Introduction: Bispecific antibodies (BsAbs) epcoritamab (Epco) and glofitamab (Glofit) are approved in the US for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs) based upon high response rates and manageable toxicity profiles reported in pivotal trials. However, data on outcomes for pts treated with BsAbs outside of clinical trials are limited. As such, we sought to investigate the safety and efficacy of Epco and Glofit for the treatment of pts with r/r LBCLs in real-world settings. Methods: We performed a retrospective study including 19 US centers evaluating pts with r/r LBCLs receiving commercially available Epco or Glofit between 2023 and 2024. Baseline characteristics and outcomes were extracted from medical records. Efficacy outcomes included overall response rate (ORR), complete and partial response (CR, PR) rates, progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan Meier method. Key safety outcomes included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: As of May 31, 2024, a total of 209 pts with r/r LBCLs were treated with Epco (n=139) or Glofit (n=70). Median age at BsAb start was 67 years (interquartile range [IQR] 58-76). Most were male (62.2%), and the most common histology was diffuse large B-cell lymphoma (n=155 [74.2%]). Of pts with molecular testing (n=168), 34 (20.2%) had double/triple hit lymphoma. Most (78.9%) had Ann Arbor stage III-IV disease and 91% had an ECOG performance status of ≤1. Median number of lines of treatment before BsAb was 3 (range 1-12). Of pts with known response assessment following front-line therapy, 54 (32.1%) had primary refractory disease, defined as failure to achieve PR or CR to front-line therapy. Most pts (n=126 [60.3%]) received prior chimeric antigen receptor (CAR) T-cell therapy and 21 (10.0%) received prior autologous hematopoietic progenitor cell transplant. CD20 expression was assessed in 106 biopsies (50.7%) prior to BsAb and was positive in 90 (84.9%). A total of 172 pts were response-evaluable. The best ORR was 50.6%, with CR in 41 (23.8%), PR in 46 (26.7%), stable disease in 10 (5.8%), and progressive disease in 75 (43.6%). The ORR and CR rates were 49% and 23% for Epco, and 53% and 25% for Glofit, respectively. With a median follow-up of 5 months, the median PFS was 2.7 months (95% CI 2.0, 3.9) and median OS was 7.2 months (95% CI 6.1, not reached [NR]). The estimated PFS and OS at six months were 35% (95% CI 29%-43%) and 59% (95% CI 52%-67%), respectively. For pts who relapsed after CAR T-cell therapy, the median PFS and OS were 2.5 (95% CI 1.8, 4.7) and 7.8 (95% CI 6.2, NR) months, respectively. Pts without detectable CD20 expression via immunohistochemistry or flow cytometry prior to BsAb therapy had significantly inferior outcomes (PFS 1.1 vs 3.4 months, P < 0.001 and OS 1.3 vs 13 months, P < 0.001) compared to pts with detectable CD20. CRS of any grade occurred in 82 pts (39.2%), corresponding to 51.1% and 28.6% of pts treated with Epco and Glofit, respectively. Grade ≥3 CRS occurred in 9 (4.3%), all of whom received Epco. CRS was treated with tocilizumab in 43 pts (53.1%). ICANS occurred in 24 (11.5%) pts; any grade ICANS occurred in 13.7% and 7.1% of pts treated with Epco and Glofit, respectively. Grade ≥3 ICANS occurred in 6 pts (2.9%), 5 of which received Epco (3.6%). Of those experiencing ICANS, 66.0% were treated with corticosteroids. Two pts had deaths attributed to ICANS and one to CRS. A total of 122 (58.4%) pts discontinued therapy after a median of 3 cycles (range 0-48), 91 (74.6%) due to disease progression and 31 (25.4%) due to adverse events (15 due to infection, 3 due to ICANS, 2 due to CRS, and 11 for other reasons). Conclusions: In this heavily pretreated group with adverse disease features and high rate of CAR T exposure, the response rates, PFS, and OS following BsAb therapy were lower compared to pivotal trials. Poor outcomes were observed for those without detectable CD20. Rates of ICANS and grade ≥3 CRS were higher than reported in pivotal trials, as was the rate of discontinuation of therapy due to adverse events. Future efforts to improve outcomes may include intensified dose escalation protocols to more rapidly achieve disease control, combination therapies, and characterization of clinicopathologic factors that predict response to BsAb to identify subgroups of pts who can derive maximal benefit from these agents.

