV, and mean A-HIPI was 77 (SD=7). Median follow-up was 75 months (Q1=53, Q3=92). At iPET, 80% (95% CI 78%, 83%) were negative and 16% (95% CI 14%, 18%) were positive. At EOT, 90% (95% CI 89%, 92%) were in the non-progression state. At 5y, 75% (95% CI 73%, 78%) were in the non-progression state, 16% (95% CI 14%, 19%) had experienced treatment failure, and 9% (7%, 11%) had died. Better A-HIPI scores (per SD) were associated with lower rates of transitioning from diagnosis to positive iPET (HR=0.80, p<0.01) and from positive iPET to treatment failure (HR=0.58, p=0.04). Better A-HIPI scores (per SD) were also associated with lower rates of transitioning from EOT non-progression to treatment failure (HR=0.78, p<0.01) and from treatment failure to death (HR=0.64, p<0.01), adjusting for iPET. Positive iPET was associated with an increased rate of transitioning from EOT non-progression to treatment failure (HR=1.90, p<0.01), adjusting for A-HIPI. The probability of 5y treatment failure for 4 sample pts was: 25% for low A-HIPI and positive iPET; 20% for high A-HIPI and positive iPET; 13% for low A-HIPI and negative iPET; and 12% for high A-HIPI and negative iPET. Conclusions: We created a novel MSM that refines prognostication across the cHL disease course by incorporating pre- and post-treatment factors (e.g., iPET) to estimate transitions to future disease states. Although the A-HIPI was developed using pre-treatment factors to predict 5y OS and PFS, we found that it was also associated with transitions to interim disease states, including iPET and EOT response. The A-HIPI and iPET each provided independent prognostic information, supporting the use of both in estimating cHL outcomes. Future analyses will develop clinical prediction models using MSMs that also incorporate varying frontline and salvage treatments and treatment-specific late effects, with the goal of providing individualized information across the disease course.

Introduction: Adults older than 60 years constitute 20-25% of newly diagnosed classic Hodgkin lymphoma (cHL) and have inferior outcomes compared to younger patients (pts). Salvage therapy followed by an autologous stem cell transplant (ASCT) is a potentially curative option for pts with relapsed/refractory (R/R cHL). There is limited data regarding outcomes of older adults with R/R cHL who undergo ASCT in the current era where novel agents are employed in the R/R setting, in comparison with younger patients. Methods: This multicenter, international, retrospective study of 18 participating institutions included adults with R/R cHL who underwent ASCT from January 1, 2010 through December 31 2020. Retrospective chart review was performed to collect data on patient and disease characteristics at relapse, including lines and type of salvage therapy, pre-ASCT response by PET, and use of brentuximab vedotin (BV) as consolidation post-ASCT. Study objectives were to assess progression-free survival (PFS), overall survival (OS), and the probability of non-relapse mortality (NRM) with relapse as a competing event. NRM was defined as death without preceding relapse. Results: Of the total 1172 adults with R/R cHL enrolled in the parent cohort, 96 (8.1%) were age 60 years or older at the time of ASCT. In this older cohort, the median age was 66 years (range: 60-72). 54 (56%) were age 60-64, 31 (32%) were of age 65-69 and 11 (11%) were of age 70-72. 59 (61%) were male, 63 (66%) had advanced stage disease, 17 (18%) had bulky disease, 37 (39%) had B symptoms and 38 (40%) had extranodal disease. All patients (pts) received ABVD or ABVD-like frontline therapy. The median time to relapse was 6 months (range: 0-174). 48 pts (50%) relapsed within a year after completion of frontline treatment and 25 (26%) had primary refractory disease. Salvage therapy prior to ASCT included platinum-based chemotherapy (65%), BV-based regimen (34%), and PD-1 inhibitor-based regimens (3%). 16 pts (16%) underwent ASCT after >1 line of salvage therapy and 75 (78%) underwent ASCT after achieving a complete metabolic response (CMR). 14 pts (14.6%) received BV consolidation. Median follow-up for entire population was 53.4 months (range: 0.3-199.0). In older adults, the 5-year PFS was 54.2% (CI95: 43.4-67.6) not statistically different compared to pts <60 years (67.7% (CI95: 64.3-71.3), p=0.2). However, 5-year OS was inferior in older adults: 71.9% (CI95: 43.4-67.6) vs. 82.6% (CI95: 43.4-67.6) in pts <60 years (p <0.0001)). In pts ≥60, 26 (27%) died including 12 (12.5%) without preceding relapse. Older adults had 3-month, 1-year and 5-year probability of NRM of 5.2% (CI95: 2.2-12.2), 7.5% (CI95: 3.6-15.3), and 10.9% (CI95: 5.8-20.8), respectively. NRM was significantly higher in older adults compared to pts <60 who had 3-month, 1-year and 5-year probability of NRM of 0.3% (CI95: 0.1-1.0), 0.9% (CI95: 0.5-1.7), and 2.5% (CI95: 1.6-3.9), respectively (p<0.0001). Older adults had 3-month, 1-year and 5-year probability of relapse of 1% (CI95: 0.2-7.3), 7.5% (CI95: 3.6-15.3), and 28.6% (CI95: 19.1-42.1), respectively, which did not differ significantly from younger pts (p=0.3) who had 3-month, 1-year and 5-year probability of relapse of 0.6% (CI95: 0.3-1.3), 5.1% (CI95: 3.8-6.6), and 29.9% (CI95: 26.6-33.5), respectively. Conclusions: Although older adults with cHL are more likely to relapse after frontline treatment, only a minority of pts (<10%) in this large multicenter cohort underwent ASCT at age ≥60. In select older adults who underwent ASCT, the risk of relapse was similar to younger pts, but NRM was significantly higher, especially in the early post-ASCT period. Detailed assessment of comorbidity scores, toxicities of salvage therapies, and prognostic factors will be presented at the conference.

