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Abstract Background Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPN) characterized by myeloproliferation and an increased risk of thrombohemorrhagic complications, progression to myelofibrosis (MF), and reduced overall survival. Risk-adapted management of PV/ET favors treatment with cytoreductive therapy in high-risk patients. Hydroxyurea (HU) is the most frequently utilized first-line cytoreductive agent, however pegylated interferon alpha-2a (PEG) and the more recently approved, ropeginterferon alfa-2b (ropeg-IFN), have demonstrated a potential to induce molecular responses and improve event free survival (EFS) (Gisslinger Leukemia 2023). The Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 investigator-initiated clinical trials established the efficacy and safety of PEG in both treatment naïve (n=82) and HU intolerant/resistant (n=115) patients. MPN-RC 111/112 reported results up to 36 months with a median duration of treatment of about 24 months (Yacoub Blood 2019, Mascarenhas Blood 2022). This study aims to characterize the longer-term follow-up and outcomes of 111/112 trial patients treated at our center after the study terminated. Methods This is a single center retrospective review of 34 patients with high-risk ET or PV who were treated on the 111/112 trials with PEG and continued to be followed at Mount Sinai. IRB approval was obtained prior to data capture. Therapies initiated after PEG were examined, including duration of treatment, therapy-free intervals, and response to subsequent therapies. Clinical outcomes (during/after trial enrollment) included thrombotic/hemorrhagic events, progression to MF, leukemic transformation, hematopoietic stem cell transplantation (HSCT), and death. PEG related toxicity data included development of hypothyroidism, autoimmune disease, depression/mood disorder, liver dysfunction, and ocular toxicity. Results 34 patients were included in the analysis (16 ET and 18 PV) with median age of 73.5 years. 26 (14 PV and 12 ET) were enrolled on 111 from 2012 to 2015 and 8 (4 PV and 4 ET) were enrolled on 112 from 2011 to 2016. 26 (81.3%) patients had mutations in JAK2, 3 (9.4%) in CALR, 1 (3.1%) in MPL, and 2 (6.3%) were triple-negative. At 12 months on trial, 12 (35.3%) patients achieved a complete response, 12 (35.3%) had a partial response, and 10 (29.4%) had no response to PEG. The median duration of follow up was 104.8 months after trial termination. 8 patients received no further therapy after the end of study, 12 received one subsequent therapy, and 14 received two or more subsequent therapies. 13 patients continued receiving commercial PEG or received it at some interval after study end and 2 patients were treated with ropeg-IFN. The median duration of PEG was 25.3 months on trial and 30.9 months when including those who continued on commercial PEG after trial termination. Median EFS was 140.4 months (95% CI 121.1 - Not estimated) including 5 (15%) patients with a thrombotic event, 1 (3%) with a hemorrhagic event, 8 (24%) progression to MF, 1 (3%) HSCT, 1 (3%) leukemic transformation, and 5 (15%) who died (2 second primary malignancies, 1 sepsis, 1 hemorrhage, 1 unknown). 25 of 34 patients developed toxicities potentially related to PEG therapy, including hypothyroidism (n=3), autoimmune disease (n=4), depression/mood disorder (n=10), liver dysfunction (n=13) and ocular toxicity (n=2). DiscussionPEG therapy is an effective therapy for ET and PV with the potential for durable responses. With a median follow up of more than 8 years, this single center retrospective analysis demonstrated a long EFS of greater than 11 years, accompanied by low rates of leukemic transformation and MPN-related death. There was no statistical difference in EFS based on response to PEG at 12 months on the initial 111/112 trials. The relatively short duration of PEG therapy may explain the rates of MPN-related events, including thrombosis and progression to MF. Future analyses should identify additional predictors of EFS, including duration of PEG treatment, best response to PEG at certain landmark intervals, and depth and/or duration of molecular response. This analysis also demonstrated high rates of PEG-related toxicities, although definitive causality was often difficult to determine. Additional clinical and molecular data will be available at the time of the meeting.