Follicular lymphoma is the most common indolent non- Hodgkin lymphoma (NHL) and accounts for approximately 20-30% of all NHL cases in Western countries. In general, systemic therapies are not considered to be curative. Despite this, prognosis is excellent with a 5-year relative survival rate of 90% and median overall survival rates ranging from 10-20 years across numerous studies. The exact incidence of central nervous system (CNS) involvement in cases of follicular lymphoma is unknown, however retrospective data suggest an incidence of 0.2% though this likely represents an underestimation of the true incidence. The optimum treatment approach for CNS disease in follicular lymphoma is poorly defined and no randomized studies exist which prove the superiority of one approach over another. Retrospective data suggest that resection, with or without adjuvant radiation, is an effective strategy for patients with local disease limited to the CNS. In cases where synchronous systemic disease is present, treatment regimens incorporating high-dose methotrexate and bendamustine or anthracycline-based chemotherapy have demonstrated efficacy. We report a case of a 59-year-old female with stage IV follicular lymphoma with synchronous systemic and leptomeningeal involvement who achieved complete remission following treatment with bendamustine, rituximab, and intra-thecal methotrexate. More long-term follow up data are needed to better characterize the prognosis for patients with CNS involvement who obtain complete remission following initial therapies. Treatment selection for patients with CNS involvement should take into account the presence or absence of systemic disease, patient comorbidities and performance status, and the likelihood of transformation to a high-grade process.

Introduction: Plasmablastic lymphoma (PBL) is a rare subtype of large B-cell lymphoma first described in 1997 in a small cohort of persons living with HIV (HIV-PBL). Since then, it has been observed post-transplant (PTLD-PBL) and even in otherwise immunocompetent patients (IC-PBL). With no current well-defined standard of care, prognosis of PBL has historically been poor (median overall survival (OS) 7-15 months), although recent studies suggest modest improvements in survival. We aimed to better characterize disease characteristics, treatment patterns, and factors associated with outcomes in a large contemporary US cohort. Methods: Patients (pts) ≥ 18 years old with PBL diagnosed between 1/2005 and 12/2022 from 20 academic centers in the United States were identified. Data on pt and disease characteristics and treatment were collected from medical records. OS, progression-free survival (PFS), lymphoma-specific survival (LSS), treatment-related mortality (TRM), and non-relapse mortality (NRM) were calculated using the Kaplan-Meier method. Cox regression and Fine-Gray competing risk regression were used to assess the association between clinical factors and survival outcomes. Results: 331 pts with PBL were identified. The median age at diagnosis was 53 years (range 20-91y). 78% were male (n = 257). 46% had HIV-PBL (n = 151), 35% had IC-PBL (n = 117), 6% had PTLD-PBL (n = 20), and 13% had PBL with other immunosuppressed states (n = 43). 66% of pts were White (n = 219), 18% were Black/African American (n = 58), and 31% were Hispanic (n = 104). 74% of Black/African American and 52% of Hispanic pts were diagnosed with HIV-PBL, compared with only 37% of White pts. The median age at diagnosis was greater in the IC-PBL group (68y) than in the HIV-PBL and PTLD-PBL groups (46y and 55y, respectively; p < 0.001). Most pts presented with Stage IV disease (61%, n = 220). Bone marrow (BM) involvement was present in 22% (n = 73). 92% of pts had extranodal sites involved at presentation (n = 302), most commonly the GI tract, BM, and oral cavity/jaw. Most tumors were CD138+, CD20-, MYC+, and EBV+ by either EBER or LMP1. EBV positivity was observed in 74% and 81% of PTLD-PBL and HIV-PBL cases, respectively, versus only 50% of IC-PBL cases (p < 0.001). Of the 298 pts who received chemotherapy, the most common first line regimen used was DA-EPOCH (70%), followed by CHOP/CHOP-like regimens (14%), hyper-CVAD (4%), and CODOX-M/IVAC (4%). As part of their initial treatment, 35% of pts received a proteasome inhibitor (n = 104), 20% received rituximab (n = 58), and 3% received daratumumab (n = 10). 35% received CNS prophylaxis with either IT MTX/AraC or HD MTX (n = 103), 19% received radiation in the first line setting (n = 56), and 8% underwent a consolidative autologous HCT in first remission (n = 24). Median FU for the entire cohort was 1.8y (range 0-17y). Median OS was 4.5y, with a median PFS of 1.4y. Median OS was 6.1y for HIV-PBL, 4.1y for IC-PBL, and 1.1y for PTLD-PBL. Factors associated with poor OS and PFS on multivariable analysis (MVA) included advanced age, stage III+, BM involvement, and EBV negativity. Female sex was associated with worse OS on MVA (HR 1.70, p = 0.027) and worse PFS on univariate analysis (HR = 1.53, p = 0.009). Use of CNS prophylaxis was associated with improved OS (HR 0.59, p = 0.031) and PFS on MVA (HR 0.68, p = 0.035). We found no significant difference in OS, PFS, and LSS for pts treated with DA-EPOCH versus pts treated with CHOP. On MVA, DA-EPOCH had a higher TRM compared to CHOP (p < 0.001). The addition of a proteasome inhibitor to 1L chemotherapy did not have a significant impact on OS, PFS, and LSS. While use of radiation and AHCT consolidation were associated with better PFS, OS was unaffected. Conclusion: In this largest US cohort of PBL patients to date, we observed improved outcomes compared to previous studies with 1- and 2y OS rates of 69% and 58%, respectively. Factors associated with worse prognosis were advanced age and stage, BM involvement, and EBV negativity, while HIV status was not associated with survival, consistent with other studies. Also, the absence of an OS benefit with DA-EPOCH and HCT with added toxicity is consistent with findings from other cohorts. We report several novel findings, including worse survival in female patients. More detailed analyses of the impact of immune status, CNS prophylaxis, and second line therapies on outcomes are pending.

