Ganesan, Nivetha

Abstract Use of brentuximab vedotin (BV) and PD-1 monoclonal antibodies (mAbs) before autologous stem cell transplantation (ASCT) could impact the benefit of post-ASCT BV maintenance in relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL). We identified 1091 patients with R/R cHL who underwent ASCT between 2010-2022. In total, 244 (22%) received a PD-1 mAb and 443 (41%) received BV before ASCT, while 305 (28%) received BV maintenance. We performed 1:1 propensity score matching to assess the efficacy of BV maintenance in different patient subgroups. Among 608 matched patients, the 3-year progression-free survival (PFS) and overall survival were 73% (95% confidence interval [CI], 70-78) and 95% (95%CI, 93-97), respectively. BV maintenance was associated with improved PFS for patients with no exposure to novel agents, especially those with 2+ modified AETHERA risk factors (0-1 factors: hazard ratio (HR), 0.51; 95%CI, 0.24-1.09; P =.083; 2+ factors: HR, 0.40; 95%CI, 0.25-0.65; P< .001). In contrast, BV maintenance was not associated with a significant PFS benefit for any patient subgroup who received novel agents before ASCT (BV-treated, 0-1: HR, 1.43; 95%CI, 0.53-3.81; P =.48; 2+: HR, 0.79; 95%CI, 0.34-1.82; P =.58; PD-1-treated, 0-1 [P>.99], 2+: HR, 0.25; 95%CI, 0.03-2.14; P =.21). In particular, we observed excellent outcomes for patients undergoing ASCT in a complete response after one line of PD-1-based salvage treatment with no significant benefit for BV maintenance observed (2-year PFS 100% vs 95%; P>.99). The benefit of BV maintenance appears to be attenuated for patients receiving novel agents with salvage therapy. Omission of BV maintenance should be considered for patients anticipated to have excellent outcomes.

Abstract Combination therapy incorporating programmed cell death protein 1 (PD-1) blockade results in unprecedented response rates in both frontline and relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). Previous retrospective studies have suggested benefit for PD-1 blockade before autologous stem cell transplant (ASCT) but included few patients receiving PD-1 blockade with cytotoxic chemotherapy. To explore the impact of anti–PD-1 based salvage on outcomes for patients with R/R cHL, we retrospectively reviewed 1280 patients with R/R cHL who underwent ASCT from 2010 to 2022 at 6 transplant centers, none of whom received PD-1 blockade as part of frontline therapy. Overall, 25% received a PD-1 inhibitor at any point before ASCT (10% in conjunction with chemotherapy), 28% received salvage brentuximab vedotin (BV) without PD-1 blockade, and the rest received salvage chemotherapy alone. Patients who received PD-1 inhibitors at any point before ASCT had a significantly higher 2-year progression-free survival than those who received BV without PD-1 inhibitors or patients receiving chemotherapy alone (88.2%, 70.2%, and 67.4%, respectively; P< .0001). When restricted to patients in complete response before ASCT, the benefit of PD-1 blockade remained significant. PD-1 blockade before ASCT is independently associated with superior post-ASCT outcomes and patients proceeding to ASCT should be treated with PD-1–based salvage.

Abstract Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse–enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.

