e19518 Background: Multiple Myeloma (MM) is a plasma cell disorder which evolves from neoplastic proliferation of clonal plasma cells. In 2014, International Myeloma Working Group (IMWG) introduced SLiM criteria (60% or more clonal plasma cells in marrow, Involved:Uninvolved Light Chain ratio >= 100 and >1 focal bone lesion (> 5 mm) on MRI) in addition to CRAB criteria (hyperCalcemia, Renal insufficiency, Anemia, Bone lesions) for diagnoses of active MM. Many studies have indicated disease burden as an independent prognostic risk. In this single institution study, we aim to evaluate the outcomes of MM patients diagnosed by SLiM vs CRAB criteria undergoing Autologous-Hematopoietic cell transplantation (Auto-HCT). Methods: This retrospective, single-center study included 103 patients with multiple myeloma (MM) who underwent autologous hematopoietic cell transplantation (Auto-HCT) between January 2019 and December 2024. Patients were divided into two cohorts: 91 patients (88%) in the CRAB cohort and 12 patients (11%) in the SLiM cohort, defined by the presence of SLiM features only. A log-rank test was used to determine overall survival (OS) and progression-free survival (PFS). Results: The median age was 62 years (range: 35–74), with 70 patients (68%) being male and 33 (32%) females. The racial distribution included 12 African Americans (13%), 2 Asians (2%), and 88 Caucasians (85%). R-ISS stage distribution differed between the CRAB and SLiM cohorts: stages III, II, and I were observed in 18% vs. 16%, 47% vs. 66%, and 22% vs. 6%, respectively. Median OS and PFS were not reached, and no statistically significant difference was observed between the two groups. Conclusions: SLiM criteria were proposed by the IMWG a decade ago to treat myeloma before end organ damage (CRAB features) are met. In our single center retrospective study, no differences were noted in either PFS or OS despite higher disease burden in the CRAB cohort. We suggest that Auto-HCT eligible patients diagnosed by either criteria should be treated similarly. A multi-institutional study with a larger sample size is warranted to validate our findings.

ABSTRACT:Epcoritamab and glofitamab are CD20-directed bispecific antibodies (BsAbs) approved in the United States for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between 1 January 2023 and 15 October 2024 were collected from 21 United States institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 2.0-3.8 months), and median overall survival (OS) was 7.8 months (95% CI, 6.2-11.0 months). The 6-month PFS was 36% (95% CI, 30-44) and the 6-month OS was 60% (95% CI, 54-67). Both trial ineligibility and undetectable CD20 pre-BsAbs portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after BsAbs with a median time to progression of 3.7 months. This analysis including patients with R/R DLBCL shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 were associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL, and underscore the importance of target antigen expression.

Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with multiply relapsed or refractory (r/r) large B-cell lymphoma (LBCL). Though response rates are relatively high, most patients (pts) eventually experience progression of disease (POD). We sought to investigate the treatment patterns and clinical outcomes following POD post-BsAb for r/r LBCL Pts, as this has not previously been described. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCL receiving commercially available epco or glofit between 2023 and 2025. Baseline characteristics and outcomes were extracted from medical records. Efficacy and survival outcomes were assessed by site investigators and 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. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAb, of whom a total of 168 (53.8%) pts experienced POD [104 of 193 (53.8%) treated with prior epco and 64 of 119 (53.8%) treated with prior glofit]. Pts with POD had a median age at BsAb start of 67 years (interquartile range [IQR] 58-76), most were male (68.4%), and the most common histology was diffuse large B-cell lymphoma not otherwise specified (n=122 [71.8%]). Sixty-seven of 168 pts (39.9%) with POD after BsAb had experienced primary refractory disease defined as failure to achieve PR or CR to frontline therapy. A total of 102 (60.7%) pts with POD to BsAb had received chimeric antigen receptor (CAR) T-cell therapy prior to BsAbs, with 33.3% of these pts being refractory to CAR T and 30.4% progressing within 6 months of CAR T-cell infusion. The median time to progression following BsAb start was 48 days. Following POD, 70 pts received no further anti-lymphoma therapy. Among 98 pts receiving subsequent therapy, 85 initially received systemic therapy and 13 initially received local therapy with radiation (concurrently with systemic therapy in 8 pts). The most commonly-used next line of systemic therapies included: loncastuximab tesirine in 19 pts (ORR 16.7%, all PR); commercial CAR T in 11 pts (ORR 50% [CR 36.4%, PR 18.2%); tafasitamab with lenalidomide in 7 (no responses); and other chemotherapy in 46 pts (ORR 27.6% [CR 24.1%]). The median follow-up time from POD was 9.2 months among survivors (95% confidence interval [CI] 7.8-13.3). Among those who initiated subsequent-line therapy following BsAbs, the median progression-free survival (PFS2) was 1.9 months (95% CI 1.5-2.4) and median overall survival (OS) from initiation of subsequent-line therapy was 3.9 months (95% CI 2.4-5.5). The estimated 1-year OS following initiation of next therapy was 12%. Conclusions: We report the outcomes of largest cohort of pts with POD post-BsAbs in r/r LBCL. Progression events occurred early after initiation of single agent BsAbs, and almost half of pts who progressed did not receive subsequent therapy. For those who received standard subsequent-line therapy after POD, response rates and survival outcomes were poor. Pts with POD after BsAB should be strongly considered for clinical trials of novel therapeutics or combination therapies.