Background: Simplified LymphPlex algorithm recently described molecular subclassification of DLBCL based on mutations of 35 genes and rearrangements of BCL2, BCL6, and MYC. Seven distinct genetic subtypes are included: TP53Mut, MCD-like (co-occurrence of MYD88L265P and CD79Mut), BN2-like (BCL6 fusions and NOTCH2Mut), N1-like (NOTCH1Mut), EZB-like with or without MYC rearrangement (EZH2, other chromatin modifier mutations and BCL2 fusions), and ST2-like (SGK1Mut and TET2Mut), with ~50% of patients (pts) assigned a molecular subtype (Shen et al, Nature 2023). Each group has potential therapeutic implications; for example, BTK inhibitors in MCD-like and N1-like subtype due to inherent NF-κB activation (Wilson et al, Cancer Cell 2021). EZH2 inhibitors in EZB-like subtype, etc. Additionally, MCD-like and TP53Mut cohorts were identified to have relatively worse outcomes compared to their counterparts. This suggests subclassifying via LymphPlex for DLBCL pts provides key information on outcomes and may be used to guide therapeutic intervention. Aim/Methods: Given the scarce application of this algorithm, our goal was to apply LymphPlex algorithm to the ORIEN Avatar cohort of 148 DLBCL pts with tumor whole exome sequencing (WES) and RNA sequencing or fluorescence in situ hybridization (FISH) data available to assign molecular subtype. We detected mutations from WES tumor samples using Haplotyper and curated known or predicted functional variants with a variant allele frequency (VAF) of ≥4% using Aster Insight's cBioPortal. Fusion calls were made from RNA-seq or clinical FISH testing records using cBioPortal. Variant and fusion data was input into LymphPlex v1 to generate DLBCL subclassifications. We described progression free survival (PFS) and overall survival (OS) stratified by molecular sub-classification. Results: Subclassification was successful in 136/148 DLBCL pts from years 1994-2022. For these pts, median age at diagnosis was 63.5 years. For 122 pts with staging information available, the majority were advanced stage (70%). We could calculate IPI score in 69% of pts, of those 11.7% had IPI score of 0-1 vs 88.3% had IPI score of ≥2. COO origin data was available in 29% of pts; of those 20% were ABC and 80% were GCB subtype. 48.5% of the pts received RCHOP and the rest received other intensive regimens (RCODOX/M/RIVAC, REPOCH, etc) as their first-line treatment. 109/136 DLBCL samples were collected before front-line treatment. LymphPlex yielded following subclassifications: 45(33%) TP53Mut, 17(13%) EZB-like [11 negative, 4 positive, 2 unknown for MYCr], 11(8%) MCD-like, 5 (4%) N1-like, 4(3%) ST2-like, 3 (2%) were BN2-like, and 51(38%) “Other”. Median follow-up for the cohort was 52.8 months (1 - 256 months). The PFS showed significant differences among genetic subtypes assigned by the LymphPlex algorithm in our cohort (p=0.03 including “Other”; p=0.052 for only classified groups). Median PFS was worst in the MCD-like and TP53Mut cohorts with 31.1 months (9.1-38.1) and 37.1 months (22.7-72.1), respectively, while median PFS was not reached for N1-like, ST2-like, BN-2 like, and EZB-like. “Other” pts had median PFS of 120 months [37-120]. PFS of the TP53Mut subtype was inferior to the TP53WT pts (p=0.04); PFS of the MCD-like subtype was inferior to all non-MCD-like subtypes (p=0.01). The OS did not show significant differences among genetic subtypes in this cohort (p=0.536). TP53Mut pts showed unfavorable outcome as compared to TP53WT pts with the median OS of 95 months [49-104 months; p=0.04]. In the “Other” unclassified group, we identified MSH6 (p=1.30E-03), RASGRF1 (p=3.71E-03), and IGF1R (p=9.53E-03) as the most significantly altered genes compared to all classified groups and upregulated expression of genes responsive to thyroglobulin triiodothyronine (T3; p=3.28E-07) and involved in glucose transport, including SLC2A1, NCOA1 and NCOA2. Conclusion: Overall, we found the LymphPlex algorithm easy to use in DLBCL pts with WES/RNA/FISH data. We were able to classify 62% of pts into one of the seven subcategories. In keeping with previous literature, TP53Mut and MCD-like had worst PFS compared to their counterparts and TP53Mut had worse OS compared to their counterparts. Our analysis highlights the need for further sub-classification strategies to guide improved therapeutic options for over one-third of DLBCL cases that do not fit currently established molecular subtypes.