Introduction There is no prospective data to guide the utilization of peri-transplant radiation (PTRT) in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). In retrospective analyses, PTRT has been associated with local disease control, however evidence supporting improved progression free survival (PFS) is less well defined (Milgrom SA et al Cancer. 2017; 123(8):1363-1371). Furthermore, the added benefit of PTRT in the era of recent advancement in salvage strategies, including brentuximab vedotin (BV) and checkpoint inhibitors (CPI), is unclear. In a multicenter, retrospective analysis, we evaluated the impact of PTRT on PFS for patients with R/R cHL. Methods We identified consecutive pts ≥7 years old at time of diagnosis with R/R cHL treated with autologous stem cell transplant (ASCT) at 5 US academic institutions between 2010-2021. PTRT was defined as radiation administered within 3 months of ASCT. The primary objective was to compare the post-ASCT PFS, defined as the time from ASCT to subsequent relapse or death from any cause, between the two groups. Univariable and Multivariable Cox regression was performed to evaluate the impact of various relevant clinical factors on post-ASCT PFS. Results A total of 958 eligible pts were identified ( Table 1). The median age at cHL diagnosis was 31 (range, 7-72). At the time of first relapse/primary refractory disease, 406 (54%) pts had early-stage disease, 167 (24%) pts had bulky disease (≥5.0 cm), 308 (36%) pts had extra-nodal disease, 182 (22%) pts had B-symptoms (B-sx), and 338 (45%) had primary refractory disease. A total of 302 (32%) pts received >1 line of salvage before ASCT. Salvage treatment at any time point before ASCT included chemotherapy only for 457 (48%) patients, BV(+/- chemotherapy) for 308 (32%) patients, and CPI (+/- BV or +/- chemotherapy) for 193 (20%) patients. In total, 239 (24.9%) pts received PTRT, 139 (58.1%) before ASCT and 100 (41.8%) after ASCT. Among pts with available dosing information (23.3%), the median radiation dose administered was 28 Gy. The most common doses administered were 30 Gy in 77 (31.7%) pts, 36 Gy in 62 (27.8%) pts, and 18 Gy in 43 (19.2%) pts. Radiated sites included mediastinum in 172 (80.7%) pts, neck/cervical lymph nodes in 68 (31.9%) pts, and supra/infra clavicular region and axilla, each in 31 (14.6%) pts. Compared to the 719 pts that did not receive PTRT, patients treated with PTRT were more likely to have early stage disease (73% vs 47%, p<0.001), bulky disease (30% vs 22%, p = 0.048), primary refractory disease (56% vs 40%, p <0.001), >1 line of salvage treatment prior to ASCT (40% vs 29%, p<0.001), and <CR prior to ASCT (36% vs 27%, p = 0.007) (Table 1). Patients treated with PTRT were less likely to have RT at initial diagnosis (5.9% vs 22%, p<0.001), extra-nodal disease (19% vs 42%, p<0.001), B-sx (17% vs 25%, p=0.035), salvage treatment that included CPI (11% vs 23%, p<0.001), and BV maintenance (20 vs 31%, p<0.001). After a median follow up from ASCT of 4.5 years (range, 2.4-7.2), 2-year PFS was 76% (73%, 79%) and 5-year PFS was 70% (67%, 73%). In univariable analysis, receipt of PTRT showed non-significant reduced hazard for PFS (HR 0.79, 95% CI 0.59-1.05, p = 0.093) (Figure 1). In a multivariable model, PTRT showed significant association with PFS (HR 0.56, 95% CI 0.36-0.88, p=0.009) when adjusting for other clinically relevant factors at relapse such as stage, B-sx, bulk, primary refractory disease, BV(+/- chemotherapy) or CPI (+/- BV or +/- chemotherapy) in salvage, PET response prior to ASCT, and BV maintenance after ASCT. To determine if specific subgroups benefited from PTRT, we tested for interaction effects between PTRT and clinically relevant factors. Only bulk (HR 0.37, 95% CI 0.16-0.85, p=0.013) and B-sx (HR 0.45, 95% CI 0.20-1.02, p=0.041) showed significant interaction with PTRT.Among pts with bulky disease, 5-year PFS was significantly improved with receipt of PTRT (81% vs 62%, p=0.013). Conclusion In this large multi-center analysis of pts with R/R cHL undergoing ASCT, there was no significant difference in PFS regardless of receipt of PTRT. However, after adjusting for known clinically relevant factors, receipt of PTRT was significantly associated with PFS and was particularly beneficial for patients with bulky disease or B-sx at relapse. We found decreased utilization of PTRT in pts receiving CPI-based salvage; therefore the role for PTRT for pts receiving CPI-based salvage is unclear.