e18577 Background: Next-generation sequencing (NGS) has revolutionized the diagnosis and management of Myelodysplastic Neoplasms (MDS), but the prognostic value of the Molecular International Prognostic Scoring System (IPSS-M) for survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. This study investigates the predictive power of IPSS-M in determining survival outcomes following allo-HSCT for MDS patients. Methods: We conducted a retrospective review of MDS patients who underwent their first allo-HSCT at our institution between 2018 and 2023, with available karyotypes and NGS data at diagnosis. IPSS-M risk scores were calculated, and patient characteristics and distribution are shown in Table 1. Kaplan-Meier curves were used to analyze progression-free survival (PFS) and overall survival (OS). Results: A total of 52 patients met the inclusion criteria, with a median age of 63.7 years; 75% were male. HSCT was performed after a median of 6.7 months from MDS diagnosis. Most patients (82.7%) underwent reduced-intensity conditioning, and 82.7% of HSCTs were from matched unrelated donors. After a median follow-up of 11.3 months (range 0.3 to 81 months), 1-year OS by IPSS-M risk categories were 66.7% (low), 33.3% (moderate-low), 80% (moderate-high), 45.5% (high), and 38.1% (very high). Additionally, t-MDS patients (n=10), regardless of their IPSS-M risk category, showed consistently poor outcomes, with a 1-year PFS of 38.1%. Conclusions: While survival varied across IPSS-M risk groups in our study, a consistent correlation with risk category was not observed, contributing to the ongoing debate regarding IPSS-M's prognostic value in MDS patients undergoing allo-HSCT. However, our findings underscore the consistently poor outcomes in t-MDS patients, regardless of their IPSS-M risk classification. These results highlight the need for further investigation into the prognostic significance of IPSS-M in this specific patient population. Due to the limited sample size of this study, larger cohorts are required to confirm these findings and provide more definitive conclusions. Baseline characteristics of the study population (N= 52 patients). Clinical Characteristics N (%) Sex Male 39 (75%) Female 13 (25%) Median age in years (range) 63.7 (28.5-73.9) IPSS- M Very Low 0 Low 9 (17) Moderate Low 6 (12) Moderate High 5 (10) High 11 (21) Very High 21(40) Donor type Related donor 9 (17.3) Unrelated Donor 43 (82.7) Conditioning Regimen Reduced Intensity 43 (82.7) Myeloablative 9 (17.3)