A 69-year-old male presented with 4 weeks of left lower quadrant abdominal with associated shortness of breath and 15 pounds of weight loss. History is significant for psoriatic arthritis, coronary artery disease s/p coronary artery bypass graft and 6 cardiac stents, mitral regurgitation, and bicuspid aortic valve. He is a former smoker and family history is significant for renal cell carcinoma in his mother. His Eastern Cooperative Oncology Group (ECOG) performance status was 1. Laboratory blood workup showed creatinine 1.4 mg/dL (normal range: 0.7-1.3 mg/dL) and LDH 716 U/L (normal range: 125-250 U/L). The remaining laboratory values were unremarkable. CT abdomen and pelvis demonstrated a large heterogeneous mass in the left retroperitoneum involving the kidney, perinephric space, adrenal gland, psoas muscle, and invasion through Gerota's fascia anteriorly. Encasement and narrowing of the left renal vein and artery by the mass was also noted. CT chest showed bilateral solid and ground glass pulmonary nodules suspicious for metastatic disease (Fig. 1 A-D, Supplementary Figure 1).

This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated; treatments following CNS relapse were heterogeneous, with poor outcomes for the vast majority of patients. Reconsideration of SCNSL prophylaxis and treatment strategies is of critical need.

Diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma (FL) (tDLBCL) has been traditionally associated with an aggressive course, but more recent studies have shown longer survivals. The clinical significance of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) is less clear. We compared outcomes of tDLBCL, cDLBCL/FL, and de novo DLBCL (dDLBCL) and then evaluated the impact of double hit (DH) rearrangements (MYC with BCL2 and/or BCL6) in these subgroups' outcomes. The progression free survival (PFS) and overall survival (OS) were not significantly different among the three groups (dDLBCL, tDLBCL, and cDLBCL/FL). The effect of DH on survival was then analyzed in two subgroups: (1) dDLBCL and (2) tDLBCL + cDLBCL/FL. PFS and OS were significantly shorter in lymphomas with DH in each of these two subgroups. We conclude that DH status drives outcomes in all DLBCLs, regardless of their transformation status.

Background: Though CD19 is expressed only rarely on multiple myeloma (MM) plasma cells (PC), rare CD19+ B cells can be identified in MM patients that are clonally related to the MM PC. These clonotypic B cells may exhibit properties of cancer stem cells (enhanced MM-propagating properties and drug resistance compared to MM PC) and thus be a potential therapeutic target in conjunction with therapies that target MM PC. CTL019 consists of autologous T cells transduced via lentiviral vector with an anti-CD19 scFv coupled to CD3-zeta and 4-1BB signaling domains and expanded ex vivo with anti-CD3/CD28-conjugated beads. To target both clonotypic B cells and MM PC, we conducted a pilot clinical trial of CTL019 administered after high-dose melphalan and autologous stem cell transplantation (ASCT) in relapsed/refractory MM patients who had previously undergone first-line ASCT with short progression-free survival (PFS).