Background: For patients with relapsed and refractory (R/R) classical Hodgkin lymphoma (HL), the standard of care remains salvage therapy followed by autologous stem cell transplant (ASCT) for responding patients. Historical data suggest 40% of patients may relapse after ASCT, and these patients have generally a poor median overall survival (OS) of less than 2 years (Moskowitz et al., Br J Haematol. 2009;146(2):158-62). However, since these reports, the treatment landscape of R/R HL has dramatically improved, most notably with the introduction of two novel therapies, brentuximab vedotin (BV) and anti-PD1 agents. To refine our understanding of clinical outcomes in this context, we characterized patients who relapsed after ASCT in the modern era. Methods: We used a multicenter retrospective patient database at 5 transplant centers in the United States to identify patients with HL aged ≥ 12 years at diagnosis who had received ASCT on or after 1/1/2010. The primary objective was to determine the median OS for patients who relapsed after ASCT (post-ASCT-relapse OS), defining survival as the time from relapse after ASCT to subsequent death from any cause. Univariable Cox regression was performed to evaluate the impact of various factors on post-ASCT OS. Outcomes by era were evaluated using three different eras based on approval dates of novel agents: (1) pre-BV approval (pre-7/31/2011), (2) post-BV approval (8/1/2011-4/30/2016), (3) post-anti-PD1 approval (5/1/16-present). Results: A total of 215 patients were identified. The median age at ASCT was 34. Before ASCT, 128 patients (62%) had no exposure to novel agents, 76 patients (35%) had received BV and no anti-PD-1 therapy, and 11 patients (5.1%) had received anti-PD-1 therapy with or without BV. Conditioning was mostly with BEAM (59%) or CBV (32%). The median time to relapse after ASCT was 6 months (range: 1-109 months). Nearly half all relapses (47%) occurred within 6 months of ASCT. Only 14% of relapses occurred after 1 year. Among 126 patients with available treatment information, the median number of post-ASCT lines of therapy was 2 (IQR: 1, 4). Therapy for post-ASCT relapse included BV and no anti-PD-1 therapy in 41 patients (29%), anti-PD-1 therapy with or without BV for 70 patients (50%), and no novel agents for only 15 patients (11%). The median followup time from the date of ASCT among survivors was 5.0 (IQR: 2.8, 7.8) years. The median post-ASCT-relapse OS was not reached ( Figure 1). The 2- and 5-year post-ASCT-relapse OS were 75% (95% CI: 70%-81%) and 59% (95% CI: 53%-67%), respectively. On univariable Cox regression for post-ASCT-relapse OS ( Table 1), time to relapse greater than 6 (HR 0.55, 95% CI 0.35-0.85) or 12 months (HR 0.53, 95% CI 0.29-0.96) were significantly associated with improved post-ASCT-relapse OS. Increasing age at relapse was associated with worse OS (HR 1.05, 95% CI 1.04-1.07). Receipt of a novel agent (compared to chemotherapy alone) as the first salvage regimen for post-ASCT relapse was associated with improved post-ASCT OS (BV: HR 0.43, 95% CI 0.20-0.96; anti-PD-1: HR 0.44, 95% CI 0.18-1.08). Outcomes improved over time as regulatory approvals for novel agents occurred (post-BV-approval: HR 0.70, 95% CI 0.39-1.24; post-anti-PD-1 approval: HR 0.45, 95% CI 0.23-0.91). Conclusion: We show prolonged overall survival post-ASCT relapse compared to historical data likely due to the introduction of BV and anti-PD1 agents. This report represents one of the largest datasets of post-ASCT relapse in cHL, and this data should serve as an updated benchmark for future evaluations.