Abstract Background: Mosunetuzumab (Mosun) is an off-the-shelf, CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate B cells, including those that cause malignant disease. Mosun is FDA- and EMA-approved for relapsed/refractory follicular lymphoma (FL) after ≥2 prior lines of therapy as a fixed-duration intravenous treatment, and can be given in an outpatient setting without mandatory hospitalization. Initial Phase I/II data with Mosun monotherapy have shown notable efficacy and manageable safety in patients with previously untreated diffuse large B-cell lymphoma (DLBCL; NCT03677154; Olszewski et al. ASH 2022). The Phase II MorningSun study is the first to assess the efficacy and safety of subcutaneous (SC) Mosun monotherapy in elderly/unfit patients with previously untreated DLBCL; we report an interim analysis for this study. Methods: MorningSun (NCT05207670) is an open-label, multicenter, Phase II, basket study evaluating the safety, efficacy, and pharmacokinetics of Mosun SC monotherapy in patients with B-cell non-Hodgkin lymphoma. In the DLBCL cohort, eligible patients aged ≥80 years or aged 65–79 and considered ineligible for chemoimmunotherapy (CIT) were enrolled, primarily in US community sites. Hospitalization was not mandatory. Step-up doses of Mosun SC were administered on Day (D) 1 (5mg), D8 (45mg) and D15 (45mg) of Cycle 1, followed by 45mg on D1 of 21-day cycles, for up to 17 cycles or until unacceptable toxicity. The primary endpoint in this cohort was progression-free survival (PFS) rate at 24 months after first study treatment. Secondary endpoints included objective response rate (ORR), complete response (CR) rate, time to response (TTR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), and safety. An exploratory circulating tumor DNA analysis was performed using an AOA-NHL assay. Results: Overall,49 patients were enrolled, the majority at community sites (community, n=34; academic, n=15). Thirty-six patients had DLBCL, 6 had high-grade [Gr] B-cell lymphoma, 2 had T-cell/histiocyte-rich large B-cell lymphoma, and 1 had Gr 3B FL (histology missing/other lymphoma, n=4). Median age was 82.5 years (range: 71–101); 63.3% and 20.4% of patients had an ECOG performance status of 1 and 2, respectively; 40.8% had Ann Arbor stage IV disease; 51.0% had extranodal involvement; 18.4% had bulky disease; and 53.1% had an IPI score of 3–5. At the clinical cut-off date of February 10, 2025, 23 (46.9%) patients had discontinued treatment, mainly due to progressive disease (n=12, 24.5%) or an adverse event (AE; n=5, 10.2%); the median duration of follow-up was 12.5 months (range: 1.4–30.8) and the median number of cycles received was 14 (range: 1–17). The PFS rate at 12 months was 68.8% (95% confidence interval [CI]: 52.1–80.6) and OS rate at 12 months was 77.2% (95% CI: 61.1–87.3). The ORR and CR rates were 73.5% and 59.2%, respectively. Median TTR was 2.7 (range: 2.5–6.1) months. DOR and DOCR rates at 12 months were 84.6% (95% CI: 66.8–93.3) and 95.0% (95% CI: 69.5–99.3), respectively. The most common AE (any grade) was injection site reaction (n=25, 51.0%), which was mostly Gr 1 (n=24, 49.0%). Gr 3/4 AEs occurred in 65.3% (n=32) of patients, most commonly infections (16.3% [n=8]) and decreased neutrophil count (10.2% [n=5]); serious AEs occurred in 42.9% (n=21) of patients. Four patients experienced Gr 5 AEs (congestive cardiac failure, volvulus, unexplained death and intracranial hemorrhage, n=1 each); none were related to Mosun per investigator assessment. Infections occurred in 46.9% (n=23) of patients (Gr 1/2, 30.6% [n=15]; Gr 3, 16.3% [n=8]); no Gr 4/5 infections were observed. No immune effector cell-associated neurotoxicity syndrome events occurred. Cytokine release syndrome was reported in 12.2% (n=6) of patients, with 10.2% (n=5) Gr 1 and 2.0% (n=1) Gr 2 events, all of which resolved. In evaluable patients with a CR (n=16), 68.8% (n=11) of patients were minimal residual disease negative (p-value cut-off 0.005).Conclusions: There remains an unmet need for effective chemotherapy-free options in previously untreated elderly and CIT-ineligible patients with DLBCL. Interim data from MorningSun demonstrate that fixed-duration Mosun SC monotherapy is active in these patients, with promising efficacy and a manageable safety profile, with predominantly mild-to-moderate AEs, allowing for outpatient administration in the community practice setting.

Abstract Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C>T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P<0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P<0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.