Abstract Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal = 6, parenchymal = 4, and both = 1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR = 3.5) and testicular (in men) or female pelvic (in women) involvement (OR = 8.1). There was no significant difference in survival outcomes between patients with HGBL NOS with (median PFS = 4 years) or without (median PFS = 2.4 years) baseline CNS involvement (P = 0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% vs 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non–germinal center B-cell subtype, and “dual-expresser lymphoma” phenotype, however, high CNS IPI was not. The prognosis of relapsed HGBL NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and chimeric antigen receptor T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease.

7053 Background: In ECHELON-1 (NCT01712490), 6-year follow-up (FU) analyses demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) with A+AVD (brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), with a comparable safety profile. Here, we report data at 7-year median FU. Methods: Analyses of OS and PFS per investigator were conducted in the intent-to-treat (ITT) population (data cut-off March 11, 2023). Patients (pts) were randomized 1:1 to receive ≤6 cycles of A+AVD (n=664) or ABVD (n=670) on days 1 and 15, every 28 days. PET scan after cycle 2 (PET2) evaluation was mandatory. Long-term safety outcomes in the safety population included resolution or improvement of peripheral neuropathy (PN), second malignancies, and pregnancies. Results: At median FU of 89.3 months (95% CI 87.0–90.2), 7-year OS rates were 93.5% (95% CI 91.1–95.2) with A+AVD and 88.8% (95% CI 85.8–91.1) with ABVD; OS favored A+AVD over ABVD (HR 0.62; 95% CI 0.42–0.90; p=0.011). Subgroup analyses showed consistent OS benefit for A+AVD, including in the age <40 years and Stage IV disease subgroups (Table). 7-year PFS rates with A+AVD vs ABVD were 82.3% (95% CI 79.1–85.0) vs 74.5% (95% CI 70.8–77.7; HR 0.68 [95% CI 0.53–0.86]; p=0.001). PN improved/resolved in most pts at last FU (A+AVD: 86%; ABVD: 87%). Median (range) time to complete resolution of PN (A+AVD vs ABVD) was 16 (0–373) vs 10 (0–343) weeks; median (range) time to improvement was 42 (2–182) vs 19 (15–142) weeks. PN was ongoing in 28% (4% grade ≥3) of A+AVD and 20% (1% grade ≥3) of ABVD pts. Second malignancies were reported in 5% of A+AVD and 6% of ABVD pts. Pts and their partners reported 84/92 livebirths/pregnancies with A+AVD and 59/73 with ABVD; no stillbirths were recorded. Conclusions: At 7-year median FU, pts with stage III/IV cHL who received A+AVD showed a sustained PFS and OS benefit vs ABVD, with PFS rates indicating potential curability. The safety profile in pts treated with A+AVD showed no new safety signals at 7 years. Clinical trial information: NCT01712490 . [Table: see text]