Background: Maintenance therapy with brentuximab vedotin (BV) after autologous stem cell transplantation (ASCT) improved progression-free survival (PFS) among high-risk patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) in the phase III AETHERA trial. However, cHL treatment has changed significantly since that trial with frequent incorporation of BV and PD-1 inhibitors into earlier lines of therapy. The efficacy of BV maintenance may be different among pts who receive novel agents before ASCT. Methods: Pts with a diagnosis of R/R cHL who underwent ASCT between 2010 and 2022 were identified at 5 US transplant centers. Pts receiving no systemic post-ASCT maintenance or BV maintenance were included, while pts receiving investigational maintenance treatments were excluded. Medical records were reviewed to identify clinical variables. Results: 921 pts were identified. Median age was 32 yrs (IQR 24-44). 641 pts (70%) had primary refractory disease or relapsed within 12 months of frontline therapy, 326 (35%) had extranodal disease at relapse, and 173 (19%) had B symptoms at relapse. Pts received a median of 2 (1-9) lines of therapy before ASCT, including 295 (32%) who received ≥3 lines. 425 (46%) pts received BV before ASCT (including 24 pts as part of frontline treatment). 70 pts (8%) were BV-refractory (defined as failure to achieve an objective response to any BV-based treatment). 169 (18%) received a PD-1 agent with salvage treatment. 638 pts (69%) had a complete response on pre-ASCT positron emission tomography (PET). BEAM (71%) or CBV (21%) conditioning were used for most pts and 236 pts (26%) received peri-ASCT radiation. 224 pts (24%) received post-ASCT BV maintenance (including 37% of pts undergoing ASCT from 2015-2022). Compared to pts receiving no maintenance, pts receiving BV maintenance were more likely to have primary refractory/early relapsed disease (79% vs 67%, p<0.001), have received only 1 salvage regimen (79% vs 65%, p=0.001), and received BEAM conditioning (83% vs 67%, p<0.001). BV maintenance pts were less likely to receive peri-ASCT radiation (20% vs 28%, p=0.022). The median number of BV maintenance cycles was 10 (1-18) and the most common reason for discontinuation was neuropathy. Median post-ASCT follow-up was 4.9 yrs. 5-yr PFS and OS after ASCT were 70% (95% CI 67-74%) and 85% (83-88%), respectively. Because BV-refractory pts were much less likely to receive BV maintenance (p=0.0044) and had inferior PFS (HR 2.2, p<0.001) (and therefore would serve as a confounder), we excluded BV-refractory pts from additional analyses. Use of BV maintenance was associated with improved PFS (5-yr 81% vs 67%, HR 0.47 [0.33-0.69], p<0.001) and OS (5-yr 92% vs 83%, HR 0.38 [0.20-0.73], p=0.004). The benefit of BV maintenance depended upon pre-ASCT therapy. BV maintenance was associated with a significant improvement in PFS for pts who received no novel agents before ASCT (HR 0.41 [0.25-0.65], p<0.001), but not for BV-treated (HR 0.69 [0.38-1.25], p=0.22) or PD-1-treated pts (HR 0.63 [0.13-3.03], p=0.56) ( Figure). Among pts with 0-1 modified AETHERA risk factors, BV maintenance was not associated with a significant PFS benefit in any treatment subgroup (no novel agents, HR 0.50, p=0.087; BV-treated, HR 1.28, p=0.67; PD-1-treated, HR 2.97, p=0.44). For pts with 2+ modified AETHERA risk factors, BV maintenance significantly improved PFS in the no novel agent group (HR 0.35, p<0.001) but not in the BV-treated (HR 0.55, p=0.099) or PD-1 treated groups (HR 0.24, p=0.19). In multivariable analyses that included key variables (age, year of ASCT, conditioning regimen, peri-ASCT radiation, early relapse/primary refractory disease, B symptoms, extranodal sites, pre-ASCT PET, lines of therapy), BV maintenance was associated with a significant PFS benefit among pts who received no novel agents before ASCT (HR 0.27 [0.12-0.65], p<0.001), but not for pts treated with BV (HR 0.56 [0.28-1.10], p=0.091) or PD-1 blockade (HR 1.10 [0.22-5.56], p=0.91) before ASCT. Conclusions: In this large cohort, BV maintenance was associated with the clearest benefit among pts who received only chemotherapy before ASCT. We were unable to identify a significant improvement in PFS for pts receiving novel agents before ASCT (which could be due to insufficient power to detect a small benefit in this population), suggesting that if these pts benefit from BV maintenance, its impact is likely more limited.