Abstract Introduction: BTK inhibitors are effective treatments for CLL/SLL; however, treatment intolerance and resistance to BTK inhibitors are major clinical challenges for many patients. BGB-16673 is an orally available protein degrader that blocks BTK signaling by tagging BTK for degradation through the cell's proteasome pathway, leading to tumor regression. CaDAnCe-101 (BGB-16673-101; NCT05006716) is an ongoing open-label, phase 1/2 study evaluating BGB-16673 monotherapy in patients with B-cell malignancies. Here, updated phase 1 safety and efficacy data are reported for patients with relapsed/refractory (R/R) CLL/SLL. Methods: Eligible patients must have confirmed R/R CLL/SLL (≥2 prior therapies), an ECOG performance status of 0-2 (0-1 in the EU), and adequate organ function. In the US, EU, and Australia, patients must have previously received a covalent BTK inhibitor (cBTKi). Patients received BGB-16673 once daily orally. The primary phase 1 objectives were to assess safety/tolerability (NCI-CTCAE v5.0; iwCLL hematologic toxicity criteria) and to establish the maximum tolerated dose and recommended dose for expansion. A secondary objective was to assess overall response rate (ORR) per iwCLL 2018 criteria with partial response with lymphocytosis (PR-L) modification and per 2014 Lugano criteria for SLL, with the first response assessment after 12 weeks of treatment. Results: As of May 23, 2025, 67 patients with CLL/SLL were enrolled and treated (50 mg, n=1; 100 mg, n=22; 200 mg, n=17; 350 mg, n=15; 500 mg, n=12). Patients had a median age of 70 years (range, 47-91 years) and a median of 4 prior lines of therapy (range, 2-10), including cBTKis (n=63 [94.0%]), BCL2is (n=55 [82.1%]), and noncovalent BTK inhibitors (ncBTKis; n=14 [20.9%]). At study baseline, 65.7% (44/67) of patients had CLL/SLL with del(17p) and/or TP53 mutation, 77.6% (38/49) with unmutated IGHV, 38.1% (24/63) with BTK mutation, and 15.9% (10/63) with PLCG2 mutation. Median study follow-up was 18.0 months (range, 0.3-31.0 months); 39 patients (58.2%) remained on treatment at the data cutoff. Overall, 95.5% of patients had any-grade treatment-emergent adverse events (TEAEs); any-grade TEAEs in ≥25% of patients were fatigue (37.3%), contusion/bruising (31.3%), diarrhea (28.4%), and neutropenia (28.4%). Grade ≥3 TEAEs occurred in 62.7% of patients; grade ≥3 TEAEs in ≥5% of patients were neutropenia (23.9%), pneumonia (10.4%), and thrombocytopenia (6.0%). Eight patients (11.9%) had a TEAE leading to dose reduction. TEAEs led to treatment discontinuation in 12 patients (17.9%), three (4.5%) of whom had treatment-related TEAEs (subdural hemorrhage, maculopapular rash, and disseminated aspergillosis). Four patients (6.0%) had TEAEs that led to death (all due to infections, including 1 fungal infection); no deaths were deemed related to treatment. In 66 response-evaluable patients (1 patient on treatment did not reach the first assessment by the data cutoff), ORR (PR-L or better) was 86.4% (n=57), with a 4.5% (n=3) complete response (CR)/CR with incomplete marrow recovery rate. At 200 mg, ORR was 93.8% (15/16), including 1 CR. The median time to first response was 2.8 months (range, 2.0-19.4 months). Thirty-three patients (49.3%) remained on treatment for ≥12 months. Responses deepened over time: of 22 patients with initial PR-L, 15 transitioned to partial response (PR); of 16 patients with initial stable disease, 1 transitioned to PR-L and 10 to PR. Responses were seen in patients previously treated with a cBTKi (53/62 [85.5%]) or ncBTKi (10/14 [71.4%]), with double (cBTKi and BCL2i; 39/42 [92.9%]) and triple exposure (cBTKi, BCL2i, and ncBTKi; 9/12 [75.0%]), with (18/24 [75.0%]) and without (36/39 [92.3%]) BTK mutations, with del(17p) and/or TP53 mutation (35/43 [81.4%]), and with PLCG2 mutation (9/10 [90.0%]). The 12-month progression-free survival rate was 79.2%; 15 patients (22.4%) had progressive disease (2 associated with Richter transformation to diffuse large B-cell lymphoma), and 4 (6.0%) died. Further exploratory analyses will be presented at the meeting.Conclusions: Data from the ongoing CaDAnCe-101 study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows robust and deepening responses in patients with heavily pretreated R/R CLL/SLL, including those with prior BTK inhibitor treatment and BTK mutations. The 200-mg dose of BGB-16673 is being evaluated in phase 2 and 3 studies in patients with R/R CLL/SLL.