PURPOSE Patients diagnosed with advanced-stage Hodgkin lymphoma (aHL) have historically been risk-stratified using the International Prognostic Score (IPS). This study investigated if a machine learning (ML) approach could outperform existing models when it comes to predicting overall survival (OS) and progression-free survival (PFS). PATIENTS AND METHODS This study used patient data from the Danish National Lymphoma Register for model development (development cohort). The ML model was developed using stacking, which combines several predictive survival models (Cox proportional hazard, flexible parametric model, IPS, principal component, penalized regression) into a single model, and was compared with two versions of IPS (IPS-3 and IPS-7) and the newly developed aHL international prognostic index (A-HIPI). Internal model validation was performed using nested cross-validation, and external validation was performed using patient data from the Swedish Lymphoma Register and Cancer Registry of Norway (validation cohort). RESULTS In total, 707 and 760 patients with aHL were included in the development and validation cohorts, respectively. Examining model performance for OS in the development cohort, the concordance index (C-index) for the ML model, IPS-7, IPS-3, and A-HIPI was found to be 0.789, 0.608, 0.650, and 0.768, respectively. The corresponding estimates in the validation cohort were 0.749, 0.700, 0.663, and 0.741. For PFS, the ML model achieved the highest C-index in both cohorts (0.665 in the development cohort and 0.691 in the validation cohort). The time-varying AUCs for both the ML model and the A-HIPI were consistently higher in both cohorts compared with the IPS models within the first 5 years after diagnosis. CONCLUSION The new prognostic model for aHL on the basis of ML techniques demonstrated a substantial improvement compared with the IPS models, but yielded a limited improvement in predictive performance compared with the A-HIPI.

Background: Prognostic modeling allows personalized risk prediction for individual patients (pt). The A-HIPI model in advanced stage classical Hodgkin lymphoma (AS-HL), developed and validated by the HoLISTIC Consortium (www.hodgkinconsortium.org), generates the individualized probability of a progression-free survival (PFS) event or death (OS) within the first 5 years (y) from diagnosis in pts based on continuous variables (www.qxmd.com/calculate/calculator_869/a-hipi). Clinical prognostic tools in lymphoma (eg, IPS, IPI, FLIPI, etc) typically use groupings of categorical values to define risk. Grouping a continuous value often results in loss of information, and most tools are not predictive for individual pts. However, discrete groupings have clinical utility & practicality for a) defining pt populations for clinical trials & real world studies, b) stratification within clinical trials, and c) crafting treatment guidelines. We studied potential approaches for utilizing the A-HIPI model to generate risk groups with input on strengths & limitations from the HoLISTIC modeling team & clinical experts. Methods: The A-HIPI model was developed via TRIPOD guidelines on 4,022 pts treated on 8 international clinical trials for AS-HL (Rodday. JCO 2023). External validation was performed on a dataset of 1,431 pts from 4 prospective registries. The 5y PFS (PFS5) in the A-HIPI development dataset was 77% (95% CI: 76-78); the 5y OS (OS5) was 92% (95% CI: 91-93). This represented the average outcome for a pt with AS-HL pt naïve to other clinical data at presentation. The distribution of PFS5 & OS5 predictions were heavily skewed (ie, asymmetric distribution) in both the A-HIPI discovery and validation dataset. While not unexpected due to the excellent PFS & OS in this disease setting, this presents challenges in the delineation of risk groups as depicted below . Three approaches were examined for the generation of A-HIPI risk groups. Proposed cutoffs were defined using the distribution of A-HIPI risk scores and data from the model-building cohort (ie, clinical trials). Validation was done using the A-HIPI validation cohort (ie, HL registries). Results: Approach 1: Risk groups based on clinical thresholds. Clinicians were queried what estimates of PFS5 would constitute high vs low risk. The positive, right-skewed distribution of A-HIPI risk scores limited this approach ( Figure), as cutoffs of PFS5 &lt;70 and PFS5&gt; 90 would only identify 15% and &lt;1% of the population, respectively. Approach 2: Risk groups based on deviation from “average” pt. The 5-y PFS was 77% (95% CI: 76-78). We explored defining “standard risk” based on this confidence interval as well as clinical boundaries, with pts above or below this classified as decreased or increased risk, respectively. Results of a +/-5% clinical boundary are presented in the Table. Approach 3: Risk groups based on “ranking” of pts. Here we ranked the A-HIPI risk scores of the 4022 AS-HL pts in the model building cohort and used the distribution of the risk scores as a benchmark. The risk profile for a future pt is then compared to this distribution (eg, how do you rank compared to your peers). Continuous results are often presented this way (eg, tertiles or quartiles). It also allows flexibility for the user to define the size of the risk groups and/or clinical threshold of interest. Application of this approach showed good alignment between the predicted model percentiles and the observed distribution of scores in the validation cohort ( Table). This is also reflected in calibration curves presented in the primary manuscript. An online application (eg, R-Shiny) will be provided at the meeting to allow users to define their own cutoffs to aid in pt prognostication as well as identify populations for clinical trial development. Conclusions: There are challenges with defining risk groups from individual risk prediction modeling in AS-HL. Different applications and purposes, the skewed distribution of events/risk estimates, as well as varying clinical definitions of high risk, make it challenging to define consensus expert-based risk groupings for AS-HL. A flexible “rank-based” approach appeared to provide the most clinical utility & data granularity, which may be leveraged for clinical trial design and pt stratification. Further analysis and discussion of how to optimally define high-risk and low-risk populations in AS-HL will be needed as new therapeutic options emerge.