e18573 Background: Myelodysplastic syndrome with increased blasts (MDS-IB) is a complex hematologic malignancy characterized by ineffective hematopoiesis and a high risk of transformation to acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potentially curative treatment option for these patients, but the optimal conditioning regimen remains a subject of ongoing debate. This retrospective study aims to compare the outcomes of patients with MDS-IB who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) using either MAC or RIC regimens between 2015 and 2023. Methods: We identified 53 patients with MDS-IB1 and MDS-IB2 who underwent allogeneic PBSCT. They received MAC (FBT or FB4) with fludarabine 50 mg/m2/day, day -6 to day -2, busulfan 3.2 mg/kg/day, day -5 to day -2, +/- TBI 200 cGy/day on day -1 and day 0. Or reduced intensity conditioning (FB2) with fludarabine 30 mg/m2/day day -6 to day -2, busulfan 3.2 mg/kg/day day -3 and day -2. The endpoints were progression-free survival (PFS) and overall survival (OS) at 2-years. Kaplan Meier method was used to study survival estimates, log-rank test was used to compare those estimates. Results: The median age at diagnosis was 63.8 years. Most patients had underlying MDS-IB2 (62%), and 79% of patients received their transplant from matched unrelated donors. Only 21% of patients received MAC with either FB4 or FBT, while the rest received RIC. The median follow-up was 9.7 months. 2-year PFS was 87.5% for the MAC group versus 48.9% for RIC group (p-value 0.099). The 2-year overall survival (OS) was 54.5% in the MAC group compared to 35.7% in the RIC (p-value = 0.737). Conclusions: Our institutional 2-year analysis showed a non-significant difference in PFS and OS between the conditioning regimens in MDS patients with increased blasts. This lack of statistical significance could be related to the small sample size and retrospective analysis. However, prospective review and multicenter analysis with a larger sample size may be warranted to validate the choice of conditioning regimen in this group of patients.

Introduction: CD20xCD3 bispecific antibodies (BsAb) have been approved for use in relapsed/refractory (RR) large B-Cell lymphomas (LBCLs) with manageable toxicities. The main adverse events of clinical interest are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The risk factors for CRS and ICANS are not well understood. Knowledge of variables that contribute to increased risk may help clinicians identify and tailor management for high-risk patients (pts) and increase the comfort level for providers using these therapies in community practices. Methods: We performed a multicenter retrospective study at 21 US centers evaluating pts with RR LBCLs receiving commercially available epcoritamab (epco) or glofitamab (glofit) between 2023 and 2025. We obtained baseline characteristics, safety and efficacy outcomes. Univariate analysis was performed to identify associations between CRS, ICANS, and clinical variables of interest. Results: As of May 31, 2025, a total of 312 pts with RR LBCLs were treated with BsAb, Epco n=193 (62%), Glofit n= 119 (38%); median age 68; 63% male; 70% ECOG PS 0-1. Most common histologic type was diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) (n=239, 84%) followed by high-grade B-cell lymphoma (HGBL) (n=46, 16%). 179 pts (57%) were previously treated with chimeric antigen receptor T-cell (CAR-T) therapy, with 47% receiving CAR-T <6 months (mo) prior to BsAb. Among pts with prior CAR-T, CRS with CAR-T therapy of any grade occurred in 63%, with 26% ≥ grade 2. ICANS of any grade (G) occurred in 25% of pts (9.4% ≥ G3). Overall and complete response (ORR and CR) rates to BsAb were 51% and 29%, respectively. With a median follow up of 5 mo, median progression-free and overall survival (PFS and OS) were 2.3 and 7.3 mo, respectively. With BsAb treatment, CRS of any grade occurred in 117 (39%) patients: 24% G1, 8.7% G2, 4% G3, 1% G4 and 1% G5. The max grade CRS occurred most frequently after the third dose of epco (35%) and the first dose of glofit (23%). CRS was managed with additional steroids in 24% of pts and tocilizumab in 22%. 13% of pts experienced ICANS: 5.8% G1, 3.4% G2, 2% G3, 1% G4 and 0.3% G5. Factors that increased the risk for any grade CRS included: bulky disease ≥ 7.5 cm at time of BsAb treatment (OR 2.04, 95% CI 1.17 – 3.55, p = 0.012), elevated LDH (OR 2.56, 95% CI 1.45– 4.76, p = 0.002) and treatment with epco compared to glofit (OR 1.69, 95% CI 1.04- 2.77, p = 0.036). As G ≥2 CRS generally requires inpatient monitoring and management, we next compared the risk factors between pts with no CRS or G1 CRS and G ≥2 CRS. Factors associated with increased risk for high grade CRS included: bone marrow involvement by lymphoma (OR 3.47, 95% CI 0.97 – 11.3, p = 0.043), platelet count ≤ 75 (OR 2.46, 95% CI 1.21 – 4.87, p = 0.011), ≥ 2 extra nodal sites (OR 2.04, 95% CI 1.07 – 3.97, p = 0.032) and ≥G2 CRS with prior CAR-T (OR 3.35, 95% CI 1.13 – 9.97, p = 0.027). Factors that increased the risk for ICANS included: bulky disease (OR 2.67, 95% CI 1.28 – 5.49, p = 0.008), elevated Cr ≥ 1.5x ULN (OR 3.79, 95% CI 1.25 – 10.4, p = 0.012), elevated AST/ALT ≥ 3x ULN (OR 4.65, 95% CI 0.92 – 19.9, p = 0.042), low albumin (OR 2.85, 95% CI 1.49 - 5.5, p = 0.002), and co-occurrence of CRS with BsAb (OR 9.1, 95% CI 3.85- 25, p < 0.001). No other clinical variables including older age, histologic subtype, ECOG PS, B symptoms, IPI score, cell of origin or histologic subtype, baseline labs such as ALC, CRP, fibrinogen or D-dimer were significantly associated with CRS or ICANS risk. There was no difference in ORR or CR rates in patients who experienced CRS or ICANS. Conclusions: Our analysis of pts treated with commercial BsAb for LBCL shows an increased risk for CRS and ICANs based on clinical variables that are routinely obtained at baseline including tumor bulk, sites of disease, laboratory parameters, and history of prior CRS with CAR-T therapy. Differences in baseline populations receiving epco and glofit treatments in this real-world analysis have been previously reported (Brooks et al, Blood 2025) and the comparative risk for CRS between these treatments remains unclear. Future plans including multivariable analysis may allow for development of a predictive model to identify pts at high risk of CRS and ICANS with BsAb treatment, potentially leading to prospective clinical trials evaluating prophylactic interventions for high-risk pts.