Abstract Background Chimeric antigen receptor T-cell (CAR-T) and bispecific antibody (BsAb) therapies are both effective for patients with relapsed/refractory (R/R) follicular lymphoma (FL), but differ in treatment schedules and associated “time toxicity,” or contact days spent physically interacting with the healthcare system. While contact days can be estimated from clinical trials, real-world data provides a more nuanced depiction of treatment-related time burden, which may guide treatment decision-making. The comparative time toxicity of CAR-T vs BsAb in R/R FL is not defined. Methods We conducted a multicenter retrospective study of adults with R/R grade 1-3A FL who received standard-of-care CAR-T (axi-cel, tisa-cel, liso-cel) or BsAb (mosunetuzumab, epcoritamab) in the third-line or later setting before Jan 1, 2025. Time toxicity was defined as outpatient or inpatient days with physical health care system contact, counting multiple visits on the same day as only one day. All days after treatment initiation were counted, regardless of disease progression, therapy completion, or relation to FL therapy. Median contact days over 1-year time horizon were compared, stratified by CAR-T vs BsAb, prior lines of therapy (LOT, 2 vs 3+), and time intervals (0-1, 1-3, 3-6, 6-9, and 9-12 months). Progression-free survival (PFS) and overall survival (OS) were calculated from day of CAR-T infusion or day 1, cycle 1 for BsAb. Cox regression and propensity matching (by age, ECOG, refractory to prior LOT, POD24) were used to assess predictors and survival associations with contact days. Results Among 209 patients from 15 U.S. academic centers, median age was 64, 37% were female, 61% received CAR-T (80% axi-cel, 7% liso-cel, 13% tisa-cel) and 39% BsAb (93% mosun, 7% epcor). Most had Grade 1-2 FL (72%), advanced stage (84%), and extranodal disease (51%). Median prior LOT was 3 (range 2-15), 41% were refractory to prior LOT, and 52% had POD24. Median number of BsAb doses was 10 (range 1-36). Patients receiving BsAb were significantly older (p<.01) and had higher CIRS comorbidity scores (p<.02) in both 2 and 3+ prior LOT cohorts, and had higher ECOG scores (p=.01) and were less likely to be refractory to prior LOT (p=.029) in 3+ LOT cohort. There were no differences in POD24 rates between CAR-T and BsAb. Median PFS for the entire cohort was 3.6 yrs; median OS was not reached. In the 2 prior LOT cohort (N=75), 60% received CAR-T and 40% BsAb. With median follow-up of 1.5 years, median PFS was not reached for CAR-T and 1.6 yrs for BsAb (p<.0001). In the 3+ prior LOT cohort (N=134), 62% received CAR-T and 38% BsAb. With median follow-up of 2 yrs, median PFS was 3.6 yrs for CAR-T and 1.6 yrs for BsAb (p=.0044). In propensity matched analysis, PFS was shorter for BsAb in both 2 LOT (HR 9.0, 95% CI 1.14-71.04, p=.037) and 3+ LOT (HR 3.25, 95% CI 1.06-9.97, p=.039) cohorts as compared to CAR-T. There were no significant differences in OS between CAR-T and BsAb. Median contact days were significantly higher for CAR-T vs BsAb in the 0-1 month interval: 19 vs 8 days in 2 LOT (p<.0001) and 18 vs 7 days in 3+ LOT (p<.0001) cohorts. There were no differences in contact days between CAR-T vs BsAb in subsequent time intervals. Over 1 year, CAR-T had significantly more time toxicity than BsAb: median 51 vs 36 contact days in 2 LOT (p<.0001) and 64 vs 38 days in 3L+ LOT (p<.0001) cohorts; these remained significant in the matched analysis. B symptoms (p=.04) and Grade ≥3 cytopenias (p=.007) were associated with higher contact days in 3+ LOT cohort in univariable analysis. Higher contact days were associated with inferior PFS (HR 1.01, 95% CI 1.00-1.02, p=.032) and OS (HR 1.01, 95% CI 1.00-1.02, p=.038) in 3+ LOT cohort regardless of treatment type. Discussion In this large real-world cohort of patients with R/R FL, CAR-T therapy resulted in better PFS but more time toxicity over the first year as compared to BsAb therapy. Excess time toxicity from CAR-T was driven by more contact days in the first month of treatment. This study provides benchmark data for counseling patients about expected time burden of CAR-T (51-64 days) and BsAb (36-38 days) over the first year of these therapies. Further, with superior PFS of CAR-T in this study and minimal impact of time toxicity on survival outcomes, these data can be used to better support shared decision-making in R/R FL by addressing patient preferences regarding both contact days as well as duration of disease control.