Introduction: Single arm studies incorporating PD-1 blockade and/or brentuximab vedotin (BV) to salvage regimen have produced encouraging results in transplant-eligible relapsed/refractory classic Hodgkin lymphoma (R/R cHL) and are increasingly used in practice. As prospective randomized studies comparing PD1 based salvage to other salvage regimens are lacking, we conducted a retrospective study comparing post-transplant outcomes of R/R cHL patients who received PD1-based regimen and other novel and conventional regimen. Methods: Consecutive adult patients with R/R cHL who received salvage therapy and underwent autologous stem cell transplant (ASCT) between 2010 and 2021 at 5 United States academic institutions were included. Demographics and clinical variables were recorded at relapse by electronic health records review. Study Objectives were post-ASCT progression free survival (PFS) and overall survival (OS). Results: 981 pts of R/R cHL were identified. At relapse, median age was 31 (IQR: 21-43) years, 504 (52%) were male, 323 (49%) had advanced stage, 353 (41%) had extranodal disease (END), 185 (22%) had B symptoms, 345 (45%) were refractory to frontline therapy and 317 (32%) relapsed within a year of frontline therapy.308 (31%) received >1 line of salvage before ASCT. Patients were divided into 3 groups based on salvage therapy received: 1) 195 (20%) patients received a PD-1 agent with or without BV at any point before ASCT (PD-1 group), 2) 312 (32%) patients received BV at any point before ASCT without PD-1 (BV group), and 3) 474 (48%) patients received no novel agent before ASCT (chemo group). PFS was significantly higher in PD1 group (2-yr PFS 93.1 (CI 95: 89.4-96.9)%); compared to BV (2 yr PFS 73.9 (CI 95: 69.1-79.1)% , p <0.0001) or chemo groups (2 yr PFS 71.6 (CI 95: 67.6-75.9)% , p<0.0001). PFS was not different between the BV and chemo groups (p=0.88) (Figure 1). OS was not significantly different between PD-1 group (2 yr OS 96.2 % (CI 95: 93.2-99.2), p=0.06), BV group (2 yr OS 94.3% (CI 95: 91.7-97.0), p=0.2) and chemo group (2 yr OS 91.8% (CI 95: 89.3-94.4)). Amongst pts who were transplanted in complete metabolic response (CMR), we assessed post-ASCT PFS and OS based on salvage therapy received immediately before ASCT. Pts who received PD-1 as last salvage therapy had improved PFS compared to chemo (HR: 0.15 (CI 95: 0.07-0.3), p= <0.0001) and BV (HR: 0.2 (CI 95: 0.08-0.5), p= <0.001). Pts receiving PD-1 immediately before ASCT also had higher OS compared to those receiving chemo (HR: 0.2 (CI 95: 0.05-0.8), p= 0.02) but not BV (HR: 0.8 (CI 95: 0.4-1.3), p=0.1). There was no difference between BV and chemo group in regards to PFS and OS. In multivariable analysis that included time to relapse, B symptoms, END, pre-ASCT response, number of salvage therapy lines before ASCT, year of transplant and BV consolidation, PD-1 salvage therapy had significantly higher PFS compared to chemotherapy (HR: 0.3 (CI 95: 0.2-0.5), p= <0.001). BV group had significantly lower PFS (HR: 3.34 (CI 95: 1.8-6.0), group=0.002) compared to PD1 group. PFS was not different between BV and chemo group (p= 0.7). OS was similar between all 3 groups. Similar PFS and OS were seen among patients receiving PD-1 + BV (n=83) and PD-1 with or without chemo (n =112) (p=0.96 for PFS; p= 0.72 for OS); as well as for patients receiving PD-1 as part of their first salvage therapy (n=151) or later salvage treatments (n=44) (p=0.45 for PFS, p= 0.3 for OS). Patients who received PD1 based regimen as last salvage therapy pre-ASCT had significantly better PFS (HR: 6.8 (CI 95: 2.4-19.2), p= <0.0001) and OS (HR: 10.6 (CI 95: 2.5-44.8), p= 0.0001) compared to patients who received PD1 prior to their last line of salvage therapy per-ASCT. Conclusion: Receipt of PD-1 based salvage therapy at any point before ASCT is associated with significantly improved PFS compared to either BV or chemotherapy-based salvage treatments. In the subgroup of patients transplanted in CMR, PD1 based last salvage regimen were associated with higher PFS compared to chemotherapy and BV and higher OS compared to chemotherapy. PD1 based last salvage therapy pre-ASCT was associated with better survival compared to PD1 prior to last salvage therapy. Results of this study strongly support the use of PD-1 based salvage therapy for patients with R/R cHL. S.D., R.M., H.S contributed equally. R.S., M.M. contributed equally.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)—histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63 -rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