Rare B-cell malignancies pose a unique management challenge because of their rarity and aggressiveness. Given their low incidence, they require a high index of suspicion for diagnosis and necessitate specialized therapeutic approaches. Herein, we discuss 3 of those rare lymphomas: plasmablastic lymphoma, lymphomatoid granulomatosis, and intravascular lymphoma. Plasmablastic lymphoma is aggressive and often linked to immunosuppression, particularly in HIV- infected individuals. It is characterized by plasmablastic morphology lacking CD20 expression, extranodal disease, MYC rearrangement, and frequent Epstein-Barr virus infection. Recent advancements in treatment involve using novel agents like bortezomib, daratumumab, and B-cell maturation antigen–targeted therapy, which are improving outcomes; however, the prognosis for relapsed disease remains poor. Lymphomatoid granulomatosis is a rare, Epstein-Barr virus–driven B-cell disorder defined by angiocentric and angiodestructive infiltrates. It primarily affects the lungs but can also involve skin and the central nervous system, causing systemic symptoms. Treatment and prognosis vary by histologic grade; low-grade cases may be treated with immunomodulation, while high-grade cases generally require chemoimmunotherapy. Intravascular lymphoma involves malignant B cells proliferating in small blood vessels, leading to nonspecific clinical symptoms. Early diagnosis through tissue biopsy is crucial. The best remission chances come from rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy combined with central nervous system–directed treatment. New research is ongoing for relapsed cases.

Introduction:About 10-25 % of chronic lymphocytic leukemia (CLL) patients experience complications related to autoimmune activity. Although less common, non-hematological autoimmune manifestations have been observed. Myasthenia gravis (MG) is rarely found in association with CLL. Since 1967, only 27 publications have reported the association between CLL and MG, encompassing just 15 cases. Our case is particularly notable for the refractory nature of the patient's MG. Case presentation:A 56-year-old male with Rai Stage II CLL and myasthenia gravis presented to the emergency department with respiratory distress, dysphagia, and weakness. He was admitted for treatment with intravenous immune globulin, pyridostigmine, and intravenous solumedrol. Notably, the patient was diagnosed with CLL approximately three months prior and MG just one week before presentation. Despite aggressive treatment, the patient's myasthenia gravis symptoms persisted, prompting suspicion of CLL-related complications. Due to the patient's refractory myasthenia gravis, weekly rituximab 375 mg/m2 was initiated. He was given the first dose of rituximab during the hospital admission after which his dysphagia clinically improved.Outpatient management included obinutuzumab and Ventoclax for CLL control, resulting in gradual resolution of MG symptoms over a few months. Discussion:Patients with myasthenia gravis (MG) generally do not require routine leukemia screening unless factors such as lymphadenopathy, splenomegaly, or refractory MG warrant further evaluation. Conversely, symptoms like ptosis in chronic lymphocytic leukemia (CLL) should prompt MG assessment. Early CLL treatment, as seen in this case, can resolve neurological symptoms and achieve remission, highlighting the need for a timely diagnosis and intervention to enhance patient outcomes.

Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs). Their use is associated with relatively high response rates, with some patients experiencing prolonged remission. It is unclear whether continuous treatment beyond 12 months for pts in remission is beneficial, as continued immunosuppression may result in additional toxicity. We sought to report the outcomes of pts with prolonged remission and survival following BsAb administration. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCLs receiving commercially available epco or glofit between 2023 and 2025. Baseline characteristics and outcomes were extracted from medical records. Efficacy and survival outcomes were assessed by site investigators and included overall response rate (ORR), complete and partial response (CR, PR) rates. Pts who responded to BsAbs and had ≥365 days of follow-up from initiation of BsAb treatment were included in the analysis. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAbs (epco n=193, glofit n=119) with a median age of 66 years (interquartile range [IQR] 59-73) at BsAb start. Most were male (64.5%), had advanced stage disease (77.4%) and had ECOG performance status of ≤1 (93.3%) at BsAb start. Of 207 pts who had initiated treatment with BsAb ≥12 months prior to data cutoff, we identified 31 pts (15.0%) who had a response to BsAbs (19 epco, 12 glofit) and were alive without progression at 12-months post-BsAb initiation and included them in this landmark analysis. Of the cohort of 19 pts treated with epco, 6 discontinued due to reasons other than disease progression including CAR-T cell therapy (n=2), secondary malignancy (n=2), allogeneic transplant (n=1), or other reasons (n=1). Thirteen of 19 pts received ≥12 months of epco treatment, and, with a median follow-up of 16 months from the start of BsAb, 12 of 13 pts continued receiving epco beyond 12 months with one pt discontinuing after 12 months (observed for an additional 41 days prior to censoring). Of the cohort of 12 pts treated with glofit, 8 pts were observed after completing all planned therapy and 4 patients underwent allogeneic transplant. Among all 31 BsAb-treated patients alive and in remission at 12 months, at the time of data cutoff, 5 pts (12.9%) had progressed (2 previously treated with epco and 3 with glofit). Three of the 4 pts who underwent allogeneic transplant after prior glofit treatment experienced disease relapse. A total of 24 pts (77.4%) were alive at the time of last follow-up, with the causes of death being disease progression (n=1), secondary malignancy (n=1), infection (n=1), and unknown cause (n=4). Conclusions: In this large cohort of r/r LBCL pts treated with BsAbs monotherapy in the standard of care setting, a relatively small proportion of pts (15%) achieve the 12 month PFS landmark. In the absence of robust evidence for what constitutes best practice, different strategies are employed, including continuation of BsAb, observation as well as consolidation with allogeneic transplant or CAR T-cell therapy. Additional follow-up will be reported to help guide clinical decision making regarding the optimal management strategy for this high risk pt population.

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.