Abstract Background: There remains an opportunity for new therapies to improve long-term outcomes for patients with low-tumor burden follicular lymphoma (FL). Mosunetuzumab is an off-the-shelf CD20xCD3 bispecific antibody, approved as an intravenous therapy for patients with relapsed/refractory FL after ≥2 lines of systemic therapy. Mosunetuzumab can be administered in the outpatient setting as a fixed-duration regimen. In an open-label, multicenter, Phase II study conducted mainly across US community sites (MorningSun; NCT05207670), mosunetuzumab administered subcutaneously (SC) induced high response rates with a manageable safety profile in patients with previously untreated low-tumor burden FL (Burke et al. ASH 2024). Here we present updated efficacy and safety data for mosunetuzumab SC in patients with previously untreated, low-tumor burden FL. Methods: Patients had untreated Grade 1 or 2 low-tumor burden FL per Groupe d'Etude des Lymphomes Folliculaires criteria, Ann Arbor stage III/IV disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2. Mosunetuzumab SC was administered with step-up dosing in Cycle 1 (Day [D]1, 5mg; D8, 45mg; D15, 45mg), then 45mg on D1 of each 21-day cycle. Hospitalization was not mandatory. Patients with a complete metabolic response after 8 cycles could complete therapy and patients with a partial metabolic response or stable disease continued treatment for up to 17 cycles. The primary endpoint was progression-free survival (PFS) at 24 months. Key secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), duration of response (DOR), duration of complete response (DOCR), and safety. Exploratory analyses assessed pharmacodynamic changes in B-cell subsets. Here, we report interim data. Results: As of February 10, 2025 (clinical cut-off date), 101 patients were enrolled from US community (n=56) and academic (n=45) centers; 52 patients had completed treatment, 21 had discontinued (mainly due to adverse events [AEs; n=6] and progressive disease [n=5]), and 28 were ongoing on treatment. Median age was 65 years (range: 34–82). Most patients had an ECOG PS of 0 (81.2%) or 1 (18.8%) and 43 patients (42.6%) had extranodal involvement. Median duration of follow-up was 13.8 months (95% confidence interval [CI]: 11.5–16.9) and median number of cycles received was 10 (range: 3–17). The ORR was 98.0% (95% CI: 93.0–99.8) and the complete response rate was 89.1% (95% CI: 81.3–94.4). Median TTR was 2.8 months (range: 1.4–8.3). Landmark DOR and DOCR rates at 12 months were 91.8% (95% CI: 81.5–96.5) and 95.7% (95% CI: 82.6–99.0), respectively. The 12-month PFS and OS rates were 92.0% (95% CI: 83.8‒96.1) and 99.0% (95% CI: 93.2‒99.9), respectively. The most common AE was injection-site reaction (ISR, 81.2%; Grade 1, 74.3%; Grade 2, 5.9%; Grade 3, 1.0%). Grade 3/4 AEs were reported in 51.5% of patients; the most common (≥10%) events were cytopenias (36.6%) and infections (11.9%). Cytokine release syndrome (CRS) was reported in 48.5% of patients (Grade 1, 40.6%; Grade 2, 7.9%). Overall,infections occurred in 63.4% of patients (Grade 1, 7.9%; Grade 2, 42.6%; Grade 3, 11.9%; Grade 5, 1.0%) with the most common (≥10%) being upper respiratory tract infection (21.8%), COVID-19 (17.8%), sinusitis (13.9%), and pneumonia (11.9%). At the time of data cut-off, ISR, CRS, and infection AEs were resolved at rates of 98.2%, 100%, and 89.0%, respectively. Two patients had a Grade 5 AE (sepsis, n=1; unknown cause, n=1).No immune effector cell-associated neurotoxicity syndrome events were reported. B-cell depletion was observed following the first dose of mosunetuzumab, with subsequent B-cell recovery observed within six months of treatment completion. Conclusions: Fixed-duration mosunetuzumab SC demonstrates high efficacy rates with deep and sustained responses in patients with previously untreated, low-tumor burden FL. The manageable safety profile supports ease of outpatient administration without mandatory hospitalization, including in community oncology practices. Additionally, exploratory analyses demonstrating B-cell recovery after treatment completion also substantiate the use of mosunetuzumab SC as a fixed-duration regimen. These data support further evaluation of mosunetuzumab SC in patients with previously untreated, low-tumor burden FL.

Abstract Introduction: Brexu-cel is a highly effective treatment for R/R B-ALL, with complete responses achieved in 71% of patients (pts) treated in the pivotal ZUMA-3 trial. Patients with B-ALL with high-risk (HR) genetics are known to have inferior outcomes with chemotherapy, but little is known about the influence of HR ALL genetics on responses to chimeric antigen receptor (CAR)-T in adults. In this study, we assessed the impact of HR ALL genetics on outcomes in a large cohort of adult patients treated with brexu-cel for R/R Philadelphia chromosome (Ph)-negative B-ALL. Methods: Patient characteristics and outcomes were obtained from the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) database which includes data from 40 U.S. centers. NCCN guidelines (NCCN Guidelines in Oncology, ALL v2.2025) were used