Background: Chemotherapy in combination with radiotherapy (RT) is the standard for early-stage (ES) Hodgkin lymphoma (cHL). Despite high cure rates (12-year overall survival (OS) &gt;93%), there is room to improve short and long-term outcomes for children and adults with ES cHL. Incorporation of immunotherapy (IO) into front line treatment of ES cHL is an opportunity to both improve progression-free survival (PFS) and maintain OS, while minimizing long-term morbidity and mortality by reducing exposure to RT and high-dose chemotherapy. Study Design and Methods: HL leaders of the NCTN groups, expert HL researchers and physicians, and representatives from the Cancer Therapy Evaluation Program (CTEP) formed a working group in April 2020 with the goals of harmonizing treatment approaches for ES cHL across pediatric and adult patients and reaching consensus regarding the optimal study design for incorporating IO therapy into frontline treatment. Study champions identified from each of the North American cooperative groups [Children's Oncology Group (COG), SWOG, ECOG-ACRIN, Alliance, NRG] and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes (PROs) were included. The resulting COG-led clinical trial, AHOD2131, represents the largest ES cHL trial in the history of North American cooperative groups and the first to enroll patients across the age continuum. AHOD2131 (NCT05675410; Figure) is a randomized, phase 3 trial enrolling patients ages 5 to 60 years with newly diagnosed, previously untreated stage I and II cHL and will investigate the addition of the CD30-antibody drug conjugate brentuximab vedotin (Bv) with PD-1 blockade (nivolumab) compared to standard chemotherapy +/- RT. Since the April 2023 activation, 97 North American sites have activated the trial, and 21 participants have enrolled. Target enrollment is 1875 patients over 5 years of accrual, for an estimated 1782 eligible and evaluable patients. The primary objective is to compare the 3-year PFS of patients with ES cHL treated through a response-adapted, superiority design with either standard therapy or with an IO approach (BV + nivolumab). All patients will be stratified as favorable or unfavorable based on disease risk features at enrollment. Based on initial response assessment by PET/CT (via central review) after 2 cycles of ABVD, patients were classified to PET2 positive (SER, defined as 5 Point Score 4 or 5, ~15% of patients) and PET negative (RER). Those who are PET positive will receive involved site RT (ISRT). The SER and RER patients will be randomized to standard chemotherapy vs. IO therapy respectively. In addition to the primary outcome of PFS, there are 11 secondary and 10 exploratory aims. The secondary aims focus on OS, PFS of subgroups, and event-free survival at 12 years, physician-reported treatment-related adverse event (AE) rates, patient-reported AE using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the capture of representation by self-report and the use of electronic PRO data collections. The exploratory aims include the assessment of imaging central review as compared to local institutional review and the use of convolutional neural networks through artificial-intelligence machine learning. The study will examine the effect of therapy on acute and long-term adverse effects including health-related quality of life (HRQoL) and OS for up to 12 years. The study will compare patient self-report and provider AE reports and evaluate the associations of self-reported race/ethnicity and social determinants of health (SDOH)and post-progression/post-relapse OS. AHOD2131 strengthens the effort between the North American cooperative groups to conduct collaborative clinical trials and aims to harmonize an improved standard of care for ES cHL across the age continuum.

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&lt;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&lt;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&lt;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.