Context Fixed-duration glofitamab monotherapy induced high complete response (CR) rates with manageable safety in relapsed/refractory (R/R) large B-cell lymphoma (LBCL; NCT03075696). We present extended follow-up and subgroup analyses in patients with prior chimeric antigen receptor T-cell therapy (CAR-T) and by baseline total metabolic tumor volume (TMTV). Design Patients with LBCL and ≥2 prior therapies received obinutuzumab pretreatment (1000mg) on Day (D)1 of Cycle (C)1, then intravenous glofitamab step-up doses during C1 (D8: 2.5mg; D15: 10mg) and target dose (30mg) on D1 of C2–12. Primary endpoint: independent review committee (IRC)-assessed CR rate. Exploratory analyses of baseline TMTV association with progression-free survival (PFS) and cytokine release syndrome (CRS) events (ASTCT criteria) were investigated. All patients provided informed consent. Results As of September 4, 2023, 154/155 patients received ≥1 dose of study treatment. Baseline characteristics were previously presented (Dickinson et al. NEJM 2022). IRC-assessed overall response and CR rates were 52% and 40%, respectively; most CRs (34/62; 55%) were ongoing at data cut-off. Median duration of CR (DoCR) was 26.9 months (95% confidence interval [CI]: 19.8–not evaluable [NE]). In patients with CR at end of treatment, 18-month PFS and overall survival rates were 67% and 81%, respectively. In patients with prior CAR-T (n=52), CR rate (37%) was consistent with the overall population (40%); median DoCR was 22.0 months (95% CI: 6.7–NE). No new safety signals were observed. Median baseline TMTV (n=144) was 128.7mL (range: 0–3820). Grade ≥2 CRS occurred in 2.8%, 11.1%, 16.7%, and 38.9% of patients in the first– fourth TMTV quartiles, respectively (Chi-square=16.273; degrees of freedom=1; P<.0001). In patients with baseline TMTV above/equal to (n=72) versus below (n=72) the median, 24-month PFS rates (95% CI) were 11.8% (6.0–23.5) and 41.6% (31.1– 55.6), respectively (hazard ratio: 2.4; 95% CI: 1.6–3.6). Conclusions Glofitamab showed durable responses in patients with R/R LBCL, with no new safety signals; this was consistent in patients with prior CAR-T, demonstrating long-term outcomes and suggesting a curative potential with fixed-duration glofitamab in R/R LBCL. Higher baseline TMTV was associated with increased risk of Grade ≥2 CRS and may be prognostic for PFS.

Background: Glofitamab is a CD20xCD3 bispecific antibody with a 2:1 (CD20:CD3) format that engages and redirects T cells to eliminate B cells. In a pivotal Phase II study (NCT03075696), fixed-duration glofitamab monotherapy induced high complete response (CR) rates and had a manageable safety profile in patients with relapsed and/or refractory (R/R) large B-cell lymphoma (LBCL; Dickinson et al. N Engl J Med 2022). Here, we present an extended follow up, as well as subgroup analyses in patients with prior chimeric antigen receptor (CAR) T-cell therapy and by baseline total metabolic tumor volume (TMTV). Methods: Patients with LBCL and ≥2 prior therapies received obinutuzumab pretreatment (1000mg) on Day (D) 1 of Cycle (C) 1. Intravenous glofitamab was then given as step-up doses during C1 (2.5mg on D8; 10mg on D15), followed by the target dose (30mg) on D1 of C2-12 (21-day cycles; total of 8.3 months). The primary endpoint was independent review committee (IRC)-assessed CR rate using Lugano criteria (Cheson et al. J Clin Oncol 2014). Cytokine release syndrome (CRS) events were assessed using American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Exploratory analyses were performed to investigate the association between TMTV at baseline and progression-free survival (PFS) and CRS. As there is currently no consensus on the method for standardized uptake value (SUV) thresholding in non-Hodgkin's lymphoma, a variety of methods are used in clinical studies (Keijzer et al. Comput Struct Biotechnol J 2023). Here, we used IRC-assessed TMTV derived from baseline positron emission tomography images using a semi-automatic method with a threshold for TMTV of 2x the SUV mean of the liver. Results: As of May 1, 2023, 155 patients were enrolled; 154 patients had received ≥1 dose of study treatment. Baseline characteristics were as previously presented (Dickinson et al. N Engl J Med 2022): median prior therapies received was 3 (range: 2-7); 33% of patients had received prior CAR T-cell therapy, and 85% were refractory to their most recent regimen. Median time on study was 25.8 months (range: 0-35). The IRC-assessed overall response and CR rates were 52% and 40%, respectively. The majority of CRs (40/62; 65%) were ongoing at data cut-off. Median duration of CR (DoCR) was 26.9 months (95% confidence interval [CI]: 18.4-not evaluable [NE]); an estimated 67% of patients with a CR at any time remained in remission at 18 months. PFS and overall survival rates at 12 months in patients with a CR at end of treatment (EOT) were 80% and 90%, respectively. In patients with prior CAR T-cell therapy (n=52), CR rates were consistent with the overall population (N=155; 37% vs 40%, respectively) and median DoCR was 22.0 months (95% CI: 6.7-NE). The safety profile of glofitamab was consistent with what has been described previously, with no new safety signals observed. Baseline TMTV was available for 144 patients and the median was 128.7mL (range: 0-3820; data cut-off: January 16, 2023). Higher TMTV was associated with an increased risk of experiencing a Grade ≥2 CRS event. The proportion of patients with Grade ≥2 CRS events in the first, second, third, and fourth TMTV quartiles was 2.8%, 11.1%, 16.7%, and 38.9%, respectively (Chi-square=16.273; degrees of freedom=1; p<0.0001). Patients with a baseline TMTV above or equal to the median (n=72) had a 12-month PFS rate of 16.8% (95% CI: 9.7-29.1), compared with 50.1% (95% CI: 39.5- 63.7) amongst patients with a baseline TMTV below the median (n=72; hazard ratio: 2.6, 95% CI: 1.7-3.9; Figure). Conclusions: Glofitamab continued to demonstrate durable responses in patients with R/R LBCL, with most patients with CR at EOT still in remission, and no new safety signals observed. These data indicate that there may be potential for favorable long-term outcomes with fixed-duration glofitamab for R/R LBCL. CR rates in patients with prior CAR T-cell therapy were durable and consistent with the overall population. Data from the subgroup analyses showed that higher baseline TMTV was associated with an increased risk of Grade ≥2 CRS and suggested that baseline TMTV may be prognostic for PFS. Updated analyses, with a follow-up of approximately 24 months post EOT, and further TMTV exploratory analyses will be presented.