to define HR B-ALL genetics; lack of HR genetics was defined as standard-risk (SR). The primary outcome was event-free survival (EFS), defined as lack of response, disease progression, or death from any cause. Secondary outcomes were overall survival (OS), relapse free survival (RFS) and response rates including complete response (CR), CR incomplete count recovery (CRi), measurable residual disease negative CR (MRD-) by flow or NGS and progressive disease (PD). Multivariable models were adjusted for age, pre-infusion blast percentage, prior allo-HCT, and post CAR-T allo-HCT (modeled as a time-varying covariate). Results: The cohort included 286 pts: 169 with HR and 117 with SR B-ALL. The HR cohort included TP53m (n=24, 14%), KMT2Ar (n=16, 9%), CRLF2r (n=65, 39%) and other HR genetics such as JAK2 and other Ph-like, IKZF1, complex cytogenetics (n=64, 38%). Relative to SR pts, HR pts were more commonly Hispanic (50% vs 28%). HR and SR pts had similar disease burden pre-apheresis (>5% blasts: 58% vs 53%), prior blinatumomab (60% vs 58%), prior inotuzumab (42% vs 46%), and prior allo HCT (27% vs 37%). The presence of CNS disease (11% HR vs 12% SR) and extramedullary disease (EMD, 22% HR vs 29% SR) at apheresis was also similar. CR/CRi was achieved in 90.5% of evaluable HR pts (n=147) and 90.2% of evaluable SR pts (n=102); MRD- rates were also similar between HR and SR pts at 78.9% and 78.2% respectively. In unadjusted analyses, EFS did not significantly differ between HR pts (median 9.6 mos; 1-yr: 46%, 95% CI 38%-54%) and SR pts (median 11.6 mos; 1-yr: 48%, 95% CI 38%- 58%). Median RFS (HR: 12.2 mos, SR: 13.3 mos) and median OS (HR: 22.4 mos, SR: 21.0 mos) were also similar. Multivariable models demonstrated no significant associations between HR B-ALL and EFS (HR 1.09, 95% CI 0.73-1.63), RFS (HR 1.13, 95% CI 0.71-1.80), or OS (HR 0.96, 95% CI 0.62- 1.48) relative to SR ALL. 28% of HR patients and 21% of SR patients underwent consolidative allo-HCT. Among the HR subgroup, CR/CRi rate was lowest in KMT2Ar (71%) relative to TP53m (95%), CRLF2r (95%), and other HR genetics (89%). The median EFS was lowest in KMT2Ar (4.1 mos), followed by TP53m (6.9 mos), CRLF2r (11.6 mos), and other HR (11.1 mos). Median OS was also lowest in KMT2Ar (6.8 mos) vs 22.4 mos in TP53m and not reached in CRLF2r or other HR. PD was highest in KMT2Ar pts (29%), as compared to 11% HR other, 10% SR, and 5% TP53 and CRLF2r. The rate of relapse among those that achieved CR across the groups was similar and ranged between 28% -40%. Rates of CD19 negative relapse were similar between all subgroups (13%-15%), however 21% of KMT2A pts underwent myeloid transformation as compared 0% for TP53 and CRLF2 pts, and 2% among other HR and SR pts. 25% of KMT2Ar patients underwent consolidative allo-HCT as compared to 32% CRLF2 pts, 29% TP53 pts, 25% other HR pts and 21% SR pts. Multivariable models evaluating the different genomic subgroups demonstrated that relative to SR B-ALL, only KMT2Ar was associated with inferior OS (HR 3.17, 95% CI 1.53-6.58, p=0020). No associations were seen between HR subgroups and EFS. Conclusion: To our knowledge, this analysis represents the largest examination of adult B-ALL recipients of CAR-T assessed by genomic risk group. We found that response rates and survival outcomes following brexu-cel were similar among HR and SR B-ALL pts, including pts with TP53m and CRLF2r. However, pts with KMT2Ar had lower response rates and dismal EFS and OS, with higher rates of PD and myeloid transformation at relapse, suggesting that alternative strategies are necessary to improve outcomes for patients with R/R KMT2Ar B-ALL.

Abstract Introduction The monoclonal gammopathies of renal significance (MGRS) are defined by the presence of a nephrotoxic monoclonal protein in the absence of a well-defined malignant entity. Mechanistically it has been postulated that, across the varied subtypes of MGRS, abnormal plasma cell or B-cell clones in the marrow produce nephrotoxic proteins; however, in many cases, no paraprotein is detected by conventional laboratory methods and the bone marrow can be morphologically normal. The genomic underpinnings of MGRS are unexplored and, due to the rarity of this disease, clinicians are often left to unable to determine the exact nature of the clonal cell populations. We carried out a pilot study to characterize ctDNA in MGRS patients (pts). The first phase of the protocol sought to collect peripheral blood samples and, when possible, matched bone marrow aspirates, from MGRS pts to evaluate the feasibility of ultra-low pass whole genome sequencing (ULP-WGS) from peripheral blood to identify and characterize ctDNA. Methods We report ULP-WGS results from peripheral blood samples in the initial phase of the study. Peripheral blood samples were collected from renal biopsy proven non-amyloidosis MGRS pts prior to the initiation of treatment. Cell free DNA (cfDNA) was extracted and quantified. A total of 5-20 ng of cfDNA input was used for ULP-WGS. Libraries were pooled and sequenced using 100-bp paired-end runs to an average genome-wide coverage of 0.5x. After