Abstract Recurrent chromosomal rearrangements are a hallmark of hematologic malignancies and play critical roles in pathogenesis. The TP53 analog TP63 is rearranged in 5-10% of diverse subtypes of both aggressive T- and B-cell lymphomas. Patients with TP63-rearranged lymphomas have dismal outcomes, with 5-year overall survival rates between 0-17%, depending on cohorts. The function and mechanisms of TP63 rearrangements and TP63 fusion proteins in tumorigenesis are poorly understood. As a result, attempts to treat these patients to date have been largely empiric. Thus, there is an urgent need to understand how TP63 fusions contribute to tumorigenesis and to translate the findings into novel therapeutic options for these patients. Here, we demonstrated that TP63 fusions are essential for the propagation of T-cell lymphomas (TCLs). Knockdown of TP63 fusions with specific shRNAs in TCL cell lines harboring TP63 fusions suppressed both cell growth in vitro and tumor growth in vivo. Retroviral expression of TBL1XR1-TP63, the most common TP63 fusion, conferred cytokine independence in Ba/F3 cells, consistent with its role as an oncogene. To investigate the role of TP63 fusions in T- and B-cell lymphomagenesis, we engineered a CAG-Loxp-Stop-Loxp-TBL1XR1-TP63 conditional knock-in mouse model and crossed with hCD2-Cre mice. This results in expression beginning during early lymphoid development. As observed in patients, transgenic mice developed multiple subtypes of both T- and B-cell lymphoma. To define the effects and mechanisms of TP63 fusions within T cells, we performed CRISPR scanning, transcriptomic, epigenomic, and proteomic analyses. Our data showed that domains within both the N-terminal TBL1XR1 and C-terminal TP63 portions contribute to the function of this fusion. We found that the N-terminal component of TP63 fusions interacts with components of the NCOR/SMRT complex. At the same time, the C-terminal portion of TP63 (which recapitulates the deltaN-p63 isoform expressed in some carcinomas) interacts with the enhancer modifier KMT2D and its complex members. TBL1XR1-TP63 binds to a novel distal enhancer to drive MYC expression, and thus upregulates the expression of the histone H3K27 methylase EZH2. Finally, we assessed whether EZH2 is a vulnerability of TP63-rearranged lymphomas. We found that knockdown of EZH2 in TP63-rearranged lines significantly impaired cell growth, as did treatment with the EZH2 and 1 dual inhibitor valemetostat. Valemetostat, which is now being tested in patients with lymphoma, counteracted the oncogenic effects of TP63 fusions in multiple preclinical models in vivo. Together, our results identify the TP63 fusion as a highly unique oncogenic driver in lymphomagenesis capable of recruiting multiple epigenetic modifier complexes and inducing a targetable dependence on EZH2. Citation Format: Gongwei Wu, Noriaki Yoshida, Jihe Liu, Xiaoyang Zhang, Yuan Xiong, Tayla Heavican-Foral, Huiyun Liu, Geoffrey Nelson, Lu Yang, Renee Chen, Katherine Donovan, Marcus Jones, Mikhail Roshal, Yanming Zhang, Ran Xu, Ajit Nirmal, Salvia Jain, Catharine Leahy, Kristen Jones, Kristen Stevenson, Natasha Galasso, Nivetha Ganesan, Tiffany Chang, Wen-Chao Wu, Abner Louissaint, Lydie Debaize, Hojong Yoon, Paola Dal Cin, Wing Chan Chan, Shannan Ho Sui Ho Sui, Samuel Ng, Andrew Feldman, Steven M. Horwitz, Mathew Meyerson, Karen Adelman, Eric Fischer, Chun-Wei Chen, David Weinstock, Myles Brown. TP63 fusions drive enhancer rewiring, lymphomagenesis, and dependence on EZH2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5755.