IntroductionGraft versus host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplant (allo-HCT). High-dose corticosteroids are the first line treatment with response rates varying from 40- 60%, however is associated with significant side effects and comorbidities. Ruxolitinib is a JAK1/2 inhibitor approved for second line treatment of both acute and chronic GVHD. Our objective was to assess the outcomes of patients following initiation of ruxolitinib as second line treatment for aGVHD following allo–HCT.Methods and PatientsWe retrospectively analyzed 112 patients who underwent an allo-HCT at our institution between Jan 2019 - September 2023. We identified 69 patients who developed acute GVHD, 46 of whom required ruxolitinib as a second line treatment. Median age of patients in ruxolitinib group was 58 years (range 20-71); median age in non-ruxolitinib group was 61 (range 20-72). Our primary endpoints were to compare overall survival and rate of viral infection between these two groups.ResultsMedian overall survival was 16.6 months in patients treated with ruxolitinib in the second line. Viral infection was seen in 34 (74%) patients, with 14 (30%) patients developing CMV reactivation. Median overall survival in the non-ruxolitinib group was 18.8 months. Viral infection occurred in 12 (52%) patients with 5 (22%) CMV reactivation.DiscussionBased on our experience, treatment with ruxolitinib as a second line agent for aGVHD had similar outcomes when compared to patients with aGVHD not requiring ruxolitinib or any other second line agent. Slightly increased risk of viral infection and CMV reactivation seen in the ruxolitinib group is of concern and close monitoring for such infectious complications is warranted. Early intervention can help mitigate the potential complications resulting from these viral infections. A randomized prospective study to evaluate the role of CMV prophylaxis may be warranted in patients who require ruxolitinib as treatment for their aGVHD.

Chimeric antigen receptor (CAR) T-cell therapy has transformed treatment of refractory B-cell malignancies; however, treatment puts patients at risk for side effects secondary to the amplified immune response it induces. Fulminant cerebral edema (FCE) is one of the rarest, yet most devastating side effects following CAR T-cell therapy. Due to this rarity, FCE has not been well characterized and the risk factors associated with its development are not fully understood. Here, we present a case of a 42-year-old male who passed away from FCE following CAR T-cell infusion with the primary goal to better understand which patients are at higher risk of developing FCE before and after infusion.