deconvolution and alignment, fragments with size 90-150bp were extracted using samtools. IchorCNA was utilized to calculate tumor fraction based on a panel of normals derived from three plasma samples from healthy controls. Model parameters were optimized for low tumor fraction and a threshold of 3% ctDNA was used to identify positive samples. Renal responses were assessed based on International Kidney and Monoclonal Gammopathy (IKMG) group criteria. Results Nine pts and were consented and gave samples for the study along with 3 healthy controls. Seven pts were sequenced, 4 of which were females and 3 were males. Median age was 58 years. Among sequenced pts, 5 presented with proliferative glomerulonephritis with monoclonal immune deposition (PGNMID) and 2 with light chain deposition disease (LCDD). Both patients with LCDD were kappa predominant and showed detectable plasma clones (8% and 3%). One of these pts displayed t(11:14) on bone marrow FISH testing. Among the 5 pts with PGNMID, 3 had IgG kappa deposition and only one had a detectable plasma clone (5%), which harbored trisomy 9 by FISH. Bone marrow flow cytometry was positive in 2 pts. Median 24-hour urine protein content was 7.11g (0.92 – 10.58), median serum albumin 3.20 g/dL (2.90 – 4.90) and median serum creatinine at the time of diagnosis was 2.15 mg/dL (1.30-6.40). CKD was present in 6 of 7 pts at the time of diagnosis. Four pts had known hypertension. One exhibited a history of malignancy and one had a history of autoimmune disease. ctDNA was detectable at a threshold of > 3.0% of cfDNA in 5 of 7 pts. Median ctDNA content was 4.0% (3.18% - 14.97%) of cfDNA. Four of the 5 samples containing ctDNA were hyperdiploid. Chromosome 19 was the most common site of copy number increase whereas chromosomes 6, 10, and 18 exhibited the most frequent decreases in copy number. Two pts with PGNMID had detectable ctDNA without evidence of a serological or marrow-based clone. All pts received daratumumab, cyclophosphamide, bortezomib and dexamethasone as initial treatment. Five pts responded to therapy. Two patients ultimately underwent autologous stem cell transplant and a single patient received venetoclax as second line therapy. Of the patients exhibiting detectable ctDNA, three did not exhibit renal response to initial treatment. Both pts without ctDNA had PGNMID and responded to frontline treatment. Mass spectrometry analysis and deep targeted sequencing of bone marrow aspirates and peripheral blood will be presented. Conclusions To our knowledge, this is the first study to detect ctDNA in MGRS. ULP-WGS, when combined with targeted sequencing and diagnostic modalities such as mass spectrometry, has the potential to not only to aid in diagnosis and treatment selection on a practical basis, but also to begin to unravel the underlying genomics of this rare disease. This approach has potential to serve as a platform for further genomic exploration and biomarker development in MGRS.

Abstract Background: Patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) have a poor prognosis with median overall survival of ~3-12 months with current therapies, highlighting an urgent unmet need for novel therapeutics. PTCL is uniquely sensitive to epigenetic modifiers. We have shown that DNMT3 inhibitors like 5-azacytidine have potent immunomodulatory effects, including upregulation of cancer testis antigens, in pre-clinical models of T-cell lymphoma. Similarly, we have shown that pralatrexate (PTX) is potentially synergistic with drugs targeting epigenetic regulation. These data suggest a role for combining the immune checkpoint inhibitor pembrolizumab (pembro) with epigenetic agents in patients with PTCL. Methods: PTCL-002 is a multicenter, multi-arm phase Ib study designed to evaluate the safety and efficacy of pembro in combination with PTX and/or decitabine (DAC) in patients with R/R PTCL and CTCL. The study included three arms: arm A (pembro+PTX), arm B (pembro+PTX+DAC), and arm C (pembro+DAC). All patients received pembro 200 mg by IV infusion every 21 days. Dose selection for DAC and PTX in arms A and C, respectively, was based on a continual reassessment method (CRM) while arm B used a partial order CRM. Primary endpoints included MTD, RP2D, dose-limiting toxicities (DLT) and clinical efficacy as assessed by overall response rate (ORR). Secondary endpoints included progression-free survival, duration of response, and overall survival. Select pharmacokinetic and pharmacodynamic endpoints were also included in order to assess immune modulation and identify potential predictors of response. Results: We enrolled 26 patients, including 9 patients in arm A, 7 in arm B, and 10 in arm C. Median age was 61 (range 27-77) with 13 males and 13 females. Racial demographics were as follows: White 62%, Black 23%, Asian 3%, and Hispanic 1%. Median number of prior treatments was 3 (range 1-6). Histologic subtypes included ATLL (n=1), AITL (n=4), PTCL-NOS (n=10), SS (n=1), MF (n=6), PCALCL (n=1), MEITL (n=1), PCAECTL (n=1), and TFh-PTCL (n=1). Twenty-four of 26 patients received at least one dose of study drug and were evaluable