Background: Glofitamab is a CD20xCD3 bispecific antibody that engages and redirects T cells to eliminate B cells. In this Phase II study (NCT03075696) of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), fixed-duration glofitamab monotherapy induced high complete response (CR) rates and durable responses with manageable toxicity (Dickinson, et al. N Engl J Med 2022). As a result, glofitamab monotherapy was approved by the FDA and EMA for use in patients with R/R LBCL after ≥2 prior lines of therapy. Here, we present updated data with an extended follow-up of over 3 years, a landmark analysis assessing outcomes of patients in CR, and exploratory biomarker analyses after end of treatment (EOT) evaluating the risk and benefit of fixed-duration treatment. Methods: Patients with LBCL and ≥2 prior therapies received obinutuzumab pretreatment (1000mg) on Day (D)1 of Cycle (C)1. Intravenous glofitamab was then given as step-up doses during C1 (2.5mg on D8; 10mg on D15), followed by the target dose (30mg) on D1 of C2-12 (21-day cycles). The primary endpoint was independent review committee (IRC)-assessed CR rate using Lugano criteria (Cheson, et al. J Clin Oncol 2014). Progression-free survival (PFS) and overall survival (OS) post-hoc analyses were performed in responders (landmark for CR at EOT). A modified AVENIO circulating tumor (ct)DNA analysis workflow (Roche; Research Use Only) was used for next-generation sequencing based on personalized cancer profiling; ctDNA was quantified as mutant molecules per milliliter of plasma (MMPM). CD19-positive B-cell count was measured centrally with the T, B, and natural killer cell (TBNK) assay. Results: As of May 17, 2024, 155 patients were enrolled; 154 patients had received ≥1 dose of study treatment. Baseline characteristics have been previously published (Dickinson, et al. N Engl J Med 2022). Median number of prior therapies was 3 (range: 2-7); 33% had received prior chimeric antigen receptor T-cells and 84% were refractory to their most recent regimen. Median time on study was 41.0 months (range: 0-52), with all patients with ongoing remission being treatment-free for ≥2 years following EOT. The IRC-assessed CR rate was 40% and overall response rate was 52%. After a median follow-up of 37.7 months (range: 0-51) in patients with a CR, median duration of CR was 29.8 months (95% CI: 22.0-not estimable [NE]). In patients with a CR at EOT, the PFS and OS rates 2 years after EOT were 57% and 77%, respectively. The incidence of adverse events (AEs) and serious AEs was stable compared with earlier analyses; two new Grade ≥3 AEs (neutropenia [Grade 3] and adenocarcinoma pancreas [Grade 4]) were reported. No new cytokine release syndrome events, infections, other cytopenia, or fatal AEs were reported since the previous analysis. Baseline ctDNA levels were previously shown to be prognostic in patients treated with glofitamab monotherapy. Patients with a CR at EOT and evaluable for ctDNA at baseline (27/45; 60%) showed a rapid and sustained decrease of ctDNA levels on treatment, maintained 12 months after EOT in patients with ongoing remission (baseline [n=27]: median MMPM 37.48 [range 3.13-23544.37]; C3 [n=27]: median MMPM 0.55 [range 0.00-471.18]; EOT [n=27]: median MMPM 0.29 [range 0.00-49.59]; 12 months follow-up [n=18]: median MMPM 0.04 [range 0.00-95.08]. B-cell depletion occurred in all patients during treatment; recovery of B cells and immunoglobulins was observed starting around 18 months after glofitamab treatment in patients with a sustained response after EOT. Conclusions: With this extended follow-up of over 3 years, durable responses continued to be observed with fixed-duration glofitamab in patients with R/R LBCL. The safety profile remains manageable and consistent with previous analyses. ctDNA kinetics showed that molecular response to glofitamab was rapid and sustained after EOT. Evidence of B cell and immunoglobulin recovery after EOT was observed in patients in remission. These data support the potential for long-lasting remissions and a beneficial effect on immune system recovery in patients with R/R LBCL treated with fixed-duration glofitamab.

Post-transplant lymphoproliferative disorders (PTLDs) are opportunistic malignancies that complicate the success of hematopoietic stem cell or solid organ transplantation. These disorders often arise post-transplant due to the immunosuppression required for minimizing the risk of rejection of donor tissue. First-line treatment of these disorders includes limiting immunosuppression when permissible. Subsequent treatment includes the use of monoclonal anti-CD20 antibody (rituximab), and/or combination chemotherapy. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm in many lymphoid malignancies. It is not approved for PTLD due to exclusion of PTLD patients from pivotal clinical trials. Also, its utilization post-transplant can be complex and multidisciplinary care is of utmost importance for successful administration of a potentially curative treatment. We present a 68-year-old patient with history of heart transplant for non-ischemic cardiomyopathy, diagnosed with PTLD that was refractory to treatment using current guidelines until successfully receiving CAR T-cell therapy.