for toxicity. Twenty-one of 26 of patients received at least one full cycle of therapy and were evaluable for response. Reasons for early discontinuation included consent withdrawal (n=1), rapid disease progression during cycle 1 (n=2), adverse event (n=1), and investigator decision (n=1). One DLT was observed each in arms A and B for prolonged grade 3 thrombocytopenia and febrile neutropenia, respectively. Three DLTs were observed in arm C including one patient with grade 3 hyponatremia and rash; one patient with grade 4 thrombocytopenia, neutropenia, and anemia; and one patient with grade 4 neutropenia. There were no treatment related deaths. Based on the observed DLTs, the RP2D for DAC in combination with pembro is 20 mg/m2on days 1-3; the RP2D for PTX in combination with pembro is 30 mg/m2on days 1, 8, and 15; for the triplet combination, the RP2D for DAC is 10 mg/m2given on days 1-5 and the RP2D for PTX is 20 mg/m2given on days 1, 8, and 15. Among 21 evaluable patients, responses were as follows: ORR 19% (4/21), CR 10% (2/21), PR 10% (2/21), and disease control rate (defined as proportion of patients with stable disease or better) 38% (8/21). ORR among evaluable patients in arms A, B, and C were 40% (2/5), 29% (2/7), and 0% (0/9), respectively. Analysis of serum cytokine levels in select patients (4 in Arm A, 4 in Arm B, and 5 in Arm C) revealed significant changes in 5 cytokines when compared to healthy age- and sex-matched controls. Of the 5 cytokines, 3 pro-inflammatory cytokines, TNFα, MIP-3α and IL-10, measured at day 1 pre-treatment were significantly higher in trial patients (p= 0.0001, 0.0008 and 0.003 respectively) than in healthy controls. Trial patients who responded to treatment (PR/CR) in any arms demonstrated a decline in serum levels of TNFα and IL-10 by day 15 of cycle 1, whereas non-responders (PD/SD) showed stable to increased levels of both TNFα and IL-10. Conclusion: We successfully identified the RP2D for DAC and/or PTX in combination with pembro in patients with R/R PTCL and CTCL. We demonstrated that an epigenetic platform incorporating the immune checkpoint inhibitor pembrolizumab is safe in heavily pretreated disease. More work on changes in cytokine profiles is needed before drawing any conclusions on their relationship to response.

Key Points Primary hyperoxaluria type 1 is a genetic disorder associated with hepatic oxalate overproduction, kidney failure, and systemic oxalosis. Lumasiran treatment for up to 60 months was associated with sustained reductions in urinary and plasma oxalate and encouraging clinical outcomes. Lumasiran's safety profile was acceptable with mild injection site reactions being the most common adverse events. Background Primary hyperoxaluria type 1 (PH1) is characterized by hepatic oxalate overproduction, kidney stones, and progressive kidney disease. Lumasiran is the first approved treatment for PH1. Methods ILLUMINATE-A (NCT03681184) was a 60-month pivotal, phase 3, multinational clinical trial of lumasiran which consisted of a 6-month double-blind, placebo-controlled period (6M DB), followed by a treatment extension period of up to 54 months in which all patients received lumasiran. Eligible patients were aged ≥6 years with genetically confirmed PH1, eGFR ≥30 ml/min per 1.73 m 2 , and mean 24-hour urinary oxalate (UOx) excretion ≥0.70 mmol/24 h per 1.73 m 2 . Results Of 39 patients enrolled, 24 of 26 randomized to lumasiran in the 6M DB (lumasiran/lumasiran group) and 13 of 13 randomized to placebo in the 6M DB (placebo/lumasiran group) completed the study. Sustained reductions in 24-hour UOx were observed in both treatment groups. At month 60 relative to study baseline, the mean (SEM) 24-hour UOx percentage reductions were 54 (6) and 54% (8%) in the lumasiran/lumasiran and placebo/lumasiran groups, respectively, and the mean (SEM) plasma oxalate concentrations had decreased by 35 (5) and 38% (7%). eGFR remained stable through the end of the study in both treatment groups. Kidney stone event rates during the study were 0.47 (95% confidence interval, 0.36 to 0.62) and 0.54 (0.37 to 0.78) per patient-year in the lumasiran/lumasiran group and placebo/lumasiran group, respectively. Medullary nephrocalcinosis grade improved at the end of the study in 21 of 28 (75%) patients with nephrocalcinosis at baseline and an end of study assessment. The safety profile of lumasiran was acceptable. Injection site reactions were the most common adverse events during lumasiran treatment. Most adverse events were mild or moderate in severity. Conclusions Lumasiran treatment for up to 60 months in ILLUMINATE-A was associated with sustained reductions in UOx excretion and plasma oxalate concentration, encouraging clinical outcomes including stable eGFR in a population that would be expected to show eGFR decline, reduced kidney stone event rates, improved medullary nephrocalcinosis, and indications of improved health-related quality of life. Clinical Trial registry name and registration number: ClinicalTrials.gov NCT03681184. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2026_03_18_CJASNMar.21.3.31820.mp3